Clinical trial NCT04154293
Conditions: Congenital Ichthyosis
Sponsor: Timber Pharmaceuticals Inc.
Start date: 2019-12-03; Completion date: 2021-08-30
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the efficacy and safety of two concentrations of topically applied ointment formulation of isotretinoin called TMB-001 (0.05% and 0.1% isotretinoin) in subjects 9 years of age and older for the treatment of congenital ichthyosis (CI), including recessive X-linked ichthyosis (RXLI) and autosomal recessive congenital ichthyosis-lamellar ichthyosis (ARCI-LI) subtypes.

Funding Source FDA-OOPD

Detailed description:
This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and efficacy of two concentrations of topical TMB-001 for the treatment of CI in subjects with either the ARCI-LI or RXLI subtypes. The duration of treatment will be 12 weeks. Each subject will participate in the study for up to 24 weeks (including up to a 90-day Screening period). Eleven study centers from United States of America and Australia participated in this global study. Each subject participated in the study for up to 24 weeks (including up to a 90-day Screening period).

Eligible subjects were randomized (1:1:1) to one of 3 treatment groups:

1. TMB-001, 0.05%, twice daily (bid)
2. TMB-001, 0.1%, bid
3. Vehicle Ointment (Control), 0%, bid

Subjects were evaluated on a monthly basis for safety and efficacy results over the 12- week treatment period. Efficacy was determined in 2 ways:

1. VIIS (or Visual Index of Ichthyosis Severity) "treatment success" (VIIS-50) was defined as ≥ 50% reduction from Baseline for VIIS scaling score for the sum of the scores for 'VIIS body areas' that had a Baseline score ≥ 3). The proportion of subjects achieving VIIS-50 at Visit 6 at Week 12 relative to Baseline was the primary efficacy endpoint and time point used to compare the two active treatments to vehicle.
2. The proportion of subjects achieving IGA (Investigator Global Assessment) treatment success will be the key secondary endpoint. For this endpoint, the IGA score was established as "treatment success" or "treatment failure" where "treatment success" is defined as at least a 2-grade decrease in severity score (for example, severe or score of 4 at baseline to mild or score of 2 at Visit 6) relative to Baseline at Visit 6 at week 12.

The safety analyses conducted were extent of exposure, changes in physical examinations and vital signs, blood and urine testing including urine pregnancy testing as indicated, local skin reactions (including burning/stinging, redness, erosions, and swelling) and other adverse events.

Arms: arm 1: Topical, BID (Twice daily) arm 2: Topical, BID ( twice daily) arm 3: Topical, BID (Twice daily)
Interventions: intervention 1: Isotretinoin intervention 2: Vehicle
Intervention descriptions: intervention 1: Topical Isotretinoin ointment intervention 2: Topical Vehicle Ointment

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol 235-9051-202 - Amendment 1 
 
1 
 
TITLE PAGE 
Protocol Title: A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study to Evaluate the Safety 
and Efficacy of Two Concentrations of Topical TMB-001 for the Treatment of Congenital Ichthyosis 
 
Protocol Number: 235-9051-202 
Amendment Number: 1  
Product: TMB-001 (previously PAT-001) (Isotretinoin) Ointment (0.05% and 0.1%) 
 
Short Title: A Vehicle-Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for 
Treatment of Congenital Ichthyosis 
Study Phase: 2b 
 
Sponsor Name: Timber Pharmaceuticals, LLC 
Legal Registered Address: 50 Tice Boulevard, Suite A26, Woodcliff Lake, NJ 07677 
Investigational New Drug (IND) number: 122,058 
 
Date of Protocol: 05 Aug 2020  
 
 


CONFIDENTIAL 
Protocol 235-9051-202 - Amendment 1 
 
2 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
 
 
Aug 5, 2020 
 
 
Amir Tavakkol, PhD, Dip. Bact 
Chief Scientific Officer 
 
Date 
 
 
 
 
 
 
 
 
The Medical Monitor’s name and contact information can be found in Appendix 2. 
The Investigator’s Agreement Page is provided in Appendix 8.   
 
 
 


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Protocol 235-9051-202 - Amendment 1 
 
3 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................3 
TABLE OF TABLES ...............................................................................................................6 
1.0 
PROTOCOL SUMMARY ..........................................................................................7 
1.1 
Synopsis .............................................................................................................7 
1.2 
Schedule of Activities .....................................................................................13 
2.0 
INTRODUCTION......................................................................................................16 
2.1 
Study Rationale ..............................................................................................17 
2.2 
Background ....................................................................................................17 
2.3 
Benefit/Risk Assessment ................................................................................18 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................20 
4.0 
STUDY DESIGN ........................................................................................................22 
4.1 
Overall Design ................................................................................................22 
4.1.1 
Treatment Groups ..............................................................................22 
4.1.2 
Treatment/Assessment Areas ............................................................22 
4.2 
Scientific Rationale for Study Design ...........................................................23 
4.3 
Justification for Dose .....................................................................................24 
4.4 
End of Study Definition .................................................................................24 
5.0 
STUDY POPULATION ............................................................................................25 
5.1 
Inclusion Criteria ...........................................................................................25 
5.2 
Exclusion Criteria ..........................................................................................26 
5.3 
Lifestyle Considerations ................................................................................27 
5.3.1 
Meals and Dietary Restrictions .........................................................27 
5.3.2 
Activity ..............................................................................................27 
5.4 
Screen Failures ...............................................................................................27 
6.0 
STUDY TREATMENT .............................................................................................29 
6.1 
Study Treatment(s) Administered ................................................................29 
6.2 
Preparation/Handling/Storage/Accountability ...........................................30 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................30 
6.4 
Study Treatment Compliance .......................................................................31 
6.5 
Concomitant Therapy ....................................................................................31 
6.6 
Dose Regimen Modification ..........................................................................32 
6.7 
Treatment after the End of the Study ..........................................................33 


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Protocol 235-9051-202 - Amendment 1 
 
4 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................34 
7.1 
Pregnancy .......................................................................................................34 
7.2 
Inadvertent Enrollment .................................................................................34 
7.3 
Adverse Events ...............................................................................................34 
7.4 
Temporary Discontinuation (Drug Interruption/Holiday) ........................34 
7.5 
Subject Discontinuation/Withdrawal from the Study ................................35 
7.6 
Lost to Follow-Up ...........................................................................................35 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................36 
8.1 
Study Visits .....................................................................................................36 
8.1.1 
Visit 1 (Screening) .............................................................................36 
8.1.2 
Visit 2 (Baseline) ...............................................................................37 
8.1.3 
Visit 3, Visit 4, and Visit 5 ................................................................37 
8.1.4 
Visit 6 (End of Study) ........................................................................38 
8.2 
Efficacy Assessments .....................................................................................38 
8.2.1 
Visual Index for Ichthyosis Severity – Scaling .................................38 
8.2.2 
Investigator’s Global Assessment .....................................................39 
8.2.3 
Itch-Numeric Rating Scale ................................................................40 
8.2.4 
Percent Body Surface Area with Active Congenital 
Ichthyosis in the Treatment/Assessment Areas and Over the 
Entire Body ........................................................................................40 
8.2.5 
Dermatology Life Quality Index .......................................................40 
8.3 
Safety Assessments .........................................................................................41 
8.3.1 
Physical Examinations .......................................................................41 
8.3.2 
Vital Signs .........................................................................................41 
8.3.3 
Local Skin Reactions .........................................................................41 
8.3.4 
Electrocardiograms ............................................................................42 
8.3.5 
Clinical Safety Laboratory Assessments ...........................................42 
8.4 
Adverse Events ...............................................................................................42 
8.4.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information ............................................43 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ................................................................................................43 
8.4.3 
Follow-Up of Adverse Events and Serious Adverse Events .............43 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ................................................................................................44 
8.4.5 
Pregnancy ..........................................................................................44 
8.4.6 
Adverse Events of Special Interest ....................................................44 
8.4.7 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as Adverse Events or Serious Adverse Events .........44 
8.5 
Treatment of Overdose ..................................................................................45 
8.6 
Pharmacokinetics ...........................................................................................45 
8.7 
Pharmacodynamics ........................................................................................45 
8.8 
Genetics ...........................................................................................................45 
8.9 
Biomarkers .....................................................................................................46 


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Protocol 235-9051-202 - Amendment 1 
 
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8.10 
Medical Resource Utilization and Health Economics.................................46 
9.0 
STATISTICAL CONSIDERATIONS .....................................................................46 
9.1 
Statistical Hypotheses ....................................................................................46 
9.2 
Sample Size Determination ...........................................................................46 
9.3 
Populations for Analyses ...............................................................................46 
9.4 
Statistical Analyses.........................................................................................47 
9.4.1 
Efficacy Analyses ..............................................................................48 
9.4.2 
Safety Analyses .................................................................................49 
9.4.3 
Other Analyses ..................................................................................50 
9.4.4 
Missing Data ......................................................................................50 
9.4.5 
Extent of Exposure ............................................................................51 
9.4.6 
Dosing Compliance ...........................................................................51 
9.5 
Interim Analyses ............................................................................................51 
9.6 
Monitoring Committee ..................................................................................51 
10.0 
REFERENCES ...........................................................................................................52 
11.0 
APPENDICES ............................................................................................................54 
Appendix 1 
Abbreviations ...................................................................................55 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations ..........57 
Regulatory and Ethical Considerations ............................................................57 
Financial Disclosure.........................................................................................57 
Insurance ..........................................................................................................58 
Informed Consent Process ...............................................................................58 
Data Protection.................................................................................................58 
Administrative Structure ..................................................................................59 
Medical Monitor ..............................................................................................59 
Study Site Initiation .........................................................................................59 
Dissemination of Clinical Study Data..............................................................59 
Data Quality Assurance ...................................................................................59 
Source Documents ...........................................................................................60 
Study and Study Center Closure ......................................................................60 
Publication Policy ............................................................................................61 
Appendix 3 
Clinical Laboratory Tests ...............................................................62 
Appendix 4 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................64 
Appendix 5 
Excluded Medications/Therapy .....................................................68 
Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................................69 
Appendix 7 
Genetics ............................................................................................72 
Appendix 8 
Signature of Investigator ................................................................73 
Appendix 9 
Dermatology Life Quality Index ....................................................74 
Appendix 10 
Children’s Dermatology Life Quality Index .................................76 
Appendix 11 
Itch-Numeric Rating Scale ..............................................................77 
  


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TABLE OF TABLES 
Table 1 
Study Objectives and Endpoints ......................................................................20 
Table 2 
Study Treatments .............................................................................................29 
Table 3 
Investigator’s Global Assessment Score (5-Point Scale) .................................39 
Table 4 
Dermatology Life Quality Index Scale ............................................................40 
Table 5 
Children’s Dermatology Life Quality Index Scale ..........................................41 
Table 6 
Analysis Sets ....................................................................................................47 
Table 7 
Protocol-Required Safety Laboratory Assessments .........................................62 
Table 8 
Highly Effective Contraceptive Methods ........................................................70 
 


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Protocol 235-9051-202 - Amendment 1 
 
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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study to Evaluate the Safety 
and Efficacy of Two Concentrations of Topical TMB-001 for the Treatment of Congenital Ichthyosis 
Short Title: A Vehicle-Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for 
Treatment of Congenital Ichthyosis 
Rationale: 
Timber Pharmaceuticals, LLC, is developing a topical ointment (0.05% and 0.1%) formulation of 
isotretinoin called TMB-001 (previously PAT-001) (isotretinoin) ointment for the treatment of congenital 
ichthyosis (CI), including recessive X-linked ichthyosis (RXLI) and autosomal recessive congenital 
ichthyosis-lamellar ichthyosis (ARCI-LI) subtypes. The purpose of this study is to investigate the efficacy 
and safety of two concentrations of topically applied TMB-001 in subjects 9 years of age and older. 
Objectives and Endpoints  
Objectives 
Endpoints 
Efficacy 
Primary Efficacy 
• 
To investigate the efficacy of two concentrations 
of topically applied TMB-001 as a treatment for 
congenital ichthyosis (CI) of either the autosomal 
recessive congenital ichthyosis-lamellar ichthyosis 
(ARCI-LI) or RXLI subtypes. 
Proportion of subjects with Visual Index for 
Ichthyosis Severity - "treatment success" (VIIS-
50), which is defined as a 50% or greater decrease 
in VIIS scaling score relative to Baseline at Visit 6 
(EOS) calculated using the sum of the scores for 
‘VIIS body areas’ that have a Baseline score ≥ 3. 
 
Key Secondary Efficacy 
 
• 
IGA scores, dichotomized to “treatment success” 
or “treatment failure” where “treatment success” is 
defined as at least a 2-grade decrease in severity 
score relative to Baseline at Visit 6 (EOS). 
 
Other Secondary Efficacy 
 
• 
Time to achieve VIIS-50 (≥ 50% reduction in VIIS 
scaling score for body sites that had a Baseline 
score ≥ 3) that is maintained at the next 
observation. 
• 
Changes in VIIS scaling score relative to Baseline 
at Visit 4 and Visit 5. 
• 
Proportion of subjects with IGA “treatment 
success” at Visit 4, Visit 5, and Visit 6 (EOS).  
• 
Proportion of subjects with an IGA score of 0 or 1 
representing “cleared” or “almost cleared” at 
Visit 6 (EOS). 
• 
Changes in percent BSA relative to Baseline with 
CI in the Treatment/Assessment Areas at Visit 3, 
Visit 4, Visit 5, and Visit 6 (EOS). 
• 
Change from Baseline in Itch-Numeric Rating 
Scale (I-NRS) score at Visit 6 (EOS). 
• 
Proportion of subjects with I-NRS “treatment 
success” where “success” is defined as at least a 


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Protocol 235-9051-202 - Amendment 1 
 
8 
Objectives 
Endpoints 
4-point reduction in I-NRS relative to Baseline at 
Visit 6 (EOS). 
• 
Change in DLQI from Baseline to Visit 6 (EOS). 
Safety 
Safety 
• 
To investigate the safety of topically applied 
TMB-001. 
• 
Incidence (severity and causality) of any local and 
systemic AEs.  
• 
Number of subjects with presence (and severity) at 
each time point of the LSRs including 
burning/stinging, erythema, erosions, and edema. 
• 
Changes from Baseline in vital signs at Visit 6 
(EOS). 
• 
Changes from Baseline in clinical laboratory test 
results (chemistry, hematology, and urinalysis) at 
Visit 6 (EOS). 
Abbreviations: AE = adverse event; ARCI-LI = autosomal recessive congenital ichthyosis-lamellar ichthyosis; 
BSA = body surface area; CI = congenital ichthyosis; DLQI = Dermatology Life Quality Index; EOS = End of 
Study; IGA = Investigator’s Global Assessment; I-NRS = Itch-Numeric Rating Scale; LSR = local skin 
reaction; RXLI = recessive X-linked ichthyosis; VIIS = Visual Index for Ichthyosis Severity. 
Overall Design: 
This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and efficacy of 
two concentrations of topical TMB-001 for the treatment of CI in subjects with either the ARCI-LI or RXLI 
subtypes. The duration of treatment will be 12 weeks. Each subject will participate in the study for up to 
24 weeks (including up to a 90-day Screening period).  
Number of Investigators and Study Centers: 
Approximately 10 study centers from United States of America and Australia are expected to participate 
in this global study. 
Number of Subjects: 
Approximately 45 subjects will be enrolled (15 per treatment arm). 
Treatment Groups and Duration: 
Each subject will participate in the study for up to 24 weeks (including up to a 90-day Screening period). 
Eligible subjects will be randomized (1:1:1) to one of 3 treatment groups:  
1. TMB-001, 0.05%, twice daily (bid) 
2. TMB-001, 0.1%, bid  
3. Vehicle Ointment (Control), 0%, bid 
Temporary Discontinuation (Drug Interruption/Holiday)  
A treatment interruption scheme will be allowed if a subject experiences skin adverse events or local skin 
reactions (LSRs) during the study that may require interruption or termination of study medication. This is 
intended to assist subjects to continue in the study if the event is likely or expected to lead to discontinuation. 
Any subjects with a local AE (especially early during treatment) will be encouraged to continue with their 
study medication since transient skin irritation is known to develop with topical retinoids, but AEs may also 
develop due to the vehicle formulation or otherwise.  
It is desirable to make every effort to maintain subjects in the study to allow adequate assessment of efficacy 
and safety, especially in this small dose ranging study. If during the Treatment Phase there is for example 
a persistent Grade 2 or greater burning/stinging, erythema, erosions, edema or pruritus, treatment will be 


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9 
temporarily interrupted (maximum of 2 weeks), and unscheduled visits/phone calls will be scheduled to 
monitor resolution. As soon as the LSR(s) have resolved, treatment will be restarted at a frequency of once 
daily for 2 weeks. If treatment is tolerated at this frequency, then treatment will be increased to twice daily 
or as per protocol. If necessary, a second drug interruption will be allowed according to the instructions 
above, as per the Investigator’s discussion and agreement with the Medical Monitor. For details see section 
6.5 and 7.4 
Treatment will be permanently discontinued if any of the following occurs: 
• 
If the LSR(s) do(es) not resolve with the interruption of therapy for 2 weeks, or 
• 
If the LSR(s) recur(s) during bid dosing, or 
• 
If a third drug interruption is needed.   
Treatment/Assessment Areas: 
Treatment/Assessment Areas are defined as: 
Treatment area- the area of the entire body with active CI where the study medication will be applied 
(the entire body except for the hands, face, neck, scalp and genitalia are possible treatment areas.)  
Assessment Area- For the purposes of assessing via the Visual Index for Ichthyosis Severity (VIIS) 
Four VIIS Assessment Areas within the Treatment Area will be defined as described below and will be 
further described using color illustrations in the Investigator Study Binder: 
(a) the upper back from the posterior axillary fold to the other encompassing the T1-T10 
(b) the upper arm (excluding elbows), left or right 
(c) the shin/lower leg (the portion below the proximal aspect of the knee cap), left or right 
(d) dorsal foot (left or right). 
The Investigator will include subjects when any of the 4 VIIS Assessment Areas have some CI disease. At 
least, 2 of the 4 VIIS Assessment Areas MUST have a scaling score of 3 or more. Since for (b), (c), and (d) 
each include two body parts, one of each left or right must be designated as the Target (upper arm, lower 
leg, or dorsal foot) and followed throughout the study for VIIS assessment. The arm, leg, or foot with more 
severe and higher score will be designated as the Target unless they have the same severity scores, in which 
case the left or right choice will be at the discretion of Investigator assuming no other issues exists, dictating 
the choice of left/right. The severity scores will be averaged by the electronic data capture system but the 
score of two body parts that have a score of 3 or higher will be used to enroll subjects and used in subsequent 
assessments. A five-point (0-4) scale will be used with increasing clinical severity (scaling) and will be 
defined in the training manual.  
.  
Assessment Area- For the purposes of assessing via the Investigator’s Global Assessment (IGA): IGA 
will be performed on the entire Treatment Area. The IGA assessment by definition will include the VIIS 
Assessment Area but it will provide a broader perspective on disease status and therapeutic response at 
baseline and subsequent visits. The IGA score is a static evaluation of the overall or “average” degree of 
severity of a subject’s disease, considering all the subject’s scaling and fissuring in the IGA Assessment 
Areas by the Investigator or designee. This evaluation takes into consideration the 2 individual 
characteristics of CI (scaling and fissuring) with the IGA score at each visit representing the average degree 
of scaling and fissuring that is eligible for treatment. The IGA will be assessed using a 5-point scale.  


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Statistical Methods: 
All statistical analyses and summaries will be prepared using SAS® unless otherwise stated. All subjects 
enrolled in the study who were dispensed and who applied study medication at least once will be included 
in the analysis of safety and will be considered the Safety population. All randomized subjects, who 
received at least one dose of study medication will be considered the intent-to-treat (ITT) population. The 
per-protocol (PP) population will be a subset of the ITT population consisting of subjects who 1) met all 
inclusion/exclusion criteria that would affect the treatment evaluation, 2) applied ≥ 80% but ≤ 120% of the 
planned doses of study treatment, 3) who had a VIIS measurement at Visit 6/End of Study (EOS), and 4) 
had no major protocol violations that would affect the treatment evaluation. The final definition of the PP 
population will be presented in the Statistical Analysis Plan (SAP). 
Efficacy analyses will be performed on both the ITT and PP populations with the ITT population considered 
primary. Additional analyses may be performed to examine the efficacy in each CI subtype or different age 
groups which will be described in the SAP prior to data base lock. 
Demographic and baseline characteristics will be summarized by treatment group for the Safety, ITT, and 
PP populations. Frequency counts and percentages will be reported for categorical data and sample size, 
mean, median, standard deviation (SD), minimum, and maximum will be reported for the continuous 
variables. 
Efficacy Analyses: 
VIIS "treatment success" (VIIS-50) is defined as ≥ 50% reduction from Baseline for VIIS scaling score for 
the sum of the scores for ‘VIIS body areas’ that had a Baseline score ≥ 3). The proportion of subjects 
achieving VIIS-50 at Visit 6 (EOS) relative to Baseline will be the primary efficacy endpoint and time point 
used to compare the two active treatments to vehicle. Treatment groups will be compared at Visit 6 (EOS) 
using the Cochran-Mantel-Haenszel (CMH) Test stratified by CI subtype and corresponding 95% 
confidence intervals will be calculated for the difference in proportions for the treatment groups. 
The proportion of subjects achieving IGA treatment success will be the key secondary endpoint. For this 
endpoint, the IGA score will be dichotomized to “treatment success” or “treatment failure” where 
“treatment success” is defined as at least a 2-grade decrease in severity score relative to Baseline at Visit 6 
(EOS). 
Additionally, one secondary endpoint is the time to achieve VIIS-50 that is maintained at the next 
observation. If VIIS-50 is first achieved at Visit 6 (EOS), then the endpoint is considered to have been met. 
A time to event analysis will be completed using the Kaplan-Meier method and log rank test. 
For each of the other secondary efficacy endpoints (VIIS scaling, IGA, and Itch-Numeric Rating Scale 
[I-NRS]), the following summaries will be prepared at Visits 3, 4, 5, and 6 (EOS) (as applicable) by 
treatment group for each CI subtype and overall: 
• 
Frequency distribution of observed scores 
• 
Frequency distribution of change from Baseline 
• 
Shift tables for changes from Baseline to Visits 3, 4, 5, and 6 
• 
Frequency distribution of treatment success rates 
Success rates between treatment groups will be compared at Visit 6 (EOS) using the CMH Test stratified 
by CI subtype and 95% confidence intervals will be calculated for the difference in proportions for the 
treatment groups.  
Descriptive statistics (including mean, median, SD, minimum, and maximum) for observed and change 
from Baseline values in the Dermatology Life Quality Index (DLQI) and percent BSA affected in the 
Treatment/Assessment Areas at each visit will be presented by treatment group for each CI subtype and 
overall.  


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For VIIS and I-NRS, the treatment groups will be compared with respect to the change from Baseline using 
mixed model of repeated measures (MMRM) including terms for treatment, visit, treatment by visit 
interaction, and the Baseline value serving as the covariate. From the model, the active to vehicle treatment 
differences will be estimated. Additionally, two-sided confidence intervals will be provided. 
Handling of missing data: Data summaries and analyses will use observed data only without imputation 
of missing values. Supplementary analysis will be performed to investigate the impact of data imputation 
on the primary endpoint as follows: 
1) by assuming that subjects with missing data are treatment successes (“best case”); and 
2) by assuming that subjects in the vehicle group with missing data are “treatment success” and that subjects 
in the TMB-001 groups with missing data are treatment failures (“worst case”).  
3) by assuming that subjects with missing data maintain their last observed rating from which treatment 
success or failure will be derived at Visit 6 (“LOCF”). 
Dosing Compliance 
Descriptive statistics will be used to summarize study treatment compliance for the ITT population. A 
subject will be considered compliant with the dosing regimen if the subject applies at least 80% but no more 
than 120% of the expected number of applications or dose. 
Safety Analyses: 
The safety analyses will be conducted on the Safety population. 
Extent of Exposure 
The total amount of study medication used (grams of study medication applied) will be calculated from the 
weights of the returned study medication tubes. Descriptive statistics (mean, median, SD, minimum and 
maximum) will be determined for the total amount of study medication used by each subject by treatment 
groups. 
Physical Examinations 
Findings from physical examinations (head and neck, cardiovascular, dermatological, respiratory, 
gastrointestinal [abdomen], and gross motor and gait) will be recorded in medical history (from assessment 
at Visit 1 [Screening] and Visit 2 [Baseline])  
Vital Signs 
Descriptive statistics of vital signs (temperature, systolic and diastolic blood pressure, heart rate, and 
respiration rate) at Visit 1 (Screening) and Visit 6 (EOS) will be provided by treatment group. 
Clinical Laboratory Tests 
Clinical laboratory tests will be evaluated for any material changes during the study period. All laboratory 
data (hematology, chemistry, and urinalysis) will be listed and reported in the units received by the 
laboratory. Shift tables by analyte and by out of range flag will be presented to facilitate the evaluation of 
change from Visit 1 (Screening) to Visit 6 (EOS).  
Urine Pregnancy Test 
Urine pregnancy test (UPT) results (if applicable) from Visit 2 (Baseline), Visit 4, Visit 5, and Visit 6 (EOS) 
will be provided in a listing. 
Local Skin Reactions 
Local skin reactions (LSRs) (including burning/stinging, erythema, erosions, and edema) will be 
summarized by frequency of each individual LSR for each treatment group. Change from Baseline in LSRs 
will be categorized into ‘worsened’ and ‘same or improved’ and will be tabulated. 


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Protocol 235-9051-202 - Amendment 1 
 
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Adverse Events 
All AEs reported during the study will be listed, documenting onset, whether therapy was required, any 
change in study treatment dosing, severity, possible relationship to study treatment, and outcome. Verbatim 
terms on the case report forms (CRFs) will be linked to preferred terms (PTs) and system organ class (SOC) 
using the Medical Dictionary for Regulatory Activities (MedDRA) mapping system. All reported AEs will 
be summarized by the number of subjects reporting AEs, SOC, PT, severity, and relationship to study 
treatment by treatment group. 
Data Monitoring Committee: No 
 


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1.2 
Schedule of Activities 
 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Screening 
Baselinea 
Week 2 
Week 4 
Week 8 
Week 12/EOSb 
Days 
-90 to -7 
1 
15 (± 4) 
29 (± 4) 
57 (± 7) 
85 (± 7) 
Informed Consent/Assent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
Xc 
 
 
 
 
Medical History 
X 
X (updated) 
 
 
 
 
Concomitant Medications and Procedures/Therapies 
X 
X 
X 
X 
X 
X 
Genetic testing/confirmation 
X 
 
 
 
 
 
Physical Examinationd 
X 
X (abbreviated) 
 
 
 
X (abbreviated) 
Vital Signse 
X 
 
 
 
 
X 
Clinical Laboratory Testsf 
X 
 
 
 
 
X 
Urine Pregnancy Testingg for WOCBPh 
 
X 
 
X 
X 
X 
Photography (Select Sites and Subjects having remote visits) 
 
X 
X 
X 
X 
X 
Clinical Evaluations (VIIS and IGA) (select Target for VIIS 
assessment) 
X 
Confirm 
(prior to treatment application) 
X 
X 
X 
X 
Record percent of BSA with CI in the VIIS Assessment Area and 
the Treatment Area  
X 
Confirm 
X 
X 
X 
X 
Age-appropriate Dermatology Life Quality Index and I-NRS 
 
X 
 
 
X 
X 
Local Skin Reactions 
 
X 
(prior to treatment application) 
X 
X 
X 
X 
Randomizationi 
X 
 
 
 
 
 
 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Screening 
Baselinea 
Week 2 
Week 4 
Week 8 
Week 12/EOSb 


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Abbreviations: AE = adverse event; β-hCG = beta human chorionic gonadotropin; BSA = body surface area; C = collect diary; CI = congenital ichthyosis; D = dispense diary; EOS = End of Study; 
IGA = Investigator’s Global Assessment; I-NRS = Itch-Numeric Rating Scale; R = review diary; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing potential. 
a Screening assessments (except for Genetic testing)may be performed up to 90 days prior to the Baseline Visit for those qualified subjects who are eligible to enroll in the study but require washout of 
medications prior to enrolling into the Treatment Phase of the study. Genetic confirmation should be obtained prior to conducting additional eligibility assessments in the screening period. There is 
no window as it pertains to obtaining Genetic confirmation, it can be obtained at any time following consent and with no restriction until the Baseline Visit. 
b Or early termination from the study. 
c For those subjects who required genetic testing or a washout period related to exclusionary medications, reaffirm these subjects meet all protocol requirements at the Baseline Visit. 
d Examination will include head and neck, dermatologic, cardiovascular, respiratory, gastrointestinal (abdomen), and gross motor and gait assessments. Abbreviated examination/ subject disposition 
via directed query will be conducted at Visit 2 (Baseline) to identify any changes since the Screening Visit and Visit 6 (EOS) to assess changes throughout the study. Abnormalities at Visit 1 
(Screening) and Visit 2 (Baseline) will be recorded as medical history. Any new or worsening abnormality at all subsequent visits will be recorded as AEs. 
e Assessments will be made after the subject has rested in a seated position for at least 5 minutes. Height and weight will also be measured at Visit 1 (Screening). 
f Clinical laboratory tests (hematology, clinical chemistry, routine urinalysis) are provided in Table 7. Additional screening tests (as mentioned in Table 7) will be performed for Screening. Subjects 
must be fasting (at least 8 hours) for Visit 1 (Screening) and, if possible, for Visit 6 (EOS). However, if a subject arrives at the clinic for Visit 6 (EOS) without fasting for at least 8 hours, 
laboratory specimens may be collected as non-fasting, at the discretion of the Investigator and documented as such on the laboratory requisition form.  
g All urine pregnancy tests must have a minimum sensitivity of 25 mIU β-hCG/mL. 
h The term WOCBP is defined in Appendix 6. 
i Subject will be assigned the next available (lowest) kit number in ascending order. 
j Study staff will provide a Subject Instruction Sheet to the subject and parent/guardian (if applicable). 
k During any washout and screening periods, any changes in the health of subjects should be recorded as changes in medical history unless an event occurred as a result of a study-related procedure 
and was unanticipated. In such cases, the event should be recorded as an AE and reported to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) as an “unanticipated 
problem” in accordance with local procedures. 
l Any treatment-related AEs that are ongoing at Visit 6 (EOS) must be followed until resolution or stabilization. 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Screening 
Baselinea 
Week 2 
Week 4 
Week 8 
Week 12/EOSb 
Days 
-90 to -7 
1 
15 (± 4) 
29 (± 4) 
57 (± 7) 
85 (± 7) 
Days 
-90 to -7 
1 
15 (± 2) 
29 (± 2) 
57 (± 2) 
85 (± 3) 
Study Treatment Accountability and dispensation to subject 
 
X 
X 
X 
X 
X 
Demonstrate how to apply the study treatmentj 
 
X 
X 
X 
X 
 
Subject Diary: Dispense (D), Review (R), and/or Collect (C) 
 
D 
C+R+D 
C+R+D 
C+R+D 
C+R 
Instruct Subject to Continue Daily Treatment 
 
X 
X 
X 
X 
 
Adverse Events 
X 
Xk 
X 
X 
X 
Xl 


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2.0 INTRODUCTION 
The classification of congenital ichthyosis (CI) is complex because the disorder presents in a 
multitude of forms and phenotypes. The main features, however, are scaling and often thickening 
of the skin (1). The presentation and severity of symptoms can differ greatly by patient and by the 
form of ichthyosis, but generally include skin inflammation and fragility, pruritus, fissuring and 
cracking of thickened skin, ectropion, anhidrosis, and in some severe cases, an increased 
susceptibility to infection. Recessive X-linked ichthyosis (RXLI), which occurs at a frequency of 
about one in 2500 (in males), is clinically characterized by widespread, dark brown, polygonal 
scales, and generalized dryness (2). The diagnosis can be confirmed using genetic testing to 
identify a complete deletion of the gene encoding steroid sulfatase (STS) that is located at the 
terminus of the X chromosome (3). Autosomal recessive congenital ichthyosis-lamellar ichthyosis 
(ARCI-LI), which occurs at a frequency of about one in 100,000 to 300,000, is a member of the 
nonsyndromic autosomal recessive CI group which manifests itself clinically as hyperkeratosis 
and dry, scaling skin across the entire body (4); pathogenesis is related to a severely disturbed 
barrier function due either abnormal corneocytes or to a defective deposition of stratum corneum 
lipids and is typically caused by truncation or missense mutations in the gene encoding 
keratinocyte transglutaminase type 1 (TGM1) (1, 4). 
Isotretinoin is a “natural” retinoid (13-cis isomer of naturally occurring tretinoin [all-trans-retinoic 
acid{RA}]) that was initially developed as a synthetic retinoid, but it is also present in cells as a 
naturally occurring metabolite (5). Isotretinoin is structurally and pharmacologically related to 
vitamin A, which regulates epithelial cell growth and differentiation (6). Isotretinoin has several 
pharmacological mechanisms of action that result in the suppression of sebaceous gland activity, 
reduction of sebum production, reduction of comedogenesis by decreasing hyperkeratinization, 
suppression of Propionibacterium acnes (P. acnes), and reduction of inflammation (7). 
Isotretinoin 
has 
at 
least 
5 
biologically 
important 
metabolites: 
13-cis-4-oxo-RA 
(4-oxo-isotretinoin), all-trans-RA (tretinoin), all-trans-4-oxo-RA (4-oxo-tretinoin), 9-cis-RA 
(alitretinoin), and 9-cis-4-oxo-RA; and can be considered a pro-drug, in which isotretinoin can be 
metabolized into the naturally occurring tretinoin (or one of the other metabolites) as the active 
intracellular moiety (7). In addition, while some of isotretinoin’s activity may be mediated by 
tretinoin, the isomerization of isotretinoin (13-cis-RA) into tretinoin (all-trans-RA) does not 
account for all of the pharmacological effects observed upon use of this retinoid (8). Thus, 
isotretinoin’s broader range of activity compared to other retinoids makes it advantageous for 
clinical development. 
Oral isotretinoin (Accutane®) capsules was first approved by the United States (US) Food and 
Drug Administration (FDA) as treatment for severe recalcitrant nodular acne in 1982 (9). 
Teratogenicity is regarded as one of the most serious potential adverse effects of oral retinoids, 
while common mucocutaneous side effects are dose-dependent and can be managed by 
modification of the dose (eg, reductions and/or drug holidays) and additional symptomatic therapy 


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(eg, moisturizers). Topical formulation of isotretinoin, Isotrex® gel and cream, 0.05%, has since 
been approved in various countries outside of the US for the treatment of mild to moderate acne 
vulgaris, characterized by comedones, papules, and pustules (6,10). Another topical formulation, 
isotretinoin cream, 0.1%, has also been studied in various indications including ichthyosis and 
other disorders of keratinization (11,12) and acne vulgaris (13, 14, 15, 16, 17). 
2.1 
Study Rationale 
Systemic retinoids, including isotretinoin, have been used for the investigational treatment of CI 
and have demonstrated remarkable efficacy in reducing the clinical signs of the disease while 
dosing of the drug is maintained. Although not FDA approved, topical formulations of isotretinoin 
(eg, 0.05% gel and 0.1% cream) have demonstrated some efficacy in reducing the clinical signs 
associated with ichthyosis and other disorders of keratinization. Timber Pharmaceuticals, LLC is 
developing a topical ointment (0.05% and 0.1%) formulation of isotretinoin called TMB-001 
(previously PAT-001) (isotretinoin) ointment for the treatment of CI, including RXLI and ARCI-
LI subtypes. For ARCI-LI subjects, enrollment is not limited to Transglutaminase 1 mutations. 
Other genetically confirmed ARCI-LI mutations can potentially be enrolled as long as the 
phenotype is consistent with ARCI-LI and the other inclusion criteria are met, as determined by 
the Investigator. The purpose of this study is to investigate the efficacy and safety of two 
concentrations of topically applied TMB-001 in subjects 9 years of age and older. More recently, 
a pilot Phase 2a, multicenter study in subjects ≥ 12 years of age showed topically applied TMB-001 
ointment (0.1%) to be safe, tolerable, and supporting a favorable efficacy signal with improvement 
in overall Investigator’s Global Assessment (IGA) for CI treatment. 
2.2 
Background 
Congenital ichthyosis is a large, heterogeneous family of inherited skin disorders of cornification 
resulting from an abnormality of skin keratinization (1).  
The management of CI is a life-long endeavor, which remains largely symptomatic (ie, emollients 
with or without keratolytics) and commonly focused on reducing scaling and/or skin lubrication 
with both systemic and topical treatments (1). A first-line therapy includes hydration and 
lubrication accomplished by creams and ointments containing low concentrations of salt, urea, or 
glycerol, which increases the water-binding capacity of the horny layer. Addition of keratolytics 
is used to decrease corneocyte cohesiveness, to promote desquamation, and to dissolve keratins 
and lipids (eg, α-hydroxy acids, salicylic acid, high-dose urea, propylene glycol, N-acetylcysteine, 
and retinoids). Systemic retinoid treatment is reserved for those patients who are refractory to 
topical agents because of long-term adverse effects and teratogenicity (5); however, the 
investigational use of oral isotretinoin has demonstrated remarkable efficacy when used for the 
treatment of ichthyoses and is believed to be attributable to isotretinoin’s ability to reduce 
comedogenesis by decreasing hyperkeratinization (1, 5). For the treatment of CI, it would be 
desirable to have a topical formulation of isotretinoin as it would afford targeted delivery of the 


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drug at the disease tissue site, while potentially minimizing systemic exposure compared to that of 
systemic retinoid treatment, and additionally providing hydration and lubrication to the diseased 
skin. 
2.3 
Benefit/Risk Assessment 
While no topical isotretinoin formulation is approved for use in treatment of CI (or any indication 
in the US), topical formulations of isotretinoin (eg, 0.05% gel and 0.1% cream) have demonstrated 
some efficacy in reducing the clinical signs associated with ichthyosis and other disorders of 
keratinization. In one study, topical 13-cis-RA (isotretinoin) cream 0.1% demonstrated a marked 
reduction in scaling and an improvement in skin smoothness after 4 weeks of treatment in 40% of 
subjects (2/7 patients with non-erythrodermic LI, 2/2 patients with Darier’s disease, and 
0/1 patients with autosomal dominant ichthyosis vulgaris). However, this clinical improvement 
was accompanied by local skin irritation (eg, itchy erythema) in responders, and dose 
modifications were often prescribed to mitigate such effects (12). Similarly, topical isotretinoin 
gel, 0.05% (Isotrex®) demonstrated partial resolution or clearance of hyperkeratosis and papules 
in the treatment area (10 cm2 area) after 3 months of treatment (up to twice daily [bid] as tolerated) 
in 50% (6/12) of patients with Darier’s disease. 
In addition, systemic retinoids, including isotretinoin, have been used for the investigational 
treatment of CI and have demonstrated remarkable efficacy in reducing the clinical signs of the 
disease while dosing of the drug is maintained (1, 5). 
More recently, a pilot Phase 2a, multicenter study in subjects ≥ 12 years of age showed topically 
applied TMB-001 ointment (0.1%) to be safe, tolerable, and supporting a favorable efficacy signal 
with improvement in overall IGA for CI treatment. 
As with any retinoid, the side effects of TMB-001 may include the following local skin reactions 
(LSRs): 
burning, 
dryness, 
edema, 
erythema, 
hyperpigmentation, 
hypopigmentation, 
photosensitivity, pruritus, scaling/peeling, stinging, and tenderness. 
Although systemic exposure is expected to be low given the route of topical administration. In 
minipigs receiving once daily dermal applications of TMB 001 ointment at concentrations of 0% 
(control), 0.025%, 0.1%, and 0.2%, there was little to no systemic absorption of isotretinoin with 
most values being near or below the limit of quantitation (0.374 ng/mL).  
In addition, in a Phase 2a clinical study of subjects with CI, the concentrations of isotretinoin and 
tretinoin were measured. Plasma concentrations of isotretinoin and tretinoin indicated that 
systemic exposure was minimal within the 4 hours following initial application. Trough 
concentrations measured on Days 8, 29, 57 and 84 approximately 12 hours following the preceding 
dose indicated that systemic concentrations of isotretinoin and tretinoin were within range of the 
endogenous levels measured at Baseline prior to the first application. 


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The most notable adverse reactions with oral isotretinoin are: dry lip, dry skin, back pain, dry eye, 
arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, renal or hepatotoxicity, 
musculoskeletal discomfort, teratogenicity, and visual acuity reduced. 
The following are concerns for women of childbearing potential (WOCBP): 
• Severe birth defects can occur during pregnancy while taking oral isotretinoin, with any 
amount and even if taken for short periods of time; 
• Pregnancy must be avoided 1 month before, during, and for 1 month after treatment. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of TMB-001 ointment may be found in the Investigator’s Brochure. 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Efficacy 
Primary Efficacy 
• 
To investigate the efficacy of two concentrations 
of topically applied TMB-001 as a treatment for 
congenital ichthyosis (CI) of either the autosomal 
recessive congenital ichthyosis-lamellar ichthyosis 
(ARCI-LI) or RXLI subtypes. 
Proportion of subjects with VIIS "treatment 
success" (VIIS-50), which is defined as a 50% or 
greater decrease in VIIS scaling score relative to 
Baseline at Visit 6 (EOS) calculated using the sum 
of the scores for ‘VIIS body areas’ that have a 
Baseline score ≥ 3. 
 
Key Secondary Efficacy 
 
• 
IGA scores, dichotomized to “treatment success” 
or “treatment failure” where “treatment success” is 
defined as at least a 2-grade decrease in severity 
score relative to Baseline at Visit 6 (EOS). 
 
Other Secondary Efficacy 
 
• 
Time to achieve VIIS-50 (≥ 50% reduction in VIIS 
scaling score for body sites that had a Baseline 
score ≥ 3) that is maintained at the next 
observation. 
• 
Changes in VIIS scaling score relative to Baseline 
at Visit 4 and Visit 5. 
• 
Proportion of subjects with IGA “treatment 
success” at Visit 4, Visit 5, and Visit 6 (EOS).  
• 
Proportion of subjects with an IGA score of 0 or 1 
representing “cleared” or “almost cleared” at 
Visit 6 (EOS). 
• 
Changes in percent BSA relative to Baseline with 
CI in the Treatment/Assessment Areas at Visit 3, 
Visit 4, Visit 5, and Visit 6 (EOS). 
• 
Change from Baseline in I-NRS score at Visit 6 
(EOS). 
• 
Proportion of subjects with I-NRS “treatment 
success” where “success” is defined as at least a 
4-point reduction in I-NRS relative to Baseline at 
Visit 6 (EOS). 
• 
Change in DLQI from Baseline to Visit 6 (EOS). 


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Objectives 
Endpoints 
Safety 
Safety 
• 
To investigate the safety of topically applied 
TMB-001. 
• 
Incidence (severity and causality) of any local and 
systemic AEs.  
• 
Number of subjects with presence (and severity) at 
each time point of the following LSRs: 
burning/stinging, erythema, erosions, and edema. 
• 
Changes from Baseline in vital signs at Visit 6 
(EOS). 
• 
Changes from Baseline in clinical laboratory test 
results (chemistry, hematology, and urinalysis) at 
Visit 6 (EOS). 
Abbreviations: AE = adverse event; ARCI-LI = autosomal recessive congenital ichthyosis-lamellar ichthyosis; 
BSA = body surface area; CI = congenital ichthyosis; DLQI = Dermatology Life Quality Index; EOS = End of 
Study; IGA = Investigator’s Global Assessment; I-NRS = Itch-Numeric Rating Scale; LSR = local skin 
reaction; RXLI = recessive X-linked ichthyosis; VIIS = Visual Index for Ichthyosis Severity. 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and 
efficacy of two concentrations of topical TMB-001 for the treatment of CI in subjects with either 
the ARCI-LI or RXLI subtypes. 
Approximately 10 study centers from United States of America and Australia are expected to 
participate in this global study. 
The duration of treatment will be 12 weeks. 
Each subject will participate in the study for up to 24 weeks (including up to a 90-day Screening 
period). 
4.1.1 
Treatment Groups 
Eligible subjects will be randomized (1:1:1) to 1 of 3 treatment groups:  
1. TMB-001 Ointment, 0.05%, bid 
2. TMB-001 Ointment, 0.1%, bid 
3. Vehicle Ointment (Control), 0%, bid 
4.1.2 
Treatment/Assessment Areas 
 Treatment/Assessment Areas are defined as: 
 
4.1.2.1 
Treatment Area 
The area of the entire body with active CI where the study medication will be applied (the entire 
body except for the hands, face, neck, scalp and genitalia are possible treatment areas.)  
 
4.1.2.2 
The Visual Index for Ichthyosis Severity (VIIS) Assessment Areas 
The primary efficacy assessment will be performed using the Visual Index for Ichthyosis Severity 
(VIIS). Four VIIS Assessment Areas will be defined as described below and will be further 
described using color illustrations in the Investigator Study Binder:  
(a) the upper back from the posterior axillary fold to the other encompassing the T1-T10,  
(b) the upper arm (excluding elbow), left or right,  
(c) the shin/lower leg (the portion below the proximal aspect of the knee cap), left or right  
(d) dorsal foot (left or right).  


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The Investigator will include subjects when any of the 4 VIIS Assessment Areas have some CI 
disease. At least 2 of the 4 VIIS Assessment Areas MUST have a scaling score of 3 or more. 
Since for (b), (c), and (d) each include two body parts, one of each left or right must be 
designated as the Target (upper arm, lower leg, or dorsal foot) and followed throughout the study 
for VIIS assessment. The arm, leg, or foot with more severe and higher score will be designated 
as the Target unless they have the same severity scores, in which case the left or right choice will 
be at the discretion of Investigator assuming no other issues exists, dictating the choice of 
left/right. The severity scores will be averaged by the electronic data capture system but the score 
of two body parts that have a score of 3 or higher will be used to enroll subjects and used in 
subsequent assessments. A five-point (0-4) scale will be used with increasing clinical severity 
(scaling) and will be defined in the training manual.  
The primary efficacy endpoint will be the proportion of subjects with VIIS "treatment success" 
(VIIS-50), which is defined as a 50% or greater decrease in VIIS scaling score relative to Baseline 
at Visit 6, End of Study (EOS) calculated using only the VIIS body areas described above that 
have a Baseline score ≥ 3. 
VIIS severity will be calculated as above via one of two methods below   
• On-site visual inspection of the VIIS areas 
• Virtual/Remote visit comprised of both photographs and tele-medicine utilizing 
synchronous video-conferencing technology. The severity score at each visit will be based 
off information gathered from both sources to yield one score. 
 
4.1.2.3 
The Investigator’s Global Assessment (IGA) Assessment Area 
The IGA will be performed on the entire Treatment Area. The IGA assessment will inherently 
include the VIIS Area but it will provide a broader perspective on disease status and therapeutic 
response at baseline and subsequent visits. The IGA score is a static evaluation of the overall or 
“average” degree of severity of a subject’s disease, considering all the subject’s scaling and 
fissuring in the - Treatment Areas by the Investigator or designee. This evaluation takes into 
consideration the 2 individual characteristics of CI (scaling and fissuring) with the IGA score at 
each visit representing the average degree of scaling and fissuring that is eligible for treatment. 
The IGA will be assessed using the 5-point scale as shown in Table 3.  
IGA severity will be calculated as above via one of two methods below:  
• On-site visual inspection  
• Virtual/Remote visit comprised of both photographs and tele-medicine utilizing 
synchronous video conferencing technology. The severity score at each visit will be based 
off information gathered from both sources to yield one score. 
 


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4.2 
Scientific Rationale for Study Design 
The proposed study will use a multicenter, randomized, double-blind, parallel group, 
vehicle-controlled study design to evaluate the efficacy and safety of 0.1% and 0.05% TMB-001 
in the treatment of CI. The subjects will be selected according to predefined entry criteria. The 
study treatment duration is 12 weeks and expected to be enough to show a treatment effect. 
Isotretinoin was first approved in the US by the FDA and formulated as an oral product, Accutane 
(isotretinoin) capsules, to treat severe recalcitrant nodular acne (9). A topical formulation of 
isotretinoin, Isotrex® (isotretinoin) gel, 0.05%, has been approved in various countries outside of 
the US for the treatment of mild to moderate inflammatory acne vulgaris (6). The pharmacology, 
pharmacokinetics, and toxicology of isotretinoin have been well characterized in the literature. 
Isotretinoin is an approved active pharmacological ingredient with a long history of safe use in 
humans under the iPLEDGE program (18). The iPLEDGE program is a risk management 
distribution program mandated by the FDA for isotretinoin because isotretinoin must not be used 
by female patients who are or may become pregnant. There is an extremely high risk that severe 
birth defects will result if pregnancy occurs while taking oral isotretinoin in any amount, even for 
a short period of time. Potentially any fetus exposed during pregnancy can be affected. 
4.3 
Justification for Dose 
The concentrations of TMB-001 ointment chosen for this study are based on the formulation 
integrity and Phase 2a clinical study, specific laboratory animal toxicology studies performed by 
the Sponsor, and a review of the published safety data for isotretinoin. The highest dose (0.2% 
topically applied ointment) tested in the Phase 2a clinical study was reported with retinoid 
dermatitis and lower tolerability, hence doses lower than 0.2% have been considered for this study. 
The doses to be applied, 0.1% and 0.05%, are based upon the potential for therapeutic benefit 
balanced with the safety risk. 
4.4 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed the last scheduled 
visit (Visit 6) per the Schedule of Activities (Section 1.2). 
The end of the study is defined as the date of the last visit of the last subject in the study globally. 


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5.0 STUDY POPULATION 
The subjects will be male and/or female subjects, 9 years of age and older, with moderate to severe 
CI genetically confirmed to be of either the ARCI-LI or RXLI subtypes according to 
protocol-specified definitions. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
1. Subject is male or female, 9 years of age and older at Visit 2 (Baseline). 
2. Subject has provided written informed consent/assent. A subject under 18 years of age must 
provide written informed assent and be accompanied by the parent or legal guardian at the time 
of consent/assent signing. The parent or legal guardian must provide informed consent for the 
subject. If a subject becomes 18 years of age during the study, the subject must provide written 
informed consent at that time to continue study participation. 
3. Females must be postmenopausal (defined as amenorrhea greater than 12 consecutive months 
in women 50 years of age and older), surgically sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), or use acceptable forms of birth control. Women 
of childbearing potential (WOCBP) must have a negative urine pregnancy test (UPT) at 
Visit 2 (Baseline) (UPTs must have a minimum sensitivity to detect 25 mIU beta-human 
chorionic gonadotropin [β-hCG]/mL). Methods of acceptable contraception are further 
defined in Appendix 6. Female subjects who become sexually active or begin to have 
relations with a partner during the study must agree to use 2 forms of birth control for 
30 days prior to having relations and to continue such forms for the duration of the study. 
4. Subject has clinical diagnosis of CI and has a genetic confirmation of either ARCI-LI (eg, 
transglutaminase 1-deficient) or RXLI (eg, deletion of steroid sulfatase gene) subtypes of CI. 
For ARCI-LI subjects, enrollment is not limited to Transglutaminase 1 mutations. Other 
genetically confirmed ARCI-LI mutations can potentially be enrolled as long as the phenotype 
is consistent with ARCI-LI and the other inclusion criteria are met, as determined by the 
Investigator.  Congenital Ichthyosis XomeDxSlice will be used to diagnose both RXLI and 
ARCI-LI. GeneDx tests detect transglutaminase mutations in the TGM1 gene, X-linked 
recessive steroid sulfatase mutations in the STS gene, and additionally analyzes 47 other genes 
linked to CI. This is a multi-gene panel testing so that all known causes of CI can be 
confirmed/ruled-out since there is phenotypic overlap between the subtypes (including STS). 
The tests are considered Laboratory Developed Tests (LDTs) and are thus regulated per US 
regulations 42 CFR 493 and the laboratory is accredited by the College of American 
Pathologists. 


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5. The amount of CI affected skin  in the Treatment Area at Baseline will be between a minimum 
of 10% and maximum of 90% of the total BSA (1% BSA is approximately equal to the surface 
area of the subject’s palm and fingers, with the fingers extended yet grouped together, creating 
a flat oval-like surface area). 
6. Subject’s designated VIIS assessment areas MUST: 
• Include any of the 4 VIIS assessment areas that have some CI disease involving: (a) the 
upper back from the posterior axillary fold to the other encompassing the T1-T10, (b) the 
upper arm (excluding elbows), left or right, (c) the shin/lower leg (the portion below the 
proximal aspect of the knee cap), left or right, and (d) dorsal foot (left or right); AND 
• At least 2 of the 4 VIIS assessment areas MUST have a scaling score of 3 or more.  
7. Subject and parent/guardian (if applicable) are willing and able to apply the study treatment(s) 
as directed, comply with study instructions, and commit to all follow-up visits for the duration 
of the study. 
8. Subject, in the Investigator’s opinion, is in good general health and free of any disease state or 
physical condition that might impair evaluation of the Treatment/Assessment Areas or exposes 
the subject to an unacceptable risk by study participation. 
5.2 
Exclusion Criteria  
A subject is ineligible to enter the study if he/she meets 1 or more of the following criteria: 
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has inflammatory skin diseases that confound the interpretation of results (eg, atopic 
dermatitis) unrelated to ichthyosis. 
3.  Subject has previously failed on topical/oral retinoid therapy for treatment of CI. 
4. Subject, in the Treatment/Assessment Areas, has used: (a) topical retinoids or any other topical 
prescription or over-the-counter therapies (except emollients, keratolytics, and topical steroids 
- see below), that are intended for, or that in the opinion of the Investigator, may improve CI 
within 2 weeks of Visit 2 (Baseline), or (b) keratolytics or topical corticosteroids within 5 days 
prior to Visit 2 (Baseline). 
5. Subject has used any topical products in the Treatment/Assessment Areas, including bland 
emollients, on Visit 2 (Baseline) prior to randomization.  
6. Subject has used ultraviolet (UV) treatment within 4 weeks prior to Visit 2 (Baseline). 
7. Subject has undergone systemic therapies using vitamin A supplements or St. John’s Wort 
within 4 weeks prior to Visit 2 (Baseline). Note: Use of a multivitamin including Vitamin A 
is not exclusionary provided it is taken as directed on the packaging. 
8. Subject has used systemic retinoids within 12 weeks of Visit 2 (Baseline) or any other systemic 
therapies that are intended for or may improve CI within 4 weeks of Visit 2 (Baseline). 
9. Subject is immunosuppressed (eg, human immunodeficiency virus, systemic malignancy, graft 
host disease) or receives systemic immunotherapy. 


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10. Subject is currently taking concomitant immunosuppressive drugs, including systemic 
corticosteroids, within 2 weeks of Visit 2 (Baseline). 
11. Subject has untreated secondary infections; however, subject may become eligible after 
successful treatment of his/her infection(s) at the Investigator’s discretion. 
12. Subject is currently enrolled in an investigational drug or device study or has used an 
investigational drug or investigational device treatment within 30 days prior to Visit 2 
(Baseline). 
13. Subject has lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or untreated 
skin cancers within the Treatment/Assessment Areas. 
14. Subject has a physical condition or other dermatologic disorder that, in the Investigator’s 
opinion, might impair evaluation of CI, or that exposes the subject to unacceptable risk by 
study participation. 
15. Subjects with ALT or AST > 2 × Upper Limit of Normal (ULN) and creatinine > 1.5 × ULN. 
16. Subject is unable to communicate or cooperate with the Investigator due to language problems, 
impaired cerebral function, or physical limitations. 
17. Subject has a history of drug or alcohol abuse within the past 6 months, or if suspected to be 
noncompliant or is unlikely to comply with the requirements of the study protocol (eg, due to 
alcoholism, drug dependency, mental incapacity) in the opinion of the Investigator. 
18. Subject has a history of sensitivity to any of the ingredients in the study treatments (see 
Section 6.1). 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Subjects must fast at least 8 hours prior to the collection of specimens for clinical laboratory testing 
at Visit 1 (Screening) and, if possible, for Visit 6 (EOS). However, if a subject arrives at the clinic 
for Visit 6 (EOS) without having fasted for at least 8 hours, laboratory specimens may be collected 
as non-fasting, at the discretion of the Investigator and documented as such on the laboratory 
requisition form.  
5.3.2 
Activity 
No activity restrictions are applicable. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized into the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, eligibility criteria, and any serious adverse 
event (SAE) will be collected and recorded in the electronic data capture system. 


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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  
Eligible subjects who are not able to complete all their screening assessments within the designated 
screening period may be rescreened at the discretion of the Sponsor. Rescreening for other reasons 
may be allowed after consultation with the Sponsor. All screening assessments except for the 
ICF/Assent, confirmation of CI diagnosis, height, and buccal swab for DNA will be repeated 
unless determined otherwise by the Sponsor. 
Participants who have a clinically nonsignificant out-of-range laboratory result may be rescreened 
1 time only at the discretion of the Investigator and after consultation with the Sponsor. For normal 
ranges, refer to the Laboratory Manual. 
Rescreened subjects should not be assigned the same subject number as for the initial screening. 


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6.0 STUDY TREATMENT 
6.1 
Study Treatment(s) Administered 
The blinded study treatments to be used in this study include: 
• TMB-001, 0.05%, bid 
• TMB-001, 0.1%, bid  
• Vehicle Ointment (Control) bid 
The study medication is intended to be applied twice daily, ideally once in the morning and once 
in the evening, but at least 6 hours apart. 
Subjects are instructed to use the indicated amount of study medication on the VIIS 
Treatment/Assessment Areas. Refer to the Subject and Site Instruction Sheet for per protocol 
amounts of medication to be applied based on subject’s BSA%.  
Product application will be clearly demonstrated by the Investigator or a designated healthcare 
professional at the Baseline Visit. 
The study treatment details are provided in Table 2. The Vehicle ointment contains only the 
inactive ingredients and color additive so that the active and vehicle formulations are 
indistinguishable. 
The Treatment/Assessment Areas are described in Section 4.1.2. 
Table 2 
Study Treatments 
Study Treatment Name: 
TMB-001 0.05% 
TMB-001 0.1% 
Vehicle 
Dosage Formulation: 
Ointment 
Ointment 
Ointment 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
0.05% 
0.1% 
Not applicable 
Route of Administration  
Topical 
Topical 
Topical 
Dosing Instructions: 
 
Twice daily (morning 
and evening) 
Twice daily (morning 
and evening) 
Twice daily (morning and 
evening) 
Packaging and Labeling  
Study medication will 
be provided in 
aluminum tubes. 
Each aluminum tube 
will be labeled as 
required per country 
requirement. 
Study medication will 
be provided in 
aluminum tubes. Each 
aluminum tube will be 
labeled as required per 
country requirement. 
Vehicle ointment will be 
provided in aluminum tubes. 
Each aluminum tube will be 
labeled as required per 
country requirement. 
Manufacturer 
Ferndale Laboratories 
in Ferndale, 
Michigan, USA 
Ferndale Laboratories 
in Ferndale, Michigan, 
USA 
Ferndale Laboratories in 
Ferndale, Michigan, USA 


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6.2 
Preparation/Handling/Storage/Accountability 
TMB-001 ointment and Vehicle ointment are manufactured in a current Good Manufacturing 
Practice (GMP)-compliant facility and tested prior to release to ensure that the quality 
characteristics of each clinical batch are met. TMB-001 ointment and Vehicle ointment are 
packaged in aluminum tubes and should be stored at the conditions specified on the label as 
follows: 
• Store at 36°F to 46°F (2°C to 8°C) until dispensed. Once dispensed, store at 68°F to 77°F 
(20°C to 25°C), excursions permitted to 59°F to 86°F (15°C to 30°C).  
For Subjects that will be seen in clinic for Visit 2, study medication will be shipped directly to the 
study site. The Investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all study medications received and any discrepancies are 
reported and resolved before use of the study medication.  
For Subjects that will have Visit 2 performed remotely, the study medication will be shipped 
directly to the subject’s home. The subject will receive confirmation from the courier that 
appropriate temperature conditions have been maintained during transit for all study medications 
received and the courier will report any discrepancies to the site. In case of discrepancies the site 
will ensure they are resolved before use of the study medication and communicate that to the 
subject. 
Prior to using any tube, the tube must be weighed. Upon return of the tube to the study center, the 
tube must be weighed. 
Only subjects enrolled in the study may receive study treatment, and only authorized study center 
staff may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center staff. 
The Investigator or designee is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records) using the Drug 
Accountability Form. These forms must be available for inspection at all times. 
Further guidance and information for the final disposition of unused study medication are provided 
in the Investigator Study Binder.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Subjects who meet all inclusion criteria and no exclusion criteria will be randomized to a treatment 
group in a 1:1:1 ratio, stratified by CI subtype.  


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All subjects will be centrally assigned to randomized study treatment using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log in information and directions for 
the IWRS will be provided to each study center. 
Study medication use will be accounted and dispensed at the study visits as summarized in the 
Schedule of Activities (Section 1.2).  
In this double-blind study, all personnel involved, ie, physicians, site staff, and participants will 
remain blinded at all times, except in an emergency, where knowledge of the randomization code 
is required to provide appropriate treatment. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a subject’s treatment assignment is warranted. 
Subject safety must always be the first consideration in making such a determination. If the 
Investigator decides that unblinding is warranted, every effort should be made to contact the 
Sponsor and Medical Monitor prior to unblinding a subject’s treatment assignment unless this 
could delay emergency treatment of the subject. If a subject’s treatment assignment is unblinded, 
the Sponsor must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and electronic Case Report Form 
(eCRF), as applicable. 
6.4 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed, except as defined 
in Section 7.4. Any departures from the intended regimen must be recorded in the eCRFs. 
During the course of the study, compliance to study drug application will be evaluated via Subject 
diaries and accountability by the site, including weighing the tubes. Subjects exhibiting poor 
compliance should be counseled on the importance of good compliance to the study dosing 
regimen.  
6.5 
Concomitant Therapy 
 
Prohibited medications include the use of the following in the Treatment Areas: 
• Topical retinoids or any other topical prescription or over-the-counter therapies that are 
intended for, or that in the opinion of the Investigator may improve, CI within 2 weeks of 
Visit 2 (Baseline) and until the Visit 6 (EOS);  
• Keratolytics, or topical corticosteroids within 7 days prior to Visit 2 (Baseline) and until 
the Visit 6 (EOS); and, 
• Topical products, at Visit 2 (Baseline) and until the Visit 6 (EOS). Bland emollients and 
over the counter low potency hydrocortisone (e.g.,1% cream) may only be used in the event 
of severe discomfort (e.g., burning/erythema/itch) and if it is the opinion of the Investigator 
that a drug interruption (per section 7.4) alone will not relieve the symptoms and these may 


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cause the subject to discontinue from study.  The duration of the mitigation plan should not 
exceed 2 weeks. 
• Topical antibiotic or antifungal can be used after consultation and at the discretion of the 
Investigator. Systemic antifungals or antibiotics must be prescribed by the Investigator if 
necessary to avoid risk of more serious or broader infections. 
 
The following systemic treatments are prohibited: 
• Vitamin A supplements or St. John’s Wort within 4 weeks prior to Visit 2 (Baseline) and 
until the Visit 6 (EOS) Note: Use of a multivitamin including Vitamin A is not exclusionary 
provided it is taken as directed as on the packaging; 
• Retinoids within 12 weeks of Visit 2 (Baseline) or any other systemic therapies which are 
intended for or may improve CI within 4 weeks of Visit 2 (Baseline) and until the Visit 6 
(EOS); and, 
• Immunosuppressive drugs, including systemic corticosteroids, within 2 weeks of Visit 2 
(Baseline) and until the Visit 6 (EOS). 
The use of UV light is prohibited within 4 weeks prior to Visit 2 (Baseline) and until the Visit 6 
(EOS). Further, subjects should limit exposure to UV via sunlight and avoid tanning beds. 
Subjects may not be enrolled in an investigational drug or device study or have used an 
investigational drug or investigational device treatment within 30 days prior to Visit 2 (Baseline). 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the 
study must be recorded on the eCRF along with: 
• Reason for use; 
• Dates of administration including start and end dates; and, 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.6 
Dose Regimen Modification 
Dose regimen modification is not allowed in this study, except for a structured treatment 
interruption scheme (drug holiday) as detailed in Section 7.4. 
6.7 
Treatment after the End of the Study 
The Sponsor will not provide any additional care to subjects after they leave the study because 
such care should not differ from what is normally expected for subjects with CI. 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
See the Schedule of Activities (Section 1.2) for a list of the data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1 
Pregnancy 
Any female subject who becomes pregnant during the study must discontinue treatment. If a 
pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning of 
the pregnancy and should follow the procedures outlined in Section 8.4.5 and Appendix 6. 
7.2 
Inadvertent Enrollment 
If a subject who does not meet enrollment criteria is inadvertently enrolled, that subject must be 
discontinued from study treatment; and the Sponsor or Sponsor designee must be contacted.  
7.3 
Adverse Events 
A subject may discontinue from the study due to an SAE or AE. In that case, the procedures in 
Section 8.4 must be followed.  
See the Schedule of Activities (Section 1.2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.4 
Temporary Discontinuation (Drug Interruption/Holiday)  
A treatment interruption scheme will be allowed if a subject experiences skin adverse events or 
LSRs during the study that may require interruption or termination of study medication. This is 
intended to assist subjects to continue in the study if the event is likely or expected to lead to 
discontinuation. Any subjects with a LSR (especially early during treatment) will be encouraged 
to continue with their study medication since transient skin irritation is known to develop with 
topical retinoids, but LSRs may also develop due to the vehicle formulation or other reasons.   
It is desirable to make every effort to maintain subjects in the study to allow adequate assessment 
of efficacy and safety, especially in this small dose-ranging study. If during the Treatment Phase 
there is a persistent Grade 2 or greater adverse event, treatment can be temporarily interrupted, and 
unscheduled visits/phone calls will be scheduled to monitor resolution. Supportive action (per 
section 6.5) can be undertaken, if in the opinion of the Investigator the drug interruption alone will 
not relieve the symptoms and may cause the subject to discontinue from study.  As soon as the 
LSR(s) have resolved, study medication will be restarted at a frequency of once daily for 2 weeks. 
If treatment is tolerated at this frequency, then treatment will be increased to twice daily or as per 
protocol. If necessary, a second drug interruption will be allowed according to the instructions 
above, as per the Investigator’s discussion and agreement with the Medical Monitor.  


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Treatment will be permanently discontinued if any of the following occurs: 
• If the LSR(s) do(es) not resolve with the interruption of therapy for 2 weeks, or 
• If the LSR(s) recur(s) during bid dosing, or 
• If a third drug interruption is needed.   
7.5 
Subject Discontinuation/Withdrawal from the Study 
Subjects may be discontinued/withdrawn from the study for reasons that include, but are not 
limited to, the following: 
• A subject may withdraw from the study at any time at his/her own request, or he/she may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
• If the subject withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the study center study records. 
• See Section 1.2 for the data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The discontinuation of specific study centers or of the study are handled as part of Appendix 2. 
7.6 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and the study center is unable to contact him/her as described below.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The study center must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• If the subject continues to be unreachable, he/she will be considered to have withdrawn 
from the study and lost to follow-up.  


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.2). 
Adherence to the study design requirements, including those specified in the Schedule of Activities, 
is essential and required for study conduct. Procedures conducted as part of the subject’s routine 
clinical management (eg, blood count) and obtained before signing the informed consent form 
(ICF) may be utilized for Screening or Baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in the Schedule of 
Activities. 
All Screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The Investigator will maintain a screening log to record the details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Protocol waivers or exemptions may be permitted at the Sponsor’s discretion, especially when 
mitigating factors associated with a global pandemic and other situations that arise that are outside 
the control of the Sponsor and/or Investigator. Immediate safety concerns should be discussed with 
the Sponsor immediately upon occurrence or awareness to determine if the subject should continue 
or discontinue study treatment. 
8.1 
Study Visits 
This study will consist of 6 visits as described in the Schedule of Activities (Section 1.2). The 
maximum amount of blood collected from each subject over the duration of the study will be 
approximately 20 mL. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
8.1.1 
Visit 1 (Screening) 
Screening will occur at Visit 1 (Day -90 to Day -7). Subjects can be screened for the study up to 
approximately 90 days before Baseline. During Screening, the study requirements and procedures 
will be reviewed and written informed consent/assent will be obtained prior to the initiation of any 
study-related procedures. Following informed consent, a review of inclusion exclusion will be 
conducted so that the Investigator can assess if the subject is likely to be eligible for enrollment. 
Once this is confirmed, the availability of genetic testing confirming the diagnosis of CI and 
specific subtype will be addressed. Subjects who already have had genetic test documenting 
ARCI-LI or RXLI types of CI will not be required to provide samples for genetic testing. However, 
the subject must provide the Investigator with a copy of the genetic report for the source 
documentation file. Subjects requiring genetic testing, will have a buccal specimen obtained and 
sent for analysis. Following confirmation of the appropriate genetic subtype, the following 
procedures will be completed in the Screening period; Demographics, medical history, 
concomitant medications, physical exam, vital signs, clinical evaluation of extent and location of 
CI, percent BSA with CI in the Treatment Area, as well as in the VIIS Assessment Area, and 


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clinical laboratory test as found in Table 7. In addition, VIIS for scaling will be performed for the 
VIIS Assessment Area and IGA for Scaling and Fissure will be performed for the Treatment Area.  
Subjects who meet all inclusion criteria and no exclusion criteria will be randomized to a 
treatment group stratified by CI subtype. Randomization will be performed as specified in 
Section 6.3.  
8.1.2 
Visit 2 (Baseline) 
Baseline activities will occur at Visit 2. This visit may be performed either on site or as a remote, 
tele-medicine visit. 
The following will be conducted at the visit: 
• The subject will be queried for any changes in health status (ie, change in medications or 
new health issues) since the previous visit, including concomitant medications and 
concurrent procedures/therapies  
• Abbreviated physical exam/ subject disposition via directed query 
• Eligibility will be confirmed. All WOCBP must have a negative UPT.  
• Photography per a photographic guide provided by the Sponsor (at select study sites and 
for all subjects where this visit will be conducted remotely) 
• Clinical evaluations will be performed prior to the application of study medication. 
Confirmation of the percent BSA with CI in the Treatment Area and the VIIS Assessment 
Area  
• VIIS for Scaling will be performed for the VIIS Assessment Area and IGA for Scaling 
and Fissure will be performed for the Treatment Area.  
• Age-appropriate Dermatology Life Quality Index (DLQI) and Itch-Numeric Rating Scale 
(I-NRS) will be completed by the subject.  
• Study personnel will review and dispense the Subject Instruction Sheet and Diary. The 
subject and parent/guardian (if applicable) will be instructed on how and where to 
dispense and apply study medication to the Treatment Area and to record applications in 
the Subject Diary. 
• If the visit is being held in clinic, the tubes with study medication will be weighed by 
study personnel prior to dispensing to subject. If the visit it being held remotely, the 
subject will weigh the tubes with study medication prior to using. Subjects will apply the 
first dose of the assigned study medication to all affected skin in the Treatment Area 
under staff supervision either in person or remotely. 
• All AEs post application will be recorded. 


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8.1.3 
Visit 3, Visit 4, and Visit 5 
Visit 3 will take place at Week 2 on Day 15 ± 4 days; Visit 4 will take place at Week 4 on Day 29 
± 4 days; and Visit 5 will take place at Week 8 on Day 57 ± 7 days. These visits may be performed 
either on site or as a remote tele-medicine visit.  
The following will be completed at these visits: 
• The subject will be queried for any changes in health status since the previous visit, 
including concomitant medications and concurrent procedures/therapies. Any AEs will be 
documented.  
• A UPT will be performed for WOCBP at Visit 4 and Visit 5 only. Note: If the UPT result 
is positive, the subject must discontinue treatment immediately; and the Investigator must 
report the pregnancy as detailed in Section 8.4.5 and Appendix 6.  
• Photography will be performed at select study site(s) per a photo guide provided by the 
Sponsor and for all subjects where any of these visits will be conducted remotely.  
• Clinical evaluations including local skin reactions and determination of the percent BSA 
with CI in the Treatment/Assessment Areas and overall percent BSA will be performed.  
• VIIS for Scaling will be performed for the VIIS Assessment Area and IGA for Scaling 
and Fissure will be performed for the Treatment Area.  
• Age-appropriate DLQI and I-NRS will be completed by the subject at Visit 5 onlyRecord 
percent of BSA with CI in the VIIS Assessment Area and the Treatment Area 
• Study treatment accountability will be performed, including weighing of all newly 
dispensed and returned tubes.  
• The Subject Diary will be collected, reviewed, and re-dispensed.  
• The Subject Instruction Sheet will be re-dispensed as necessary. Subjects will be 
instructed to continue bid treatment in the morning and evening until the next visit and to 
record all applications in the Subject Diary.  
• The subject will be scheduled for the next visit. 
8.1.4 
Visit 6 (End of Study) 
The EOS visit will occur at Week 12 on Day 85 ± 7 days. Any subject who is discontinued from 
study prior to Visit 6 (EOS) should complete the procedures listed for EOS during their last study 
visit or Early Termination visit. This visit may be performed either on site or as a remote visit, 
although all efforts should be made for an on-site visit. 
The following will be completed at this visit: 
• The subject will be queried for any changes in health status since the previous visit, 
including concomitant medications and concurrent procedures/therapies. Any AEs will be 
recorded. 
• Age-appropriate DLQI and I-NRS will be completed by the subject.  


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• Abbreviated physical examination/ subject disposition via directed query, vital signs, 
clinical laboratory tests 
• Photography (select study sites and for all subjects where this visit will be conducted 
remotely) 
• UPT for WOCBP will be performed 
• The study staff will perform the clinical evaluations , including local skin reactions and 
record the percent BSA with CI in the Treatment Area and VIIS Assessment Areas  
• VIIS for Scaling will be performed for the VIIS Assessment Area and IGA for Scaling 
and Fissure will be performed for the Treatment Area. 
•  
• Study treatment accountability will be performed, including weighing of all returned 
tubes.  
• The Subject Diary will be collected and reviewed.  
8.2 
Efficacy Assessments  
At each visit, the skin affected with CI in the Treatment/Assessment Areas defined at the Baseline 
Visit will be assessed as described below. 
8.2.1 
Visual Index for Ichthyosis Severity – Scaling 
The Investigator will include subjects when any of the 4 VIIS Assessment Areas have some CI 
disease. At least 2 of the 4 VIIS Assessment Areas MUST have a scaling score of 3 or more. The 
upper arm, lower leg/shin, and dorsal foot each include left and right body parts. Therefore, one of 
each left or right must be designated as the Target (upper arm, lower leg, or dorsal foot) and 
followed throughout the study for VIIS assessment. The arm, leg, or foot with more severe and 
higher score will be designated as the Target unless they have the same severity scores, in which 
case the left or right choice will be at the discretion of Investigator assuming no other issues exists, 
dictating the choice of left/right. The severity scores will be averaged by the electronic data capture 
system but the score of the two body parts that have a score of 3 or higher will be used to enroll 
subjects and used in subsequent assessments.  
The location of the CI to be treated and the percent body surface area (BSA) with CI in the  
Treatment Area and in the VIIS Assessment Areas will be recorded prior to application of study 
medication.   
Scaling in the VIIS Assessment Areas will be graded using the 5-point VIIS scale: 0 to 4. This is 
a visual assessment tool to assist with scoring in 4 specific body sites, so it is essential to include 
at least 2 or more of the 4 body sites with CI in the Treatment/Assessment Areas. The Assessment 
Areas are described in Section 4.1.2.1. Visual Index for Ichthyosis Severity “Treatment success” 
(VIIS-50) is defined as a 50% or greater decrease in VIIS scaling score relative to Baseline at 
Visit 6 (EOS) calculated using the sum of the scores for ‘VIIS body areas’ that have a Baseline 
score ≥ 3. 


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VIIS severity will be calculated as above using the scores obtained via one of two methods below:  
a) On-site visual inspection of the VIIS areas 
b) Virtual/ Remote visit comprised of both photographs and tele-medicine utilizing 
synchronous video conferencing technology. The severity score at each visit will be based 
off information gathered from both sources to yield one score. 
 
8.2.2 
Investigator’s Global Assessment 
The IGA score is a static evaluation of the overall or “average” degree of severity of a subject’s 
disease, considering all the subject’s scaling and fissuring in the Treatment Areas by the 
Investigator or designee. This evaluation takes into consideration the 2 individual characteristics 
of CI (scaling and fissuring) with the IGA score at each visit representing the average degree of 
scaling and fissuring that is eligible for treatment. The Treatment Areas are described in 
Section 4.1.2.2. The IGA will be assessed using the following 5-point scale shown in Table 3: 
Table 3 
Investigator’s Global Assessment Score (5-Point Scale) 
0 = 
Clear 
No scaling and no roughness, no fissure 
1 = 
Almost Clear 
Occasional fine scales, hardly palpable roughness (mostly smooth) no 
fissure 
2 = 
Mild 
Small and fine scales predominate, no more than a few large scales, 
mild roughness on palpation, few fissures may be present 
3 = 
Moderate 
Large rather thick scales predominate, coarse roughness on palpation, 
few fissures may be present 
4 = 
Severe 
Large coalescent scales dominate, sharp edges on palpation with 
plate-like hyperkeratosis, many fissures may be present 
IGA severity will be calculated as above using the scores obtained via one of the two methods 
below:   
c) On-site visual inspection  
d) Virtual/remote visit comprised of both photographs and tele-medicine utilizing 
synchronous videoconferencing technology. The severity score at each visit will be based 
off information gathered from both sources to yield one score. 
 
8.2.3 
Itch-Numeric Rating Scale 
Pruritus will be assessed with a self-administered Patient Reported Outcome questionnaire using 
the I-NRS at Visit 2 (Baseline), Visit 5, and at Visit 6 (EOS). Subjects will indicate itch severity 
by circling the integer that best describes the worst level of itching due to CI in the past 24 hours 
on an 11-point scale anchored at 0 representing “no itching” and 10 representing “worst itch 
imaginable.” (see Appendix 11). The study staff should review the I-NRS with each subject and 


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ask him/her to indicate the response that best describes his/her experience. Pruritus assessed by 
this evaluation should be reported as an AE only if therapy is required. 
8.2.4 
Percent Body Surface Area with Active Congenital Ichthyosis in the 
Treatment/Assessment Areas  
The percent BSA with active CI within the Treatment Area will be calculated at Visit 1 (Screening).  
The Treatment Area includes all affected skin excluding the hands, face, neck, scalp and genitalia. 
This calculation is confirmed at Visit 2 (Baseline) and assessed at all follow-up visits.    The 
minimum affected area to be treated will be no less than 10% and no more than 90% of the whole 
BSA at Visit 1 (Screening). In addition, the percent BSA with active CI within the designated VIIS 
/Assessment Areas will be calculated at Visit 1 (Screening) and at all follow-up visits. Note that 
the Treatment Area is at least equal to or larger than the VIIS Assessment Area.  Based on the 
Treatment and VIIS Assessment Areas selected in a given subject and the extent of his/her disease, 
these two areas may or may not be the same.  Two examples are provided below for clarity: 
 
 
Treatment Area 
% BSA   
VIIS Assessment area 
% BSA 
Subject 1 
90% 
(entire 
body 
minus hands, face, 
neck, scalp, genitalia) 
24% 
(upper 
back, 
upper arms, lower 
legs and dorsal feet) 
Subject 2 
70% 
13% (upper back and 
upper arms) 
 
8.2.5 
Dermatology Life Quality Index 
The DLQI (Dermatology Quality of Life Index), is a dermatology-specific Quality of Life 
instrument. Age-appropriate DLQI will be completed at Visit 2 (Baseline), Visit 5, and Visit 6 
(EOS). The standard DLQI is a questionnaire designed for subjects ≥ 16 years of age that measures 
the impact of skin disease on the previous week’s quality of life. There are 10 questions related to 
the following topics: symptoms, embarrassment, shopping and home care, clothes, social and 
leisure, sport, work or study, close relationships, sex, treatment (see Appendix 9). Questions are 
scored from 0 to 3 with a possible score range from 0 (no impact of skin disease on quality of life) 
to 30 (maximum impact on quality of life). The score ranges are shown in Table 4. 
Table 4 
Dermatology Life Quality Index Scale 
0 to 1 = 
No effect on patient’s life 
2 to 5 = 
Small effect 


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6 to 10 = 
Moderate effect 
11 to 20 = 
Very large effect 
21 to 30 = 
Extremely large effect. 
The minimal clinically important difference (MCID) is the minimum difference in score that is 
meaningful for a subject. This is considered 4 for inflammatory skin diseases. 
Children’s DLQI will be used for subjects < 16 years of age to measure the impact of skin disease 
on the previous week’s quality of life. There are 10 questions related to the following topics: 
symptoms and feelings, leisure, school or holidays, personal relationships, sleep, treatment (see 
Appendix 10). Questions are scored from 0 to 3 with a possible score range from 0 (no effect on 
child’s life) to 30 (extremely large effect). The score ranges are shown in Table 5. 
Table 5 
Children’s Dermatology Life Quality Index Scale 
0 to 1 = 
No effect on child’s life 
2 to 6 = 
Small effect 
7 to 12 = 
Moderate effect 
13 to 18 = 
Very large effect 
19 to 30 = 
Extremely large effect. 
8.3 
Safety Assessments  
The planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.2). 
8.3.1 
Physical Examinations 
A brief physical examination will be performed at Visit 1 (Screening).Abbreviated examination/ 
subject disposition will be conducted at Visit 2 (Baseline) to identify any changes since the 
Screening visit and at Visit 6 EOS to assess for any changes during the study. The examination 
will evaluate head and neck, dermatological, cardiovascular, respiratory, gastrointestinal 
(abdomen), and gross motor and gait body assessments. Abnormalities at Visit 1 (Screening) and 
Visit 2 (Baseline) prior to treatment will be recorded as medical history. Any new or worsening 
abnormalities at Visit 6 (EOS) will be recorded as AEs. 
8.3.2 
Vital Signs 
Vital signs including temperature, systolic and diastolic blood pressure, heart rate, and respiration 
rate will be measured at Visit 1 (Screening) and Visit 6 (EOS). Assessments will be made after the 
subject has rested in a seated position for at least 5 minutes in a quiet setting without distractions 
(eg, television, cell phones). Height and weight will only be measured at Visit 1 (Screening). 


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8.3.3 
Local Skin Reactions 
At every study visit (except Screening), the Investigator or designee will evaluate LSRs known to 
be associated with retinoids (burning/stinging, erythema, erosions, and edema) or other causes 
regardless of blinded causality assessment within the areas treated with study medication using a 
4-point ordinal scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Note: At Visit 2 
(Baseline), the LSR assessment must be performed prior to the application of study medication. 
Only LSRs that require medical intervention (eg, prescription medication) or that require 
withholding application of the study medication will be documented as AEs. Any LSRs that are 
not listed above will be recorded as AEs. For drug interruption due to LSRs, refer structured drug 
interruption scheme (drug holiday) described in Section 7.4. 
8.3.4 
Electrocardiograms 
Electrocardiogram monitoring will not be performed in this study. 
8.3.5 
Clinical Safety Laboratory Assessments 
Urine and blood samples will be collected from each subject for safety laboratory analyses at 
Visit 1 (Screening) and Visit 6 (EOS).  
Subjects must be fasting (at least 8 hours) for Visit 1 (Screening) and, if possible, for Visit 6 (EOS); 
however, if a subject arrives at the clinic for Visit 6 (EOS) without fasting for at least 8 hours, 
laboratory specimens may be collected as non-fasting, at the discretion of the Investigator, and 
with the appropriate fasting status documented on the laboratory requisition form.  
For subjects that will have the Visit 6 (EOS) conducted remotely, urine and blood samples may be 
collected by a home health care provider supplied by the Sponsor. 
See Appendix 3 for the list of clinical laboratory tests to be performed and to the Schedule of 
Activities (Section 1.2) for the timing and frequency.  
The Investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the eCRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings are 
those that are not associated with the underlying disease unless judged by the Investigator to be 
out of range to a greater degree  than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study medication should be repeated until the 
values, stabilize, return to normal or Baseline, or are no longer considered clinically significant by 
the Investigator or Medical Monitor. 
• If such values do not return to normal/Baseline within a period judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor should be notified. 


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• All protocol-required laboratory assessments, as defined in Appendix 3, must be conducted 
in accordance with the laboratory manual and the Schedule of Activities (Section 1.2).  
• If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered 
clinically significant by the Investigator (eg, SAE, AE, dose interruption), then the results 
must be recorded in the eCRF.  
Any new or worsening of clinically significant abnormalities at Visit 6 (EOS) will be recorded as 
AEs. 
8.4 
Adverse Events 
All AEs will be recorded. At each post-Baseline Visit, subjects will also be questioned specifically 
about the status of any ongoing AEs. 
The definitions of an AE or SAE can be found in Appendix 4. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or 
the subject’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study medication or study procedures, or that caused the 
subject to discontinue the study (see Section 7.0). The trial blind may be broken for an individual 
only if knowledge of the IMP is essential for clinical management of the subject.  
8.4.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
All AEs and SAEs will be collected from signing the ICF until the Visit 6 (EOS) at the time points 
specified in the Schedule of Activities (Section 1.2). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obligated to actively seek AE or SAE information after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study medication or study participation, the Investigator must promptly notify the 
Sponsor. 
The methods of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 


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8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.4.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.6). Further 
information on follow-up procedures is given in Appendix 4. 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), 
and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and the Sponsor’s policy and forwarded to 
the Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.4.5 
Pregnancy 
A UPT will be performed at Visit 2 (Baseline), Visit 4, Visit 5, and Visit 6 (EOS) for WOCBP. 
Women who are pregnant or breastfeeding may not be administered TMB-001 ointment. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 6. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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8.4.6 
Adverse Events of Special Interest 
No events will be considered as AEs of special interest for this study. 
8.4.7 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Disease attributes that are associated with underlying disease condition should not be reported as 
AEs. Local skin reactions associated with retinoids should not be reported as AEs unless the LSRs 
required medical intervention or withholding application of study medication (refer Section 8.3.3 
for complete details). 
8.5 
Treatment of Overdose 
Overdose in this study can be defined as either oral ingestion of a tube of TMB-001 or applying 
the TMB-001 ointment more than the protocol specified regimen of twice daily. 
Oral ingestion of a tube of TMB-001 ointment 0.1% would result in less exposure than achieved 
with the recommended dosage of oral isotretinoin. Consequently, the theoretical occurrence of 
symptoms of overdosage (eg, hypervitaminosis A) is highly unlikely. 
If a subject does receive an overdose of TMB-001 ointment, the subject should be counseled about 
the teratogenicity of isotretinoin and counseled on the prevention of pregnancy. Any WOCBP must 
be evaluated for pregnancy and must be warned to avoid pregnancy per the contraceptive measures 
outlined in the protocol for at least 1 month after overdose. Men should use a condom or avoid 
reproductive sexual activity with a female who is or might become pregnant for at least 1 month 
after an overdose. Subjects who present with an overdose should not donate blood for at least 
1 month. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AEs, SAEs, and laboratory abnormalities for 1 month 
after the overdose. 
3. Obtain a plasma sample for pharmacokinetic analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 


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8.6 
Pharmacokinetics 
Pharmacokinetic parameters will not be evaluated in this study. 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters will not be evaluated in this study. 
8.8 
Genetics 
To be eligible for the study, subjects must have moderate to severe CI that has been genetically 
confirmed to be of either the ARCI-LI or RXLI subtype. For ARCI-LI subjects, enrollment is not 
limited to Transglutaminase 1 mutations. Other genetically confirmed ARCI-LI mutations can 
potentially be enrolled as long as the phenotype is consistent with ARCI-LI and the other inclusion 
criteria are met, as determined by the Investigator. Subjects requiring genetic test confirmation 
will have the testing performed by an independent laboratory after the Investigator or designee has 
determined they are likely to be otherwise eligible for enrollment. A buccal sample from the 
subject will be taken and sent to the laboratory for genotyping. Congenital Ichthyosis 
XomeDxSlice will be used to diagnose both RXLI and the ARCI-LI. subtype of CI. GeneDx tests 
detect transglutaminase mutations in the TGM1 gene, X-linked recessive steroid sulfatase 
mutations in the STS gene, and additionally analyzes 47 other genes linked to CI. This is a multi-
gene panel testing so that all known causes of CI can be confirmed/ruled-out since there is 
phenotypic overlap between the subtypes (including STS). The tests are considered Laboratory 
Developed Tests (LDTs) and are thus regulated per US regulations 42 CFR 493 and the laboratory 
is accredited by the College of American Pathologists. 
See Appendix 7 for Information regarding genetic research. 
8.9 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.10 Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
9.2 
Sample Size Determination  
This is the first study of TMB-001 using the VIIS index. No formal power calculations were 
performed to establish sample size since there were no VIIS response data available. A sample 


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size of 45 subjects (15 per treatment group) has been selected to provide initial data on VIIS 
response and to enable formal sample size calculations for future studies, as well as to assist in 
dose selection for Phase 3 study. 
9.3 
Populations for Analyses 
For purposes of analysis, the analysis sets are defined in Table 6. 
Table 6 
Analysis Sets 
Analysis Set 
Description 
Intent-to-Treat (ITT) Population 
All randomized subjects who received at least one dose of study medication . 
Subjects will be analyzed according to the treatment they are planned to 
receive according to the randomization schedule. 
Per-Protocol (PP) Population 
Subset of the ITT population consisting of subjects who 1) meet all 
inclusion/exclusion criteria that would affect the treatment evaluation, 
2) apply ≥ 80% but ≤ 120% of the planned doses of study treatment, 3) who 
had a VIIS measurement at Visit 6 (EOS), and 4) have no major protocol 
violations that would affect the treatment evaluation. The final definition of 
the PP population will be presented in the SAP. Subjects will be analyzed 
according to the treatment they are planned to receive according to the 
randomization schedule.   
Safety Population 
All subjects randomly assigned to study treatment and who take at least 1 dose 
of study medication. Subjects will be analyzed according to the treatment they 
actually receive. 
Abbreviations: ITT = intent-to-treat; PP = per-protocol; SAP = Statistical Analysis Plan. 
9.4 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the subject analysis sets to be included in the analyses and procedures for accounting for 
missing, unused, and spurious data. Efficacy analyses will be performed on both the intent-to-treat 
(ITT) and per-protocol (PP) populations with the ITT population considered primary. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. All statistical analyses and summaries will be prepared using SAS unless otherwise 
stated. 
Demographic and Baseline characteristics will be summarized by treatment group for the Safety, 
ITT, and PP populations. Frequency counts and percentages will be reported for categorical data 
and sample size, mean, median, standard deviation (SD), minimum (min), and maximum (max) 
will be reported for the continuous variables. 
All statistical analyses and summaries will be prepared using SAS unless otherwise stated. All 
subjects enrolled in the study who are dispensed and apply study medication at least once will be 
included in the analysis of safety and will be considered the Safety population. All randomized 


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subjects who received at least one dose of study medication will be considered the ITT population. 
The PP population will be a subset of the ITT population consisting of subjects who: 1) meet all 
inclusion/exclusion criteria that would affect the treatment evaluation, 2) apply ≥ 80% but ≤ 120% 
of the planned doses of study treatment, 3) who had a VIIS measurement at Visit 6 (EOS), and 
4) have no major protocol violations that would affect the treatment evaluation. The final definition 
of the PP population will be presented in the SAP. 
The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
• Continuous variables: sample size, mean, SD, median, min, and max. 
• Categorical variables: frequencies and percentages. 
Individual subject data will be presented in listings. 
9.4.1 
Efficacy Analyses 
All efficacy analyses will be performed on both the ITT and PP populations with the ITT 
population considered primary. Other post hoc analysis may be conducted using a modified ITT 
population. Any such analyses will be fully described in the SAP prior to database lock. 
9.4.1.1 
Primary Efficacy Endpoint 
The proportion of subjects achieving VIIS-50 (≥ 50% reduction from Baseline for VIIS scaling 
score for the sum of the scores for ‘VIIS body areas’ who had a Baseline score ≥ 3) at Visit 6 
(EOS) relative to Baseline will be the primary efficacy endpoint and time point used to compare 
active treatment to vehicle. Treatment groups will be compared at Visit 6 (EOS) using the 
Cochran-Mantel-Haenszel (CMH) Test stratified by CI subtype and corresponding 95% 
confidence intervals will be calculated for the difference in proportions for the treatment groups. 
9.4.1.2 
Secondary Efficacy Endpoints 
The proportion of subjects achieving IGA treatment success will be the key secondary endpoint. 
For this endpoint, the IGA score will be dichotomized to “treatment success” or “treatment 
failure” where “treatment success” is defined as at least a 2-grade decrease in severity score 
relative to Baseline. Active treatment will be compared with vehicle at Visit 6 (EOS) using the 
CMH test stratified by CI subtype and 95% confidence intervals will be calculated for the 
difference in proportions for the treatment groups. 
Additionally, one secondary endpoint is the time to achieve VIIS-50 that is maintained at the 
next observation. If VIIS-50 is first achieved at Visit 6 (EOS), then the endpoint is considered to 
have been met. A time to event analysis will be completed using the Kaplan-Meier method and 
log rank test to compare active treatment with vehicle. 


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For each of the other secondary efficacy endpoints (VIIS scaling, IGA, and I-NRS), the 
following summaries will be prepared at Visits 3, 4, 5, and 6 (EOS) (as applicable) by treatment 
group for each CI subtype and overall: 
• Frequency distribution of observed scores; 
• Frequency distribution of change from Baseline; 
• Shift tables for changes from Baseline to Visits 3, 4, 5, and 6; and, 
• Frequency distribution of treatment success rates. 
Success rates between treatment groups will be compared at Visit 6 (EOS) using the CMH Test 
stratified by CI subtype, and 95% confidence intervals will be calculated for the difference in 
proportions for the treatment groups. The VIIS scaling success is defined as a ≥ 50% reduction 
from Baseline for body sites that had a Baseline score ≥ 3. For IGA, success is defined as a 
≥ 2-point reduction from Baseline. For I-NRS, success is defined as ≥ 4-point reduction from 
Baseline. 
Descriptive statistics (including mean, median, SD, min, and max) for observed and change from 
Baseline values in the DLQI and percent BSA affected in the Treatment/Assessment Areas at each 
visit will be presented by treatment group for each CI subtype and overall.  
For VIIS and I-NRS, the treatment groups will be compared with respect to the change from 
Baseline using a mixed model of repeated measures (MMRM) including terms for treatment, visit, 
treatment by visit interaction, and the Baseline value serving as the covariate. From the model, the 
active to vehicle treatment differences will be estimated. Additionally, two-sided confidence 
intervals will be provided. 
9.4.2 
Safety Analyses 
All subjects enrolled in the study who were dispensed study medication and who applied study 
medication at least once will be included in the analysis of safety and will be considered the Safety 
population. 
All AEs reported during the study will be listed, documenting onset, whether therapy was required, 
any change in study treatment dosing, severity, possible relationship to study treatment, and 
outcome. Verbatim terms on the eCRFs will be linked to preferred terms (PTs) and system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) mapping system. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occur or worsen in 
severity after the first administration of study treatment and prior to 30 days after the last 
administration of study treatment. All reported TEAEs and incidence rates will be summarized by 
the number of subjects reporting AEs, SOC, PT, severity, and relationship to study treatment by 
treatment group. 


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Treatment-emergent AEs by maximum severity, TEAEs by relationship to study treatment, SAEs, 
TEAEs leading to death, and TEAEs leading to discontinuation of study treatment will be tabulated 
for each treatment group. Commonly occurring TEAEs, ie, those that occur in 5% or more of the 
subjects in either treatment group, will be summarized using descriptive statistics. 
All laboratory test results, vital signs measurements, and weight will be summarized for each 
treatment group using descriptive statistics for raw numbers and change from Baseline. The 
incidence of treatment-emergent abnormal laboratory and vital signs values will also be 
summarized using descriptive statistics. 
9.4.3 
Other Analyses  
9.4.3.1 
Physical Examinations 
Findings from physical examinations (head and neck, cardiovascular, dermatological, respiratory, 
gastrointestinal [abdomen], and gross motor and gait assessments) will be recorded in the medical 
history (from assessment at Visit 1 [Screening] and Visit 2 [Baseline]) or as AEs (from assessment 
at Visit 6 [EOS]). 
9.4.3.2 
Vital Signs 
Descriptive statistics of vital signs (temperature, systolic and diastolic blood pressure, heart rate, 
and respiration rate) at Visit 1 (Screening) and Visit 6 (EOS), and change from baseline, will be 
provided by treatment group. 
9.4.3.3 
Clinical Laboratory Tests 
Clinical laboratory tests will be evaluated for any material changes during the study period. All 
laboratory data (hematology, chemistry, and urinalysis) will be listed and reported in the units 
received by the laboratory. Summary tables by analyte and by out of range flag, at Visit 1 
(Screening) and Visit 6 (EOS), and change from baseline, will be presented to facilitate the 
evaluation of change from Visit 1 (Screening) to Visit 6 (EOS).  
9.4.3.4 
Urine Pregnancy Test 
The UPT results (if applicable) from Visit 2 (Baseline), Visit 4, Visit 5, and Visit 6 (EOS) will be 
provided in a listing. 
9.4.3.5 
Local Skin Reactions 
The LSRs (burning/stinging, erythema, erosions, and edema) and others will be summarized by 
frequency of each individual LSR for each treatment group. Change from Baseline in LSRs will 
be categorized into “worsened” and “same or improved” and will be tabulated. 


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9.4.4 
Missing Data 
Data summaries and analyses will use observed data only without imputation of missing values. 
Supplementary analysis will be performed to investigate the impact of data imputation on the 
primary endpoint as follows: 
1. By assuming that subjects with missing data are treatment successes (“best case”); and 
2. By assuming that subjects in the Vehicle group with missing data are “treatment success” and 
that subjects in the TMB-001 groups with missing data are treatment failures (“worst case”).  
3. By assuming that subjects with missing data maintain their last observed rating from which 
treatment success or failure will be derived at Visit 6 (“LOCF”). 
9.4.5 
Extent of Exposure 
The total amount of study medication used (grams of study medication applied) will be calculated 
from the weights of the returned study medications. Descriptive statistics (mean, median, SD, min, 
and max) will be determined for the total amount of study medication used by each subject by 
treatment group. 
9.4.6 
Dosing Compliance 
Descriptive statistics will be used to summarize study treatment compliance for the ITT population. 
A subject will be considered compliant with the dosing regimen if the subject applies at least 80% 
but no more than 120% of the expected number of applications or dose. 
Measures of overall study treatment compliance will include the duration of treatment (number of 
days dosed), the total number of applications (determined from the actual number of applications 
reported by the subject), quantity of dose, and the percent of expected doses applied. A subject 
will be considered compliant with the dosing regimen if the subject applies at least 80% but no 
more than 120% of the expected number of applications or dose. 
9.5 
Interim Analyses  
No interim analysis for efficacy is planned. 
9.6 
Monitoring Committee 
No Safety Monitoring Committee is planned for this study. 
 


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10.0 REFERENCES 
1. Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88:4-14. 
2. Takeichi T, Akiyama M. Inherited ichthyosis: Non-syndromic forms. J Dermatol. 
2016;43:242-51. 
3. Nomura K, Nakano H, Umeki K, et al. A study of the steroid sulfatase gene in families with 
X-linked ichthyosis using polymerase chain reaction. Acta Derm Venereol. 1995;75:340-2. 
4. Vahlquist A, Blockhuys S, Steijlen P, et al. Oral liarozole in the treatment of patients with 
moderate/severe lamellar ichthyosis: Results of a randomized, double-blind, multinational, 
placebo-controlled phase II/III trial. Br J Dermatol. 2014;170:173-81. 
5. Digiovanna JJ, Mauro T, Milstone LM, Schmuth M, Toro JR. Systemic retinoids in the 
management of ichthyoses and related skin types. Dermatol Ther. 2013;26:26-38. 
6. Isotrex® (isotretinoin) Gel, 0.05% (Australian Register of Therapeutic Goods Product 
Information). Abbotsford Victoria, Australia: GlaxoSmithKline Australia Pty Ltd; 2013. 
7. Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1:162-9. 
8. Blaner WS. Cellular metabolism and actions of 13-cis-retinoic acid. J Am Acad Dermatol. 
2001;45:S129-S135. 
9. Accutane® (isotretinoin) capsules, 10-mg, 20-mg, 40-mg (US Package Insert). Nutley, NJ: 
Roche Laboratories Inc; 1982. 
10. Isotrex® (isotretinoin) Cream, 0.05% (UK Package Leaflet). Uxbridge, Middlesex, UK: 
GlaxoSmithKline UK Limited; 2014. 
11. Burge SM, Buxton PK. Topical isotretinoin in Darier’s disease. Br J Dermatol. 
1995;133:924-8. 
12. Steijlen PM, Reifenschweiler DO, Ramaekers FC, et al. Topical treatment of ichthyoses and 
Darier’s disease with 13-cis-retinoic acid. A clinical and immunohistochemical study. Arch 
Dermatol Res. 1993;285:221-6. 
13. Chalker DK, Lesher JL Jr., Smith JG, Jr., et al. Efficacy of topical isotretinoin 0.05% gel in 
acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol. 
1987;17:251-4. 
14. Dominguez J, Hojyo MT, Celayo JL, Dominguez-Soto L, Teixeira F. Topical isotretinoin vs. 
topical retinoic acid in the treatment of acne vulgaris. Int J Dermatol. 1998;37:54-5. 


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15. Hughes BR, Norris JF, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, 
benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol. 
1992;17:165-8. 
16. Ioannides D, Rigopoulos D, Katsambas A. Topical adapalene gel 0.1% vs. isotretinoin gel 
0.05% in the treatment of acne vulgaris: a randomized open-label clinical trial. Br J 
Dermatol. 2002;147:523-7. 
17. Jensen BK, McGann LA, Kachevsky V, Franz TJ. The negligible systemic availability of 
retinoids with multiple and excessive topical application of isotretinoin 0.05% gel (Isotrex) in 
patients with acne vulgaris. J Am Acad Dermatol. 1991;24:425-8. 
18. 3136456. Risk evaluation and mitigation strategy (REMS): The iPLEDGE Program – single 
shared system for isotretinoin. Apr 2012. Accessed 15 Aug 2019. 
https://www.fda.gov/media/80023/download.  
 


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ARCI-LI 
Autosomal recessive congenital ichthyosis-lamellar ichthyosis 
β-hCG 
beta human chorionic gonadotropin 
bid 
Twice daily 
BSA 
Body surface area 
CFR 
Code of Federal Regulation 
CI 
Congenital ichthyosis 
CMH 
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
DLQI 
Dermatology Life Quality Index 
eCRF 
Electronic case report form 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormonal replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment 
I-NRS 
Itch-Numeric Rating Scale 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat  
IWRS 
Interactive Web Response System 
LI 
Lamellar ichthyosis 
LSR 
Local skin reaction 
Max 
Maximum 
MCID 
Minimal clinically important difference 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MMRM 
Mixed model of repeated measures 
PP 
Per-protocol population 
PT 
Preferred term 
RA 
Retinoic acid 
RXLI 
Recessive X-Linked ichthyosis 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit of Normal 
UPT 
Urine pregnancy test 
US 
United States 
UV 
Ultraviolet light 
VIIS 
Visual Index for Ichthyosis Severity 
VIIS-50 
Visual Index for Ichthyosis Severity – Scale “treatment 
success” 
WOCBP 
Women of childbearing potential 
 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
− Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the study center and adherence 
to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
• After reading the protocol, each Investigator will sign the protocol signature page and send 
a copy of the signed page to the Sponsor or representative (Appendix 8). The study will 
not start at any study center at which the Investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with enough, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 


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Insurance 
The Sponsor has obtained liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the 
insurance will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the subject 
or his/her legally authorized representative and answer all questions regarding the study.  
• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 Code of Federal Regulations (CFR) 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
• The Sponsor or its representative will not provide individual genotype results to subjects, 
any insurance company, any employer, their family members, general physician, or any 
other third party, unless required to do so by law. 
• Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a subject. For 
example, in the case of a medical emergency, the Sponsor or representative physician or 


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an Investigator might know a subject’s identity and have access to his or her genetic data. 
Also, regulatory authorities may require access to the relevant files. 
Administrative Structure 
The Sponsor of this study is Timber Pharmaceuticals, LLC (Address: 50 Tice Boulevard, Suite 
A26, Woodcliff Lake, NJ 07677). Study administrative structure including emergency contacts, 
Clinical Research Organization (CRO), Laboratory, and ancillary services can be found in the 
Investigator Study Binder. 
Medical Monitor 
David A. Amato, DO, FAAD 
IQVIA Biotech 
Phone +1 317-626-3143 
Email: david.amato@novellaclinical.com 
Study Site Initiation  
The Investigator must not screen any subject prior to completion of the study initiation visit, 
conducted by CRO. This initiation visit will include a detailed review of the protocol and study 
procedures. 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to the ClinicalTrials.gov database a summary 
of the results of the clinical study within 1 year from the end of the clinical study. It shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic case report 
forms (eCRFs) unless transmitted to the Sponsor or designee electronically (eg, laboratory 
data). The Investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and verifiable 


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from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may 
be transferred to another location or party without written notification to the Sponsor.  
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study center. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• Definition of what constitutes source data can be found in Investigator Study Binder. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further study treatment development. 


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Publication Policy 
• The results of this study in aggregate may be published or presented at scientific meetings. 
If this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary information and 
to provide comments. No individual site related study results will be allowed to be 
presented. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual study center 
data. In this case, a Coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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Appendix 3 
Clinical Laboratory Tests  
Subjects must be fasting (at least 8 hours) for Visit 1 (Screening) and, if possible, for Visit 6 (EOS); 
however, if a subject arrives at the clinic for Visit 6 (EOS) without fasting for at least 8 hours, 
laboratory specimens may be collected as non-fasting, at the discretion of the Investigator, and 
documented as such on the laboratory requisition form. 
• The tests detailed in Table 7 will be performed by the central laboratory.  
• Local laboratory results are only required if the central laboratory results are not available 
in time for either study treatment administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
treatment decision or response evaluation, the results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.0. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 7 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean Corpuscular Volume 
(MCV) 
Mean Corpuscular Hemoglobin 
(MCH) 
% Reticulocytes 
White Blood Cell Count 
with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red Blood Cell (RBC) Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen 
Potassium 
Aspartate Aminotransferase 
(AST)/Serum Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and 
Direct Bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/Serum Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose (Fasting) 
Calcium 
Alkaline Phosphatase 
 
Routine 
Urinalysis 
• 
Specific Gravity 
• 
pH, Glucose, Protein, Blood, Ketones, (Bilirubin, Urobilinogen, Nitrite, Leukocyte 
Esterase) by Dipstick 
• 
Microscopic Examination (if Blood or Protein Is Abnormal) 
Other Screening 
Tests 
• 
Urine Human Chorionic Gonadotropin (hCG) Pregnancy Test (as Needed for Women of 
Childbearing Potential)a 
• 
Serology (human immunodeficiency virus [HIV] Antibody) 


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Laboratory 
Assessments 
Parameters 
• 
All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of urine pregnancy testing. 
The results of each test must be entered into the (e)CRF. 
 


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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or subject, temporally associated with the use 
of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
Baseline, considered clinically significant in the medical and scientific judgment of the Investigator 
(ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the 
definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
 


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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject was at risk 
of death at the time of the event. It does not refer to an event that hypothetically might have caused death if 
it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is not 
considered an AE. 
d) Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Recording and Follow-Up of AE and/or SAE 


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AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. Each event must be 
recorded separately.  
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to IQVIA 
Biotech Safety in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by IQVIA 
Biotech Safety. In this case, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records before submission to IQVIA Biotech Safety. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering 
with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not 
be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and both AEs 
and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. The AE must be characterized as unrelated, unlikely to be related, possibly related, 
probably related, or unknown (unable to judge). 
o 
“Probably related” conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship, rather than a relationship cannot be ruled out. 
o 
“Possibly related” suggests that the association of the AE with the study treatment is 
unknown; however, the AE is not reasonably supported by other conditions. 
o 
“Unlikely to be related” suggests that only a remote connection exists between the study 
treatment and the AE. Other conditions, including chronic illness, progression or expression 
of the disease state or reaction to concomitant therapy, appear to explain the reported AE. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the 
AE.  
o 
All efforts should be made to classify the AE according to the above categories. The category 
“unknown” (unable to judge) may be used only if the causality is not assessable, eg, because 
of insufficient evidence, conflicting evidence, conflicting data, or poor documentation. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study treatment administration will be considered and 
investigated. 


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• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information 
to include in the initial report to IQVIA Biotech Safety. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial transmission of 
the SAE data to IQVIA Biotech Safety. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an 
SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-Up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by IQVIA Biotech Safety to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide IQVIA Biotech Safety with a copy of any postmortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor/IQVIA Biotech Safety within 24 
hours of receipt of the information. 
 
Reporting of SAEs 
SAE Reporting to IQVIA Biotech Safety via Paper CRF 
• 
E-mail transmission of the SAE paper CRF is the preferred method to transmit this information to 
IQVIA Biotech Safety with Facsimile transmission as back-up method. 
• 
In rare circumstances and in the absence of e-mail/facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE eCRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in  Investigator Study Binder. All SAEs must also be reported 
to IQVIA Biotech Safety within 24 hours of first awareness of the event. A paper SAE Report Form 
should be completed and submitted via e-mail to Safety-Inbox.Biotech@IQVIA.com or faxed to +1-
919-313-1412. 


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Appendix 5 
Excluded Medications/Therapy 
Excluded medications/therapy are listed in Section 5.2 and Section 6.5. The use of an excluded 
medication/therapy is a protocol violation and must be recorded in the eCRF. 
 


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Appendix 6 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Contraception Guidance 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 8 below. 


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Table 8 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
• 
Oral.  
• 
Intravaginal.  
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable.  
Highly Effective Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during 
the treatment period and for at least 30 days after the last dose of study treatment.  
 
Pregnancy Testing: 
• WOCBP will only be included in the study after a confirmed negative urine pregnancy test 
at Visit 2 (Baseline). The UPT must have a minimum sensitivity of 25 mIU beta human 
chorionic gonadotropin. 
• Additional pregnancy testing will occur at times specified in the schedule of assessments 
during the treatment period, at the Visit 6 (EOS), and as required locally. 
 


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Collection of Pregnancy Information 
Female subjects who become pregnant  
• The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a subject’s pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the subject and the neonate, and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in Section 8.4.5. 
While the Investigator is not obligated to actively seek this information in former subjects, 
he or she may learn of an SAE through spontaneous reporting.  
• Any female subject who becomes pregnant while participating in the study will be 
withdrawn from the study. 


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Appendix 7 
Genetics 
Use/Analysis of Deoxyribonucleic Acid (DNA) 
• Genetic variation may impact a subject’s response to study treatment, susceptibility to, and 
severity and progression of disease. Variable response to study treatment may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood/saliva /buccal 
sample will be collected for DNA analysis from consenting subjects. 
• DNA samples will be used for research related to topical iso tretinoin for treatment of 
congenital ichthyosis and related diseases. Genetic research may consist of the analysis of 
1 or more candidate genes or the analysis of genetic markers throughout the genome (as 
appropriate). 
• DNA samples will be analyzed to detect transglutaminase mutations in the TGM1 gene, 
X-linked recessive steroid sulfatase mutations in the STS gene. Additionally, analysis may 
be performed to look at other genes linked to CI. Further analyses may be conducted if it 
is hypothesized that this may help further understand the clinical data. 
• DNA samples will be analyzed using Congenital Ichthyosis XomeDxSlice to diagnose both 
RXLI and ARCI-LI. Additional analyses may be conducted if it is hypothesized that this 
may help resolve issues with the clinical data.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study treatment or study treatments of this class to understand 
study disease or related conditions. 
• The results of genetic analyses may be reported in the Clinical Study Report or in a separate 
study summary. 
• The DNA samples will be handled by an independent laboratory and will be destroyed 
upon the completion of study. They will be in a secure storage space with adequate 
measures to protect confidentiality. The tests are considered Laboratory Developed Tests 
(LDTs) and are thus regulated per US regulations 42 CFR 493 and the laboratory is 
accredited by the College of American Pathologists. 


CONFIDENTIAL 
Protocol 235-9051-202 - Amendment 1 
 
73 
Appendix 8 
Signature of Investigator 
PROTOCOL TITLE:  A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Safety and Efficacy of Two Concentrations of Topical TMB-001 for the Treatment 
of Congenital Ichthyosis  
PROTOCOL NO: 
235-9051-202 
VERSION:  
 
Original Protocol 
This protocol is a confidential communication of Timber Pharmaceuticals, LLC. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and that 
are consistent with Good Clinical Practices and the applicable laws and regulations. Acceptance 
of this document constitutes my agreement that no unpublished information contained herein will 
be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Center:               
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 
 


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74 
Appendix 9 
Dermatology Life Quality Index 
 


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75 
 
 


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76 
Appendix 10 
Children’s Dermatology Life Quality Index 
 


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77 
Appendix 11 
Itch-Numeric Rating Scale 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
                                     Version 1.0, 02 APR 2021 
Protocol No.: 235-9051-202 
Sponsor: Timber Pharmaceuticals, LLC 
 
CONFIDENTIAL 
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Page 1 of 33 
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Effective Date: 29 Apr 2019 
 
 
Statistical Analysis Plan – Timber Pharmaceuticals, LLC 
 
 
TITLE:  A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study to Evaluate the 
Safety and Efficacy of Two Concentrations of Topical TMB-001 for the Treatment 
of Congenital Ichthyosis 
 
 
 
STUDY SPONSOR: 
 
SPONSOR CONTACT: 
Timber Pharmaceuticals, LLC 
50 Tice Boulevard, Suite A26,  
Woodcliff Lake, NJ 07677  
 
Jessica Raiz, MPH 
Senior Director, Clinical Operations 
Timber Pharmaceuticals  
Phone: (973) 214-9208 
Email: jraiz@timberpharma.com 
 
 
 
 
 
 
 
 
 
Document History: 
 
 
 
Document 
Version 
Version Date 
Statistical Analysis Plan – Timber Pharmaceuticals 
Draft 0.1 
21 DEC 2020 
Statistical Analysis Plan – Timber Pharmaceuticals 
Draft 0.2 
25 FEB 2021 
Statistical Analysis Plan – Timber Pharmaceuticals 
Draft 0.3 
25 MAR 2021 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT: 
 
 
All information concerning the study drug supplied by the Sponsor in connection with this study, 
and not previously published, is considered confidential and proprietary information. This 
information includes the Investigator’s Brochure, clinical protocol, subject information and 
informed consent, and case report forms. This confidential information shall remain the sole 
property of the Sponsor, shall not be disclosed to others without prior written consent from the 
Sponsor and shall not be used except in the performance of this study. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by the Sponsor in connection with the development of the study 
drug. This information may be disclosed as deemed necessary by the Sponsor. 
 
 
 


 
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This Statistical Analysis Plan has been prepared by Avance Clinical Pty Ltd (Avance) for the 
Timber Pharmaceuticals study 235-9051-202. The contents of this procedure are confidential 
and reproduction, in part or whole, is not permitted without prior written permission from 
Avance and the Sponsor. The SAP has been approved before the database has been locked and 
the study has been unblinded. 
 
 
 
 
 
 
 
 
 
 
Prepared by:  
 
Date 
Bilyana Dabin 
Principal Biostatistician/Pharmacokineticist 
Avance Clinical Pty Ltd 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
Date 
René Kroon 
Biometrics Team Mgr/Sr Biostatistician 
Avance Clinical Pty Ltd 
 
 
 


 
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Approved by:  
 
Date 
Jessica Raiz, MPH 
Senior Director, Clinical Operations 
Timber Pharmaceuticals 
 
 
 
 
 
 
 
 
 
 
 
Approved by:  
 
Date 
Alan Mendelsohn, MD FACC 
CMO 
Timber Pharmaceuticals 
 
 


 
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TABLE OF CONTENTS 
 
1. 
Scope of the Statistical Analysis Plan.................................................................................... 6 
2. 
Abbreviations ......................................................................................................................... 6 
3. 
Relevant Avance Standard Operating Procedures and Guidances ........................................ 7 
4. 
Introduction ............................................................................................................................ 7 
4.1. 
Study Overview .......................................................................................................... 7 
4.2. 
Study Objectives ......................................................................................................... 7 
4.3. 
Study Design ............................................................................................................... 7 
4.4. 
Study Treatment .......................................................................................................... 8 
4.5. 
Sample Size ................................................................................................................ 8 
4.6. 
Study Endpoints .......................................................................................................... 8 
4.6.1  
Efficacy Endpoints ..................................................................................................... 8 
4.6.2  
Safety Endpoints ........................................................................................................ 9 
4.6.3 
Exploratory Endpoints ................................................................................................ 9 
5. 
Data Listings ........................................................................................................................ 10 
5.1. 
Sources of Data ......................................................................................................... 10 
5.2. 
Randomization and Subject Identification Code ...................................................... 10 
5.3. 
Maintaining the Study Blind ..................................................................................... 10 
5.4. 
Assessment Time Point Identifiers ........................................................................... 11 
5.5. 
Data Derived by Calculation .................................................................................... 11 
5.6. 
Handling of Missing Data ......................................................................................... 12 
5.6.1. 
Efficacy Missing Data Rules: .................................................................................... 12 
5.6.2. 
Adverse Events Missing Data Rules: ......................................................................... 12 
5.6.3. 
Baseline for safety assessments: ................................................................................ 13 
5.7. 
Use of Abbreviations ................................................................................................ 13 
6. 
Analysis Populations ............................................................................................................ 13 
6.1. 
Intent-to-Treat (ITT) Population ............................................................................... 13 
6.2. 
Per-Protocol (PP) Population .................................................................................... 14 
6.3. 
Safety Population ...................................................................................................... 14 
7. 
Subject Disposition/Background Data ................................................................................. 14 
7.1. 
Subject Disposition ................................................................................................... 14 
7.2. 
Baseline and Eligibility Assessments ....................................................................... 15 
7.3. 
Baseline Data Analysis ............................................................................................. 15 
8. 
Safety Data ........................................................................................................................... 15 
8.1. 
Safety Assessments ................................................................................................... 15 
8.2. 
Safety Data Presentation and Analysis ..................................................................... 16 
9. 
Efficacy Data ....................................................................................................................... 17 
9.1. 
Efficacy Data Presentation ....................................................................................... 17 
9.1.1. 
VIIS........................................................................................................................ 17 
9.1.2. 
IGA ........................................................................................................................ 17 
9.1.3. 
I-NRS ..................................................................................................................... 18 
9.1.4. 
DLQI ...................................................................................................................... 18 
9.1.5. 
Percent BSA affected ............................................................................................... 18 
9.2. 
Efficacy Analysis ...................................................................................................... 18 
9.2.1. 
Primary Efficacy Endpoint........................................................................................ 18 
9.2.2. 
Secondary Efficacy Endpoints .................................................................................. 18 
9.2.3. 
Exploratory Endpoints .............................................................................................. 20 
10. 
Pharmacokinetic/Pharmacodynamic Data ........................................................................... 23 


 
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11. 
Changes from the Analysis Planned in the Protocol ............................................................ 23 
12. 
Data Listings and Summary Tables ..................................................................................... 23 
12.1. Interim/Preliminary Data Analysis ........................................................................... 23 
12.2. Listings and Tables for Clinical Study Report ......................................................... 23 
12.3. Data Transfer to the Study Sponsor .......................................................................... 23 
13. 
General Considerations for Data Management and Analysis .............................................. 24 
13.1. Analysis Packages .................................................................................................... 24 
13.2. Electronic Data Management ................................................................................... 24 
13.3. Archiving .................................................................................................................. 24 
Appendix 1: Planned Data Listings ..................................................................................... 25 
Appendix 2: Planned Summary Tables ............................................................................... 27 
 
 
 


 
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1. SCOPE OF THE STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan is an adjunct to Timber Pharmaceuticals Protocol No. 235-
9051-202 Amendment 1 dated 05 August 2020. The Statistical Analysis Plan details the 
procedures for the statistical methods used in the presentation and analysis of the clinical 
study data. 
2. ABBREVIATIONS 
ADaM  
 
Analysis Data Model 
AE 
 
Adverse event 
ARCI-LI   
Autosomal recessive congenital ichthyosis-lamellar ichthyosis  
BSA 
 
Body Surface Area 
BMI 
 
Body mass index 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CI 
 
Congenital ichthyosis 
CMH 
 
Cochran-Mantel-Haenszel 
CRF 
        Case report form 
DEC 
 
Dose escalation committee  
DLQI 
 
Dermatology Life Quality Index 
EOS 
 
End of Study 
ICH 
 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
 
Investigator’s Global Assessment 
I-NRS 
 
Itch-Numeric Rating Scale 
IWRS 
 
Interactive Web Response System 
IP 
 
Investigational Product  
ITT 
 
Intent-to-treat 
LSR 
 
Local skin reaction 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM   
Mixed Model Repeated Measures  
PP 
 
Per-Protocol 
QC 
 
Quality control 
RXLI 
 
Recessive X-Linked ichthyosis 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SDTM 
 
Standard Data Tabulation Model 


 
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SOP 
 
Standard operating procedure 
VIIS 
 
Visual Index for Ichthyosis Severity 
 
3. RELEVANT AVANCE STANDARD OPERATING PROCEDURES AND 
GUIDANCES 
The following Avance SOPs and regulatory guidances are relevant to this Statistical 
Analysis Plan: 
 SOP-BIOM-0002 Clinical Data Analysis and Presentation  
 SOP BIOM-0003 Blinding: Codes and Code Breaking 
 SOP-BIOM-0004 Randomisation Generation  
 SOP-BIOM-0009 Statistical Analysis Plans  
 ICH: Statistical Principles for Clinical Trials (ICH E9, Current Step 4 version 
dated 5 February 1998)  
4. INTRODUCTION 
4.1. 
Study Overview 
Timber Pharmaceuticals, LLC, is developing a topical ointment (0.05% and 0.1%) 
formulation of isotretinoin called TMB-001 (previously PAT-001) (isotretinoin) ointment 
for the treatment of congenital ichthyosis (CI), including recessive X-linked ichthyosis 
(RXLI) and autosomal recessive congenital ichthyosis-lamellar ichthyosis (ARCI-LI) 
subtypes. The purpose of this study is to investigate the efficacy and safety of these two 
concentrations of topically applied TMB-001 in subjects 9 years of age and older. 
4.2. 
Study Objectives 
 To investigate the efficacy of two concentrations of topically applied TMB-001 as a 
treatment for congenital ichthyosis (CI) of either the autosomal recessive congenital 
ichthyosis-lamellar ichthyosis (ARCI-LI) or RXLI subtypes. 
 
 To investigate the safety of topically applied TMB-001. 
 
4.3. 
Study Design 
This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety 
and efficacy of two concentrations of topical TMB-001 for the treatment of CI in subjects 
with either the ARCI-LI or RXLI subtypes. 
11 study centers from United States of America and Australia are expected to participate 
in this global study. 
The duration of treatment will be 12 weeks. 


 
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Each subject will participate in the study for up to 24 weeks (including up to a 90-day 
Screening period). 
4.4. 
Study Treatment 
 
Investigational Product 
Name  
Dosage of 
study 
medication? 
Dose 
Frequency  
Route of Administration  
TMB-001 
0.05% 
BID  
Topical  
TMB-001 
0.1% 
BID  
Topical 
Vehicle Ointment (Control) 
0% 
BID 
Topical 
4.5. 
Sample Size 
This is the first study of TMB-001 using the VIIS index. No formal power calculations 
were performed to establish sample size since there were no VIIS response data available. 
A sample size of 45 subjects (15 per treatment group) has been selected to provide initial 
data on VIIS response and to enable formal sample size calculations for future studies, as 
well as to assist in dose selection for Phase 3 study. 
4.6. 
Study Endpoints 
 
4.6.1  Efficacy Endpoints 
 
4.6.1.1 Primary Efficacy: 
 Proportion of subjects with VIIS "treatment success" (VIIS-50), which is defined 
as a 50% or greater decrease at Visit 6 (EOS) relative to Baseline in the sum of 
the scores for VIIS target sites that have a Baseline score of ≥ 3.  
 
4.6.1.2 Key Secondary Efficacy: 
 Proportion of subjects achieving IGA treatment success, where “treatment 
success” is defined as at least a 2-grade decrease in IGA severity score relative to 
Baseline at Visit 6 (EOS). 
 
4.6.1.3  Other Secondary Efficacy: 
 Time to achieve VIIS-50 (≥ 50% reduction in VIIS scaling score for body sites 
that had a Baseline score ≥ 3) that is maintained at the next observation.  
 Changes in VIIS scaling score relative to Baseline at Visit 4 and Visit 5. 
 Changes in percent BSA with CI relative to Baseline in the Treatment and 
Assessment Areas at Visit 3, Visit 4, Visit 5, and Visit 6 (EOS). 
 Proportion of subjects with IGA “treatment success” at Visit 4, Visit 5, and 
Visit 6 (EOS).  
 Proportion of subjects with an IGA score of 0 or 1 representing “cleared” or 
“almost cleared” at Visit 6 (EOS).   


 
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 Proportion of subjects with I-NRS “treatment success” where “success” is defined 
as at least a 4-point reduction in I-NRS relative to Baseline at Visit 6 (EOS). 
 Change from Baseline in I-NRS score at Visit 6 (EOS). 
 Change in DLQI from Baseline to Visit 6 (EOS). 
4.6.2  Safety Endpoints 
 Incidence (severity and causality) of any local skin reactions (LSRs) and systemic 
AEs.  
 Number of subjects with presence (and severity) at each time point of the 
following LSRs: burning/stinging, erythema, erosions, and edema. 
 Changes from Baseline in vital signs at Visit 6 (EOS). 
 Changes from Baseline in clinical laboratory test results (chemistry, hematology, 
and urinalysis) at Visit 6 (EOS). 
 AEs and SAE reported (severity, relatedness etc) 
4.6.3 Exploratory Endpoints 
 
 Time to 2 or more points decrease from baseline in IGA 
 Time to achieve a score of 0 for both IGA and VIIS scaling 
 Time to achieve a score of 1 for both IGA and VIIS scaling 
 Kapa agreement analysis for VIIS and IGA scores at each visit 
 Correlation of IGA scores and VIIS scaling at each visit 
 Correlation of IGA scores and VIIS target sites scores at each visit 
 Proportion of subjects with VIIS treatment success by body region 
 Proportion of subjects with VIIS treatment success by genetic mutation 
 Proportion of subjects with IGA treatment success by genetic mutation 
 Proportion of subjects with VIIS treatment success by phenotype 
 Proportion of subjects with IGA treatment success by phenotype 
 Proportion of subjects with VIIS treatment success by drug/BSA ratio 
 Proportion of subjects with IGA treatment success by drug/BSA ratio 
 Proportion of subjects with VIIS treatment success by drug/BMI ratio 
 Proportion of subjects with IGA treatment success by drug/BMI ratio 
 Proportion of subjects with VIIS treatment success by drug/kg ratio 
 Proportion of subjects with IGA treatment success by drug/kg ratio 
 Proportion of subjects with VIIS treatment success by Baseline BSA Stratification 
 Proportion of subjects with IGA treatment success by Baseline BSA Stratification 
 Proportion of subjects with VIIS treatment success by OTC steroid cream usage 
 Proportion of subjects with IGA treatment success by OTC steroid cream usage 
 Proportion of subjects with VIIS treatment success by assessment medium 
 Proportion of subjects with IGA treatment success by assessment medium 
 Proportion of subjects with VIIS treatment success by drug interruption 
 Proportion of subjects with IGA treatment success by drug interruption 
 Proportion of subjects who meet both the primary and major secondary endpoint 
 Proportion of subjects who achieve VIIS->75 at target body sites  


 
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 Proportion of subjects who achieve VIIS->50 at non-target body sites 
 Changes from Baseline in VIIS scaling, Active Vs Vehicle – MMRM analysis 
 Changes from Baseline in I-NRS score, Active Vs Vehicle – MMRM analysis 
 
5. DATA LISTINGS  
5.1. 
Sources of Data 
Data sets containing raw data will be provided by the Data Management group, extracted 
from the clinical study database of data entered into a Case Report Form (CRF). It is 
assumed that the database will contain the data from Screening through to the Follow-up 
Safety Visit of the study. Minimal information will be captured for screen failures. 
Analysis datasets (SDTM and ADaM) will be generated from the data extracted from the 
study database, along with the following data entered separately or received from other 
sources: 
 Randomization, from statistician responsible for its preparation 
 Clinical laboratory safety data, provided by the clinical laboratory to Data 
Management at Avance Clinical 
All data entered into the CRF or provided from other sources as described above will be 
presented (explicitly or implicitly) in data listings or figures as described in Appendix 1. 
5.2. 
Randomization and Subject Identification Code 
Subjects who meet all inclusion criteria and no exclusion criteria will be randomized to a 
treatment group in a 1:1:1 ratio, stratified by CI subtype.  
All subjects will be centrally assigned to randomized study treatment using an Interactive 
Web Response System (IWRS). Before the study is initiated, the log in information and 
directions for the IWRS will be provided to each study center. 
Study medication use will be accounted and dispensed at the study visits as summarized in 
the Schedule of Activities (Section 1.2 of the protocol).  
Subjects will be assigned a randomization number formatted, Rsnn where s is an 
indicator for the CI subtype (1 = ARCI-LI, 2 = RXLI) and nn is the random permutation 
of 01 - 45. 
The listings for inclusion in an appendix to the clinical study report will be prepared after 
the study has been unblinded.  
In the listings, subjects will be identified by subject number (assigned at randomization), 
with treatment as a secondary grouping identifier. Screening number will be shown only 
on the listing of informed consent data and screen failure data. 
5.3. 
Maintaining the Study Blind  
In this double-blind study, all personnel involved, i.e., physicians, site staff, and subjects 
will remain blinded at all times, except in an emergency, where knowledge of the 


 
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randomization code is required to provide appropriate treatment. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a subject’s 
treatment assignment is warranted. Subject safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, every 
effort should be made to contact the Sponsor and Medical Monitor prior to unblinding a 
subject’s treatment assignment unless this could delay emergency treatment of the subject. 
If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 24 
hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and electronic Case Report Form (eCRF), as 
applicable. 
5.4. 
Assessment Time Point Identifiers 
In the data listings for the report, scheduled assessment time points will be identified as 
follows: 
 Scheduled safety assessments will be identified by treatment group, study day, and 
also nominal study time point, where relevant. 
 Assessments at Screening and End of Study will be identified as such for both study 
day and time-point, as appropriate. 
5.5. 
Data Derived by Calculation 
The following data fields for inclusion in the data listings will be derived by calculation 
as per clinical data interchange standards consortium (CDISC) standard: 
 Treatment-emergent Indicator for adverse event, assigned as 
Treatment-Emergent if  
  (Onset Date + Onset Time) >= (Date of First Dose + Time of First Dose) 
 
Non Treatment-Emergent if 
  (Onset Date + Onset Time) < (Date of First Dose + Time of First Dose) 
 Adverse event time since first dose (in days, to two decimal places), calculated as  
(Onset Date + Onset Time) – (Date of First Dose + Time of First Dose) 
AE Duration: 
 Adverse event duration (in days, to two decimal places), calculated as  
(Resolution Date + Resolution Time – Onset Date - Onset Time) 
Safety Assessments Change from Baseline: 
 Baseline for Vital Signs and serum clinical laboratory parameters will be the most 
recent scheduled assessment prior to first dose  
Clinical Safety Laboratory Assessments: 
 If a clinical laboratory result is above the upper limit of normal, then Out of Range 
flag will be set to “H” 


 
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 If a clinical laboratory result is below the lower limit of normal, then Out of Range 
flag will be set to “L” 
 Clinical Laboratory parameters that are outside the reference range and assessed by 
the Principal Investigator as clinically significant will be identified as 
“Abnormal CS” 
 Clinical Laboratory parameters that are outside the reference range and assessed by 
the Principal Investigator as not clinically significant will be identified as 
“Abnormal NCS” 
5.6. 
Handling of Missing Data 
5.6.1. Efficacy Missing Data Rules: 
Data summaries and analyses will use observed data only without imputation of missing 
values. Supplementary analysis will be performed to investigate the impact of data 
imputation on the primary endpoint as follows: 
1) by assuming that subjects with missing data are treatment successes (“best case”) 
and 
2) by assuming that subjects in the vehicle group with missing data are “treatment 
success” and that subjects in the TMB-001 groups with missing data are treatment 
failures (“worst case”) and 
3) by assuming that subjects with missing data maintain their last observed rating 
from which treatment success or failure will be derived at Visit 6 (“LOCF”) and 
4) by assuming that subjects with missing data are treatment failures (“non-
responder”) 
 
5.6.2. Adverse Events Missing Data Rules: 
For adverse events with unknown intensity (severity) or unknown relationship to study 
treatment, these will be imputed as follows: 
 
If the intensity (severity) of an adverse event is unknown/missing, the intensity will 
be imputed for the summary of adverse events as being the highest intensity that is 
not immediately life-threatening or resulting in death, i.e. “Severe”.  
 
If the relationship to investigational product of an adverse event is 
unknown/missing, and the adverse event onset occurred after first dose, or if onset 
date/time is unknown and it cannot be determined if onset occurred prior to dosing 
the relationship will be imputed for the summary of adverse events as related.  
For adverse events, where either the onset time or resolution time is unknown, time 
since first dose and duration will be imputed as follows: 
 
If onset date is unknown, and it cannot be confirmed that onset was prior to the start 
of dose administration, then the AE will be classified as treatment-emergent, with 
unknown time since first dose. 


 
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 
If either the date of onset or the date of resolution is unknown, then duration will be 
shown as unknown. 
 If onset time is unknown: 
o If the date of onset is known to be the date of first dose administration, and it is 
confirmed by a CRF comment or communication with the site that onset was 
prior to the start of dose administration, then the AE will be classified as not 
treatment-emergent. 
o If the date of onset is known to be same as the date of first dose administration, 
and it is confirmed by a CRF comment or communication with the site that 
onset was after the start of dose administration, then the AE will be classified 
as treatment-emergent and the time since first dose will be shown on the listing 
as “<1” day. 
o If the date of onset is known to be later than the date of first dose 
administration, then Time since first dose will be determined as the number of 
days since first dose, shown on the listing as “~n” days, where n is the number 
of days difference between the date of dose administration and the date of 
onset. 
 If either the onset time or resolution time is unknown: 
o If the date of onset and the date of resolution are known to be the same, then 
Duration will be shown on the listing as “<1” day. 
o If the date of onset and the date of resolution are known and are different, then 
Duration will be determined as the number of days difference between the date 
of onset and the date of resolution, shown on the listing as “~n” days. 
5.6.3. Baseline for safety assessments: 
 
Missing values for safety assessments will not be imputed. If change from baseline 
is to be determined and the pre-dose baseline assessment is missing, then the 
previous scheduled result (e.g. Screening) will be used as the baseline. However, if 
the baseline is missing due to technical reasons and a subsequent unscheduled pre-
dose assessment is used to confirm eligibility, this unscheduled assessment may be 
used as baseline. 
5.7. 
Use of Abbreviations 
Any abbreviations used in data listings will be included in the key in a footnote, as 
appropriate. 
6. ANALYSIS POPULATIONS 
6.1. 
Intent-to-Treat (ITT) Population  
All randomized subjects who received at least one dose of study medication will be 
included in the ITT population. Subjects will be analysed according to the treatment they 
are planned to receive according to the randomization schedule. The ITT population will 
be used for the analysis and presentation of all efficacy data.  


 
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6.2. 
Per-Protocol (PP) Population  
Subset of the ITT population consisting of subjects who 1) meet all inclusion/exclusion 
criteria that would affect the treatment evaluation, 2) apply ≥ 80% but ≤ 120% of the 
planned doses of study treatment, 3) who had a VIIS measurement at Visit 6 (EOS), and 
4) have no major protocol violations that would affect the treatment evaluation. Subjects 
will be analysed according to the treatment they are planned to receive according to the 
randomization schedule. All efficacy data will be analysed using the PP population.  
6.3. 
Safety Population 
All subjects randomly assigned to study treatment and who take at least 1 dose of study 
medication will be included in the Safety Population. Subjects will be analysed according 
to the treatment they actually receive. Safety data will be presented for all subjects in the 
safety analysis set and summarised by dose level / treatment group. 
Subject disposition and background data, including demographics, relevant background 
and participation data, will be presented for all subjects in the safety analysis set. 
Subjects who are assigned a randomization number but withdraw prior to dosing will not 
be included in the safety analysis set. Available details of their participation and reason 
for withdrawal will be listed separately. 
 
7. SUBJECT DISPOSITION/BACKGROUND DATA 
7.1. 
Subject Disposition  
Subject disposition and administration procedures recorded in the CRF are as follows: 
 Written informed consent 
 Randomization 
 Administration of IP 
 Study completion /discontinuation 
 Protocol deviations 
 Additional comments 
Details of participation and inclusion in analysis populations will be listed by subject. 
Completion status will be summarised by dose level / treatment group. 
Details of administration of IP will be listed by subject. Exposure to IP will be 
summarised by dose level / treatment group. Descriptive statistics will be used to 
summarize study treatment compliance for the ITT population. A subject will be 
considered compliant with the dosing regimen if the subject applies at least 80% but no 
more than 120% of the expected number of applications or dose. 
Protocol deviations will be listed by subject.  
Screen failures will be listed by subject. Demography, screen failure details, eligibility 
criteria, and any SAEs will be listed for screen failures. 


 
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7.2. 
Baseline and Eligibility Assessments 
Baseline and eligibility assessments are as follows:  
 Demographic details 
 Medical and surgical history 
 Physical examination 
 Eligibility 
 Genetic testing 
 Serology (HIV) 
 Urine pregnancy tests 
 Assessments at screening and up to pre-dose baseline of safety assessments 
performed throughout the study, including physical examinations and vital signs 
7.3. 
Baseline Data Analysis 
Demographic and Baseline characteristics will be summarized by treatment group for the 
Safety, ITT, and PP populations. Frequency counts and percentages will be reported for 
categorical data and sample size, mean, median, standard deviation (SD), minimum (min), 
and maximum (max) will be reported for the continuous variables. 
8. SAFETY DATA 
8.1. 
Safety Assessments 
Safety assessments are as follows:  
 Adverse events and concomitant medications used: 
o Continuous monitoring throughout the study period 
 Vital signs including temperature, systolic and diastolic blood pressure, heart rate, 
and respiration rate will be measured at Visit 1 (Screening) and Visit 6 (EOS).  
 Clinical laboratory tests:  
o Clinical Chemistry: Blood Urea Nitrogen, Creatinine, Glucose (Fasting), 
Potassium, Sodium, Calcium, Aspartate aminotransferase (AST)/ Serum 
Glutamic-Oxaloacetic Transaminase (SGOT), Alanine aminotransferase 
(ALT)/Serum Glutamic-Pyruvic Transaminase (SGPT), Alkaline Phosphatase, 
Total and Direct Bilirubin and Total Protein 
o Hematology: Platelet Count, Red Blood Cell (RBC) Count, Haemoglobin, 
Hematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular 
Hemoglobin (MCH), % Reticulocytes, lymphocytes, monocytes, eosinophils, 
basophils, neutrophils 
o Routine Urinalysis: Specific Gravity, pH, Glucose, Protein, Blood, Ketones, 
(Bilirubin, Urobilinogen, Nitrite, Leukocyte Esterase) by Dipstick, 
Microscopic Examination (if Blood or Protein Is Abnormal) 


 
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o Serology: human immunodeficiency virus [HIV] Antibody 
o Drug and alcohol screen: Opiates, methadone, cocaine, amphetamines 
(including ecstasy), cannabinoids, barbiturates, benzodiazepines, tricyclic 
antidepressants, and alcohol  
o Pregnancy test (Women of Childbearing Potential): Urine Human Chorionic 
Gonadotropin (hCG) Pregnancy Test 
 Physical examination: A brief physical examination will be performed at Visit 1 
(Screening). Abbreviated examination/ subject disposition will be conducted at Visit 2 
(Baseline) to identify any changes since the Screening visit and at Visit 6 EOS to assess 
for any changes during the study. The examination will evaluate head and neck, 
dermatological, cardiovascular, respiratory, gastrointestinal (abdomen), and gross motor 
and gait body assessments. Abnormalities at Visit 1 (Screening) and Visit 2 (Baseline) 
prior to treatment will be recorded as medical history. Any new or worsening 
abnormalities at Visit 6 (EOS) will be recorded as AEs. 
 Local Skin Reactions (LSRs) known to be associated with retinoids (burning/stinging, 
erythema, erosions, and edema) or other causes regardless of blinded causality 
assessment within the areas treated with study medication will be evaluated at every 
study visit (except Screening), using a 4-point ordinal scale where 0 = none, 1 = mild, 
2 = moderate, and 3 = severe. 
8.2. 
Safety Data Presentation and Analysis 
All clinical safety and tolerability data will be listed for each subject.  
Safety data will be presented for all subjects in the safety analysis set and summarised by 
dose level / treatment group.  
Safety data will be summarized descriptively in tabular form. Summaries of key safety data 
assessed over time may also be presented in graphical form, as appropriate. Where 
summaries include changes from baseline, the relevant baseline value will be determined 
as described in Section 5.5 above.  
All treatment-emergent adverse events reported in this study will be presented using 
MedDRA terms, as coded per the Data Management Plan.  AEs and SAEs with onset 
following administration of the investigational product will be summarised by dose level / 
treatment, grouped according to system organ class and preferred term, and tabulated with 
descriptive statistics, where appropriate, for number of subjects and number of AEs per 
category, for all AEs and for AEs deemed drug-related. AEs will also be summarised by 
severity and by relationship to investigational product. Where a subject has more than one 
AE for the same MedDRA category, the subject will be counted only once, for the AE of 
highest severity or least favourable relationship. 
Prior and concomitant medication will be coded using the WHO Drug Dictionary 
(WHODrug), as coded per the Data Management Plan. The number and percentage of 
subjects taking prior medication, and concomitant medication will be summarised using 
frequency tables according to WHO Drug ATC Level 1 Code Description and the WHO 
Drug Dictionary Preferred Name. If a subject has more than one prior or concomitant 
medication coded to the same category, the subject will be counted only once. 


 
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Clinical laboratory parameters will be tabulated and summarised by dose level / treatment 
group and study time point.  A summary of changes from baseline will also be presented 
for clinical laboratory parameters. Medical assessments of blood and urine parameters will 
be summarised by treatment group and study time point.  Individual subject profiles will 
be presented for any laboratory parameters with at least one post-dose value outside the 
laboratory’s reference ranges and deemed clinically significant. 
Vital signs (systolic/diastolic blood pressure, heart rate, body temperature and respiratory 
rate) will be tabulated and summarised by dose level / treatment and study time point, 
separately for supine and standing. A summary of changes from baseline will also be 
presented.   
Changes from screening or previous visit in physical examination findings will be listed 
for each subject. It is noted that any untoward findings identified on physical and 
neurological examinations after the start of administration of the study medication will be 
captured as an adverse event if those findings meet the definition of an adverse event as 
defined in the protocol. 
 
Local skin reactions (LSRs) (including burning/stinging, erythema, erosions, and edema) 
will be summarized by frequency of each individual LSR for each treatment group. 
Change from Baseline in LSRs will be categorized into ‘worsened’ and ‘same or 
improved’ and will be tabulated.  
 
9. EFFICACY DATA  
9.1. 
Efficacy Data Presentation  
9.1.1. VIIS 
VIIS scores will be listed, for each body area, per subject, per visit. Body areas will be 
identified as target or non-target and this information will be provided in the individual 
listing as well. Descriptive statistics (including frequencies and percentages) for 
observed, change from Baseline values in VIIS scaling at each visit, success rate, as well 
as a shift table will be presented by treatment group for each CI subtype and overall. VIIS 
scaling is defined as the average of the severity scores for the VIIS body areas, where the 
numerator is the sum of the severity scores and denominator is the number of body areas 
assessed at that visit. Success is defined as a ≥ 50% reduction at Visit 6 relative to 
Baseline in the sum of VIIS scores for target body sites that had a Baseline score ≥ 3. 
That is, a participant is flagged as treatment success if, at Visit 6 (or EOS), the sum of the 
VIIS scores for the same target body sites identified at Baseline is ≥ 50% lower than the 
sum of VIIS scores for these target body sites at Baseline. Results from 
Cochran-Mantel-Haenszel test at Visit 6 (EOS) will be presented together with 
corresponding 95% confidence intervals. Time from baseline to treatment success will be 
estimated using KM analysis and individual results will be listed and summarized using 
descriptive statistics.   
9.1.2. IGA 
IGA scores will be listed per subject, per visit. Descriptive statistics (including 
frequencies and percentages) for observed, change from Baseline values in IGA at each 


 
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visit, success rate, as well as a shift table will be presented by treatment group for each CI 
subtype and overall. Success is defined as a at least 2-grade decrease in severity score 
relative to baseline. Time from baseline to treatment success will be estimated using KM 
analysis and individual results will be listed and summarized using descriptive statistics.   
9.1.3. I-NRS 
I-NRS scores at each visit and change from baseline at each visit will be listed per subject 
for Visit 2 (Baseline), Visit 5, and at Visit 6 (EOS). Descriptive statistics (including 
frequencies and percentages) for observed and change from Baseline values in I-NRS at 
each visit, success rate as well as a shift table will be presented by treatment group for 
each CI subtype and overall. Success is defined as ≥ 4-point reduction from Baseline. 
Results from Cochran-Mantel-Haenszel test at Visit 6 (EOS) will be presented together 
with corresponding 95% confidence intervals.  
9.1.4. DLQI 
DLQI scores will be listed per subject for Visit 2 (Baseline), Visit 5, and at Visit 6 (EOS). 
Descriptive statistics (including mean, median, SD, min, and max) for observed and 
change from Baseline values in DLQI at each visit will be presented by treatment group 
for each CI subtype and overall. Subgroup analysis using descriptive statistics for 
observed and change from baseline values in DLQI at each visit will be performed on 
subjects with DLQI less than 10 and greater or equal to 10 at baseline. The same 
subgroup analysis will be performed for CDLQI values, where the subgroups will be: a 
score less than 13 on CDLQI at baseline vs score of 13 or more on CDLQI at baseline. 
Proportion of subjects with DLQI improvement of 4 or greater points from baseline will 
be described using frequency tables.  
9.1.5. Percent BSA affected 
Descriptive statistics (including mean, median, SD, min, and max) for observed and 
change from Baseline values in percent BSA affected in the Treatment/Assessment Areas 
at each visit will be presented by treatment group for each CI subtype and overall. 
9.2. 
Efficacy Analysis 
Efficacy analyses will be performed on both the ITT and PP populations with the ITT 
population considered primary. 
9.2.1. Primary Efficacy Endpoint 
The proportion of subjects achieving VIIS-50 (≥ 50% reduction from Baseline for VIIS 
scaling score for the sum of the scores for ‘VIIS target body areas’ who had a Baseline 
score ≥ 3) at Visit 6 (EOS) relative to Baseline will be the primary efficacy endpoint. 
Treatment groups will be compared at Visit 6 (EOS) using the Cochran-Mantel-Haenszel 
(CMH) Test stratified by CI subtype and corresponding 95% confidence intervals will be 
calculated for the difference in proportions for the treatment groups. The proportion of 
subjects achieving VIIS-50 will be the response variable in the CMH test.  
9.2.2.  Secondary Efficacy Endpoints 
 The proportion of subjects achieving IGA treatment success will be the key 
secondary endpoint. The IGA score will be dichotomized to “treatment success” or 


 
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“treatment failure” where “treatment success” is defined as at least a 2-grade decrease 
in severity score relative to Baseline. Active treatment will be compared with vehicle 
at Visit 6 (EOS) using the CMH test stratified by CI subtype and 95% confidence 
intervals will be calculated for the difference in proportions for the treatment groups.  
 
Other Secondary Endpoints: 
 The time to achieve VIIS-50 (≥ 50% reduction in VIIS scaling score for body sites 
that had a Baseline score ≥ 3) that is maintained at the next observation. If VIIS-50 is 
first achieved at Visit 6 (EOS), then the endpoint is considered to have been met. A 
time to event analysis will be performed using the Kaplan-Meier (K-M) method and 
log rank test to compare active treatment with vehicle. The results from K-M analysis 
will be tabulated as well as graphically presented.  
 
 Changes in VIIS scaling score relative to Baseline at Visit 4 and Visit 5: 
The treatment groups will be compared with respect to the change from Baseline 
using mixed model of repeated measures (MMRM) including terms for treatment, 
visit, treatment by visit interaction, and the Baseline VIIS scaling score serving as the 
covariate. VIIS scaling score is defined as the average score of grades for all body 
areas assessed at that visit. From the model, the active to vehicle treatment 
differences will be estimated. Additionally, two-sided confidence intervals will be 
provided. 
 Proportion of subjects with IGA “treatment success” at Visit 4, Visit 5, and Visit 6 
(EOS):  
Descriptive statistics (including frequencies and percentages) for IGA success rate 
will be presented by treatment group for each CI subtype and overall. Success is 
defined as a ≥ 2-point reduction in IGA score from Baseline. 
 Proportion of subjects with IGA score representing “cleared” or “almost cleared” at 
Visit 6 (EOS): 
Descriptive statistics (including frequencies and percentages) for IGA scores 
representing “cleared” or “almost cleared” will be presented by treatment group for 
each CI subtype and overall. “Cleared” or “Almost cleared” is defined as an IGA 
score of 0 or 1. 
 Changes in percent BSA relative to Baseline with CI in the Treatment/Assessment 
Areas at Visit 3, Visit 4, Visit 5, and Visit 6 (EOS): 
Descriptive statistics (including mean, median, SD, min, and max) for observed and 
change from Baseline values in percent BSA at each visit will be presented by 
treatment group for each CI subtype and overall. 
 Change from Baseline in Itch-Numeric Rating Scale (I-NRS) score at Visit 6 (EOS):  
The treatment groups will be compared with respect to the change from Baseline 
using mixed model of repeated measures (MMRM) including terms for treatment, 
visit, treatment by visit interaction, and the Baseline I-NRS value serving as the 
covariate. From the model, the active to vehicle treatment differences will be 
estimated. Additionally, two-sided confidence intervals will be provided. 


 
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 Change in DLQI from Baseline to Visit 6 (EOS):  
Descriptive statistics (including mean, median, SD, min, and max) for observed and 
change from Baseline values in DLQI and CDLQI at each visit will be presented by 
treatment group for each CI subtype and overall. 
9.2.3. Exploratory Endpoints 
 Time to 2 or more points decrease from baseline in IGA: 
A time to event analysis will be performed using the Kaplan-Meier (K-M) method 
and log rank test to describe the time to 2 or more points decrease from baseline in 
IGA. 
 
 Time to achieve a score of 0 for both IGA and VIIS scaling: 
A time to event analysis will be performed using the Kaplan-Meier (K-M) method 
and log rank test to describe the time to achieve a score of 0 for both IGA and VIIS 
scaling.  
 
 Time to achieve a score of 1 for both IGA and VIIS scaling: 
A time to event analysis will be performed using the Kaplan-Meier (K-M) method 
and log rank test to describe the time to achieve a score of 1 for both IGA and VIIS 
scaling. 
 
 Kappa agreement analysis for VIIS and IGA scores at each visit: 
Kappa coefficients will be calculated for VIIS scaling and IGA score agreement at 
each visit. 
 
 Spearman and Pearson Correlation coefficient will be calculated between VIIS 
scaling scores and IGA scores, and between VIIS target sites scores and IGA at each 
visit. 
 
 Proportion of subjects with VIIS treatment success by body region: 
If data allows, proportion of subjects with VIIS treatment success will be compared 
between treatment groups in cases where the same body areas have been treated. 
Descriptive statistics (including frequencies and percentages) VIIS treatment success 
will be presented by body region. 
 Proportion of subjects with VIIS treatment success by genetic mutation: 
Descriptive statistics (including frequencies and percentages) for VIIS treatment 
success will be presented by genetic mutation. 
 Proportion of subjects with IGA treatment success by genetic mutation: 
Descriptive statistics (including frequencies and percentages) for IGA treatment 
success will be presented by genetic mutation. 
 Proportion of subjects with VIIS treatment success by phenotype: 
Descriptive statistics (including frequencies and percentages) for VIIS treatment 
success will be presented by phenotype. 
 Proportion of subjects with IGA treatment success by phenotype: 


 
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Descriptive statistics (including frequencies and percentages) for IGA treatment 
success will be presented by phenotype. 
 Proportion of subjects with VIIS treatment success by drug/BSA ratio: 
Drug/BSA ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for VIIS treatment success will be presented by 
drug/BSA ratio. 
 Proportion of subjects with IGA treatment success by drug/BSA ratio: 
Drug/BSA ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for IGA treatment success will be presented by 
drug/BSA ratio. 
 Proportion of subjects with VIIS treatment success by drug/BMI ratio: 
Drug/ BMI ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for VIIS treatment success will be presented by drug/ 
BMI ratio. 
 Proportion of subjects with IGA treatment success by drug/BMI ratio: 
Drug/ BMI ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for IGA treatment success will be presented by drug/ 
BMI ratio. 
 Proportion of subjects with VIIS treatment success by drug/kg ratio: 
Drug/ kg ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for VIIS treatment success will be presented by drug/ kg 
ratio. 
 Proportion of subjects with IGA treatment success by drug/kg ratio: 
Drug/ kg ratio will be calculated for each participant and values will be flagged 
according to median ratio as above or below median. Descriptive statistics (including 
frequencies and percentages) for IGA treatment success will be presented by drug/ kg 
ratio. 
 Proportion of subjects with VIIS treatment success based on BSA Stratification: 
Participants will be stratified according to Baseline BSA data. Descriptive statistics 
(including frequencies and percentages) of VIIS treatment success will be presented 
by BSA stratification. 
 
 Proportion of subjects with IGA treatment success based on BSA Stratification: 
Participants will be stratified according to Baseline BSA data. Descriptive statistics 
(including frequencies and percentages) of VIIS treatment success will be presented 
by BSA stratification. 
 


 
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 Proportion of subjects with VIIS treatment success by OTC steroid cream usage: 
Descriptive statistics (including frequencies and percentages) for VIIS treatment 
success will be presented by OTC steroid cream. 
 Proportion of subjects with IGA treatment success by OTC steroid cream usage: 
Descriptive statistics (including frequencies and percentages) for IGA treatment 
success will be presented by OTC steroid cream. 
 Proportion of subjects with VIIS treatment success by assessment medium: 
Descriptive statistics (including frequencies and percentages) for VIIS treatment 
success will be presented by assessment medium (online vs onsite). 
 Proportion of subjects with IGA treatment success by assessment medium: 
Descriptive statistics (including frequencies and percentages) for IGA treatment 
success will be presented by assessment medium (online vs onsite). 
 Proportion of subjects with VIIS treatment success by drug interruption: 
If data allows, descriptive statistics (including frequencies and percentages) for VIIS 
treatment success will be presented by the following drug interruption categories: 
frequency, duration, location and action outcome of the drug interruption. 
 Proportion of subjects with IGA treatment success by drug interruption: 
If data allows, descriptive statistics (including frequencies and percentages) for IGA 
treatment success will be presented by the following drug interruption categories: 
frequency, duration, location and action outcome of the drug interruption. 
 
 Proportion of subjects who meet both the primary and major secondary endpoint: 
Descriptive statistics (including frequencies and percentages) of subjects who meet 
both the primary and major secondary endpoint. 
 Proportion of subjects who meet VIIS 75 scaling at visit 6: 
Descriptive statistics (including frequencies and percentages) of subjects who meet 
VIIS 75 (≥ 75% reduction in VIIS scaling score for VIIS target body sites that had a 
Baseline score ≥ 3) at visit 6. 
 Proportion of subjects with VIIS "treatment success" (VIIS-50) at non-target body 
sites:  
In cases where VIIS body areas have been identified as non-target sites, and had a 
baseline score of ≥ 3, the proportion of subjects at Visit 6 (EOS) relative to Baseline 
with 50% or greater decrease in sum of VIIS scaling score in non-target sites will be 
presented using frequency statistics.  
 
 Changes from Baseline in VIIS score, Active Vs Vehicle  
Active treatment groups will be combined into one group and compared to vehicle 
group with respect to the change from Baseline using mixed model of repeated 
measures (MMRM) including terms for treatment, visit, treatment by visit interaction, 
and the Baseline VIIS value serving as the covariate.  
 Changes from Baseline in I-NRS score, Active Vs Vehicle  


 
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Active treatment groups will be combined into one group and compared to vehicle 
group with respect to the change from Baseline using mixed model of repeated 
measures (MMRM) including terms for treatment, visit, treatment by visit interaction, 
and the Baseline I-NRS value serving as the covariate.  
 
10. PHARMACOKINETIC/PHARMACODYNAMIC DATA 
Pharmacokinetic/Pharmacodynamic parameters will not be evaluated in this study.  
11. CHANGES FROM THE ANALYSIS PLANNED IN THE PROTOCOL 
 
There are no changes from the planned analysis described in the protocol. 
12. DATA LISTINGS AND SUMMARY TABLES 
12.1. Interim/Preliminary Data Analysis 
No interim analyses are planned. 
12.2. Listings and Tables for Clinical Study Report 
The data listings and summary tables, and associated figures, planned to be generated 
from the study data are listed in Appendix 1 and Appendix 2, respectively. The 
numbering and titles may vary in the final presentation, depending on the amount of data 
to be presented.  
Listings, tables and figures will be provided to the Sponsor in a form suitable for 
inclusion as appendices to the Clinical Study Report, in RTF or PDF format. The layout 
will be landscape A4 size, with a margin of 1 inch. The default font for listings and tables 
will be Courier New 8 pt.  
In the summary tables other than those included in the main text of the report, special 
characters and formatting will not be used. For example, units will be shown as ug (µg) 
and m^2 (m²), if/where these example units are applicable. 
Data in listings will be ordered by treatment, then subject, then date/time. 
Data to be presented graphically includes: Visual Index for Ichthyosis Severity success 
rate, Time to VIIS-50 - Kaplan-Meier Analysis, Investigator’s Global Assessment 
success rate and Itch- Numeric Rating Scale success rate. All of these efficacy endpoints 
will be graphically presented using both, ITT and PP population.  
12.3. Data Transfer to the Study Sponsor 
At the conclusion of the study, Avance will provide the Sponsor with an electronic copy 
of the listings, tables and graphs, along with analysis data sets in SAS transport format 
and XPT format. This may be provided by email or by upload, as determined by the 
Sponsor.  
Details of the statistical analyses will be retained in the Avance study file for reference. 


 
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13. GENERAL CONSIDERATIONS FOR DATA MANAGEMENT AND ANALYSIS 
13.1. Analysis Packages 
SAS 9.4 or higher (SAS Institute Inc., Cary, NC, USA) will be used for generating data 
listings and summary tables and associated figures, and for performing statistical analysis. 
13.2. Electronic Data Management 
All listings, tables and figures for inclusion in the appendices of the clinical study report 
will be generated using SAS programs.  
A copy of final listings, tables and figures will be retained in the Avance internal study 
file. A tracking log will be maintained detailing the date and initials of the staff member 
responsible for generating each listing, table or figure, and the staff member conducting 
the quality control review. Any erroneous results identified during subsequent checking 
process will be corrected by update of the SAS program, and the document recreated and 
then re-checked. To ensure an accurate data trail is maintained, corrections to electronic 
documents will be included on the tracking log, detailing the correction along with the 
date of the new version as well as the initials of the staff member responsible for the 
change and the verifying staff member. If statistical analysis is repeated with a modified 
data set, the new data produced will be saved as a new file. 
13.3. Archiving 
At the conclusion of the study, the final listings, tables and figures and associated QC 
documentation will be archived along with the SDTM (SDTM v1.7 and SDTMIG v3.3) 
and ADaM (ADaM v2.1 and ADaMIG v1.1) data sets, programs and CDISC 
documentation. Copies will be retained in the Avance study file for a minimum of 15 
years, and in the Avance secure archives in accordance with Avance standard operating 
procedures. 
 
 


 
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Appendix 1: Planned Data Listings 
The following listings and figures of individual subject data are planned to be generated for this 
study, however the numbering and titles may vary depending on CDISC datasets: 
Listing/Figure # 
Listings/Figure Title 
Subject Participation 
Listing 16.2.1.1 
Informed Consent 
Listing 16.2.1.2 
Subjects who did not meet Inclusion and Exclusion Criteria 
Listing 16.2.1.3 
Study Completion / Discontinuation 
Listing 16.2.1.4 
Screen Failures 
Listing 16.2.1.5 
Randomization  
Protocol Deviations 
Listing 16.2.2.1 
Protocol Deviations 
Listing 16.2.2.2 
Additional Comments 
Analysis Populations 
Listing 16.2.3.1 
Analysis Set Inclusion by Subject 
Demographics and Baseline Information 
Listing 16.2.4.1 
Demographics (Safety Population) 
Listing 16.2.4.2 
Demographics (ITT) 
Listing 16.2.4.3 
Demographics (PP) 
Listing 16.2.4.4 
Genetic Testing Confirmation (Safety Population) 
Listing 16.2.4.5 
Genetic Testing Confirmation (ITT) 
Listing 16.2.4.6 
Genetic Testing Confirmation (PP) 
Listing 16.2.4.7 
Assessment Medium (Safety Population) 
Listing 16.2.4.8 
Assessment Medium (ITT) 
Listing 16.2.4.9 
Assessment Medium (PP) 
Listing 16.2.4.10 
Percent BSA with Active Congenital Ichthyosis (Safety Population) 
Listing 16.2.4.11 
Percent BSA with Active Congenital Ichthyosis (ITT) 
Listing 16.2.4.12 
Percent BSA with Active Congenital Ichthyosis (PP) 
Listing 16.2.4.13 
Medical and Surgical History (Safety Population) 
Listing 16.2.4.14 
Medical and Surgical History (ITT) 
Listing 16.2.4.15 
Medical and Surgical History (PP) 
Listing 16.2.4.16 
Serology Screening (Safety Population) 
Listing 16.2.4.17 
Serology Screening (ITT) 
Listing 16.2.4.18 
Serology Screening (PP) 
Listing 16.2.4.19 
Drug and Alcohol Screening (Safety Population) 
Listing 16.2.4.20 
Drug and Alcohol Screening (ITT) 
Listing 16.2.4.21 
Drug and Alcohol Screening (PP) 
Listing 16.2.4.22 
Urine Pregnancy Tests (Safety Population) 
Listing 16.2.4.23 
Urine Pregnancy Tests (ITT) 
Listing 16.2.4.24 
Urine Pregnancy Tests (PP) 
Listing 16.2.4.25 
Height and Weight (Safety Population) 


 
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Listing/Figure # 
Listings/Figure Title 
Listing 16.2.4.26 
Height and Weight (ITT) 
Listing 16.2.4.27 
Height and Weight (PP) 
Listing 16.2.4.28 
Drug/Weight Ratios (Safety Population) 
Listing 16.2.4.29 
Drug/Weight Ratios (ITT) 
Listing 16.2.4.30 
Drug/Weight Ratios (PP) 
Listing 16.2.4.31 
Prior and Concomitant Medications (Safety Population) 
Listing 16.2.4.32 
Prior and Concomitant Medications (ITT) 
Listing 16.2.4.33 
Prior and Concomitant Medications (PP) 
Treatment Administration 
Listing 16.2.5.1 
Study Drug Administration 
Listing 16.2.5.2 
Investigation Product (IP) Compliance 
Listing 16.2.5.3 
Drug Interruption Details 
Listing 16.2.5.4 
Pre-dose Eligibility Reviews 
Efficacy Data 
Listing 16.2.6.1 
Visual Index for Ichthyosis Severity  
Listing 16.2.6.2 
Investigator’s Global Assessment  
Listing 16.2.6.3 
VIIS – Kappa Coefficients 
Listing 16.2.6.4 
IGA – Kappa Coefficients 
Listing 16.2.6.5 
VIIS Scaling Scores and IGA– Correlation Coefficients 
Listing 16.2.6.6 
VIIS Target Sites Scores and IGA– Correlation Coefficients 
Listing 16.2.6.7 
Itch - Numeric Rating Scale 
Listing 16.2.6.8 
Dermatology Quality of Life Index - Adults 
Listing 16.2.6.9 
Dermatology Quality of Life Index - Children 
Safety Data (Adverse Events) 
Listing 16.2.7.1 
Adverse Events  
Listing 16.2.7.2 
Serious Adverse Events 
Listing 16.2.7.3 
Incidence (severity and causality) of local skin reactions (LSRs) and systemic  
AEs 
Safety Data (Clinical Laboratory Evaluations) 
Listing 16.2.8.1 
Clinical Laboratory Blood Sample Collection 
Listing 16.2.8.2 
Hematology Results 
Listing 16.2.8.3 
Clinical Chemistry Results 
Listing 16.2.8.4 
Clinical Laboratory Urine Sample Collection 
Listing 16.2.8.5 
Urinalysis Results 
Safety Data (Other Assessments) 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Vital Signs, Calculated Changes from Baseline 
Listing 16.2.9.3 
Local Skin Reactions 
Listing 16.2.9.4 
Physical Examinations  
 
 


 
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Appendix 2: Planned Summary Tables  
The following summary tables are planned to be produced, however the table numbers and titles 
may vary, depending on the amount of data to be presented: 
14.1 Subject Data Summaries  
Table 14.1.1 
Summary of Study Disposition  
Table 14.1.2          Summary of Demographics (Safety Population) 
Table 14.1.3          Summary of Demographics (ITT) 
Table 14.1.4          Summary of Demographics (PP) 
Table 14.1.5 
Summary of Treatment / Total Dose Administered (Safety Population) 
Table 14.1.6 
Summary of Treatment Compliance (ITT) 
Table 14.1.7 
Summary of Concomitant Medication (ITT) 
14.2 Efficacy Data Summaries  
Table 14.2.1.1.1 
Visual Index for Ichthyosis Severity – Change From Baseline (ITT) 
Table 14.2.1.1.2 
Visual Index for Ichthyosis Severity – Change From Baseline (PP) 
Table 14.2.1.2.1 
Visual Index for Ichthyosis Severity – Shift Table (ITT) 
Table 14.2.1.2.2 
Visual Index for Ichthyosis Severity – Shift Table (PP) 
Table 14.2.1.3.1 
Visual Index for Ichthyosis Severity – Success Rate (ITT)  
Figure 14.2.1.3.1 
Visual Index for Ichthyosis Severity – Success Rate (ITT) 
Table 14.2.1.3.2 
Visual Index for Ichthyosis Severity – Success Rate (PP)  
Figure 14.2.1.3.2 
Visual Index for Ichthyosis Severity – Success Rate (PP) 
Table 14.2.1.4.1 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (ITT)  
Table 14.2.1.4.2 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (ITT) (Best Case Analysis) 
Table 14.2.1.4.3 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (ITT) (Worst Case Analysis) 
Table 14.2.1.4.4 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (ITT) (LOCF) 
Table 14.2.1.4.5 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (ITT) (Non-Responder Analysis) 
Table 14.2.1.4.6 
Visual Index for Ichthyosis Severity – Success Rate – CMH analysis at Visit 
6 (EOS) (PP) 
Table 14.2.1.5.1 
 Changes from Baseline in VIIS score relative to Visit 4 and Visit 5 – 
MMRM analysis (ITT) 
Table 14.2.1.5.2 
Changes from Baseline in VIIS score relative to Visit 4 and Visit 5 – 
MMRM analysis (PP) 


 
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Table 14.2.1.6.1 
Time to VIIS-50 - Kaplan-Meier Analysis (ITT)  
Figure 14.2.1.6.1 
Time to VIIS-50 - Kaplan-Meier Analysis (ITT) 
Table 14.2.1.6.2 
Time to VIIS-50 - Kaplan-Meier Analysis (PP)  
Figure 14.2.1.6.2 
Time to VIIS-50 - Kaplan-Meier Analysis (PP) 
Table 14.2.1.7.1 
 Visual Index for Ichthyosis Severity – Success Rate by identical body part 
(ITT)  
Table 14.2.1.7.2 
 Visual Index for Ichthyosis Severity – Success Rate by identical body part 
(PP)  
Table 14.2.1.8.1 
 Visual Index for Ichthyosis Severity – Success Rate by genetic mutation 
(ITT) 
Table 14.2.1.8.2 
 Visual Index for Ichthyosis Severity – Success Rate by genetic mutation 
(PP)  
Table 14.2.1.9.1 
 Visual Index for Ichthyosis Severity – Success Rate by phenotype (ITT) 
Table 14.2.1.9.2 
 Visual Index for Ichthyosis Severity – Success Rate by phenotype (PP)  
Table 14.2.1.10.1 
 Visual Index for Ichthyosis Severity – Success Rate by drug/BSA ratio 
(ITT)  
Table 14.2.1.10.2 
 Visual Index for Ichthyosis Severity – Success Rate by drug/BSA ratio (PP)  
Table 14.2.1.11.1 
 Visual Index for Ichthyosis Severity – Success Rate by drug/BMI ratio 
(ITT)  
Table 14.2.1.11.2 
 Visual Index for Ichthyosis Severity – Success Rate by drug/BMI ratio (PP)  
Table 14.2.1.12.1 
 Visual Index for Ichthyosis Severity – Success Rate by drug/kg ratio (ITT)  
Figure 14.2.1.12.1  Visual Index for Ichthyosis Severity – Success Rate by drug/weight ratio 
(ITT)  
Table 14.2.1.12.2 
 Visual Index for Ichthyosis Severity – Success Rate by drug/kg ratio (PP)  
Figure 14.2.1.12.2  Visual Index for Ichthyosis Severity – Success Rate by drug/weight ratio 
(PP)  
Table 14.2.1.13.1 
 Visual Index for Ichthyosis Severity – Success Rate by OTC Steroid Cream 
(ITT)  
Table 14.2.1.13.2 
 Visual Index for Ichthyosis Severity – Success Rate by OTC Steroid Cream 
(PP)  
Table 14.2.1.14.1 
 Visual Index for Ichthyosis Severity – Success Rate by assessment medium 
(ITT)  
Table 14.2.1.14.2 
 Visual Index for Ichthyosis Severity – Success Rate by assessment medium 
(PP)  
Table 14.2.1.15.1 
Visual Index for Ichthyosis Severity – Success Rate by VIIS Body Region 
(ITT)  


 
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Table 14.2.1.15.2 
Visual Index for Ichthyosis Severity – Success Rate by VIIS Body Region 
(PP)  
Table 14.2.1.16.1 
Visual Index for Ichthyosis Severity – Success Rate by BSA Stratification 
(ITT)  
Table 14.2.1.16.2 
Visual Index for Ichthyosis Severity – Success Rate by BSA Stratification 
(PP) 
Table 14.2.1.17.1 
 Changes from Baseline in VIIS score, Active Vs Vehicle – MMRM analysis 
(ITT) 
Table 14.2.1.17.2 
 Changes from Baseline in VIIS score, Active Vs Vehicle – MMRM analysis 
(PP) 
Table 14.2.1.18.1 
Visual Index for Ichthyosis Severity – Non-Target Sites Success Rate (ITT) 
Table 14.2.1.18.2 
Visual Index for Ichthyosis Severity – Non-Target Sites Success Rate (PP) 
Table 14.2.1.19.1 
Visual Index for Ichthyosis Severity – Success Rate by Drug Interruption 
(ITT) 
Table 14.2.1.19.2 
Visual Index for Ichthyosis Severity – Success Rate by Drug Interruption 
(PP) 
Table 14.2.2.1.1 
Investigator’s Global Assessment – Change From Baseline (ITT) 
Table 14.2.2.1.2 
Investigator’s Global Assessment – Change From Baseline (PP) 
Table 14.2.2.2.1 
Investigator’s Global Assessment – Shift Table (ITT) 
Table 14.2.2.2.2 
Investigator’s Global Assessment – Shift Table (PP) 
Table 14.2.2.3.1 
Investigator’s Global Assessment – Success Rate (ITT)  
Figure 14.2.2.3.1 
Investigator’s Global Assessment – Success Rate (ITT)  
Table 14.2.2.3.2 
Investigator’s Global Assessment – Success Rate (PP) 
Figure 14.2.2.3.2 
Investigator’s Global Assessment – Success Rate (PP) 
Table 14.2.2.4.1 
Investigator’s Global Assessment – CMH analysis at Visit 6 (EOS) (ITT)  
Table 14.2.2.4.2 
Investigator’s Global Assessment – CMH analysis at Visit 6 (EOS) (PP) 
Table 14.2.2.5.1 
Investigator’s Global Assessment – Cleared/Almost Cleared (ITT)  
Table 14.2.2.5.2 
Investigator’s Global Assessment – Cleared/Almost Cleared (PP) 
Table 14.2.2.6.1 
 Time to 2 point decrease from baseline in IGA - Kaplan-Meier Analysis 
(ITT) 
Table 14.2.2.6.2 
 Time to 2 point decrease from baseline in IGA - Kaplan-Meier Analysis 
(PP) 
Table 14.2.2.7.1 
Investigator’s Global Assessment – Success Rate by genetic mutation (ITT) 
Table 14.2.2.7.2 
Investigator’s Global Assessment – Success Rate by genetic mutation (PP) 
Table 14.2.2.8.1 
Investigator’s Global Assessment – Success Rate by phenotype (ITT) 
Table 14.2.2.8.2 
Investigator’s Global Assessment – Success Rate by phenotype (PP) 


 
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Table 14.2.2.9.1 
Investigator’s Global Assessment – Success Rate by drug/BSA ratio (ITT)  
Table 14.2.2.9.2 
 Investigator’s Global Assessment – Success Rate by drug/BSA ratio (PP)  
Table 14.2.2.10.1 
 Investigator’s Global Assessment – Success Rate by drug/BMI ratio (ITT)  
Table 14.2.2.10.2 
 Investigator’s Global Assessment – Success Rate by drug/BMI ratio (PP)  
Table 14.2.2.11.1 
Investigator’s Global Assessment – Success Rate by drug/kg ratio (ITT)  
Table 14.2.2.11.2 
Investigator’s Global Assessment – Success Rate by drug/kg ratio (PP)  
Figure 14.2.2.11.1 Investigator’s Global Assessment – Success Rate by drug/weight ratio (ITT) 
Figure 14.2.2.11.2 Investigator’s Global Assessment – Success Rate by drug/weight ratio (PP) 
Table 14.2.2.12.1 
Investigator’s Global Assessment – Success Rate by OTC Steroid Cream 
Usage (ITT)  
Table 14.2.2.12.2 
Investigator’s Global Assessment – Success Rate by OTC Steroid Cream 
Usage (PP)  
Table 14.2.2.13.1 
Investigator’s Global Assessment – Success Rate by assessment medium 
(ITT)  
Table 14.2.2.13.2 
Investigator’s Global Assessment – Success Rate by assessment medium 
(PP)  
Table 14.2.2.14.1 
Investigator’s Global Assessment – Success Rate by Drug Interruption 
(ITT)  
Table 14.2.2.14.2 
Investigator’s Global Assessment – Success Rate by Drug Interruption (PP) 
Table 14.2.2.15.1 
Proportion of Subjects with VIIS and IGA Treatment Success (ITT)  
Table 14.2.2.15.2 
Proportion of Subjects with VIIS and IGA Treatment Success (PP) 
 
Table 14.2.2.16.1     Correlation Coefficients for IGA scores and VIIS scaling, per visit (ITT) 
 
Table 14.2.2.16.2     Correlation Coefficients for IGA scores and VIIS scaling, per visit (PP) 
 
Table 14.2.2.17.1     Correlation Coefficients for IGA scores and VIIS target sites scores, per  
visit (ITT) 
 
Table 14.2.2.17.2     Correlation Coefficients for IGA scores and VIIS target sites scores, per 
visit (PP) 
Table 14.2.2.18.1 
Kappa Coefficients for VIIS and IGA (ITT)  
Table 14.2.2.18.2 
Kappa Coefficients for VIIS and IGA (PP)  
Table 14.2.3.1.1 
Itch- Numeric Rating Scale – Change From Baseline (ITT) 
Table 14.2.3.1.2 
Itch- Numeric Rating Scale – Change From Baseline (PP) 
Table 14.2.3.2.1 
Itch- Numeric Rating Scale – Shift Table (ITT) 
Table 14.2.3.2.2 
Itch- Numeric Rating Scale – Shift Table (PP) 


 
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Table 14.2.3.3.1 
Itch- Numeric Rating Scale – Success Rate (ITT)  
Figure 14.2.3.3.2 
Itch- Numeric Rating Scale – Success Rate (ITT)  
Table 14.2.3.4.1 
Itch- Numeric Rating Scale – Success Rate (PP) 
Figure 14.2.3.4.2 
Itch- Numeric Rating Scale – Success Rate (PP)  
Table 14.2.3.5.1 
Change from Baseline in I-NRS score (EOS) – MMRM analysis (ITT) 
Table 14.2.3.5.2 
Change from Baseline in I-NRS score (EOS) – MMRM analysis (PP) 
Table 14.2.3.6.1 
 Changes from Baseline in I-NRS score, Active Vs Vehicle – MMRM 
analysis (ITT) 
Table 14.2.3.6.2 
 Changes from Baseline in I-NRS score, Active Vs Vehicle – MMRM 
analysis (PP) 
Table 14.2.4.1.1 
Percent Body Surface Area with Active Congenital Ichthyosis (ITT) 
Table 14.2.4.1.2 
Percent Body Surface Area with Active Congenital Ichthyosis (PP) 
Table 14.2.5.1.1 
Dermatology Quality of Life Index (Adults) – Change From Baseline (ITT) 
Table 14.2.5.1.2 
Dermatology Quality of Life Index (Adults) – Change From Baseline (PP) 
Table 14.2.5.2.1 
 Dermatology Quality of Life Index (Children) – Change From Baseline 
(ITT) 
Table 14.2.5.2.2 
Dermatology Quality of Life Index (Children) – Change From Baseline (PP) 
Table 14.2.5.3.1 
Subgroup Analysis of Dermatology Quality of Life Index (Adults) – Change 
From Baseline (ITT) 
Table 14.2.5.3.2 
Subgroup Analysis of Dermatology Quality of Life Index (Adults) – Change 
From Baseline (PP) 
Table 14.2.5.4.1 
 Subgroup Analysis of Dermatology Quality of Life Index (Children) – 
Change From Baseline (ITT) 
Table 14.2.5.4.2 
Subgroup Analysis of Dermatology Quality of Life Index (Children) – 
Change From Baseline (PP) 
Table 14.2.5.5.1 
Proportion of subjects with DLQI improvement of 4 or more points (ITT) 
Table 14.2.5.5.2 
Proportion of subjects with DLQI improvement of 4 or more points (PP) 
14.3 Safety Data Summaries  
14.3.1 Adverse Event Summaries 
Table 14.3.1.1 
  Overall Summary of Treatment-Emergent Adverse Events by Treatment 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by MedDRA Term and 
Treatment 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by Intensity (Severity) 
and Treatment 
Table 14.3.1.4 
Summary of Treatment-Related Treatment-Emergent Adverse Events 


 
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Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events of at least Moderate 
Intensity and Related to Study Treatment 
Table 14.3.1.6 
Incidence (severity and causality) of any local skin reactions (LSRs) and 
systemic AEs 
 
14.3.2 Deaths, Other Serious and Significant Adverse Events  
Table 14.3.2.1 
Subjects with Serious Adverse Events 
Table 14.3.2.2 
Subjects with Adverse Events Leading to Study Withdrawal 
Table 14.3.2.3 
Subjects Who Died During the Study 
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Event  
<Narratives by Subject, to be provided by Safety Officer> 
14.3.4 Clinical Laboratory Assessments  
Table 14.3.4.1 
Summary of Haematology Results by Treatment 
Table 14.3.4.2 
Summary of Clinical Chemistry Results by Treatment 
Table 14.3.4.3 
Summary of Assessments of Haematology Results by Treatment 
Table 14.3.4.4 
Summary of Assessments of Clinical Chemistry Results by Treatment 
Table 14.3.4.5 
Summary of Assessments of Urinalysis Results by Treatment 
Table 14.3.4.6 
Shift Table of Haematology Results by Treatment 
Table 14.3.4.7 
Shift Table of Clinical Chemistry Results by Treatment 
Table 14.3.4.8 
Shift Table of Urinalysis Chemistry Results by Treatment 
Table 14.3.4.9 
Individual Subject Profiles for Clinical Laboratory Parameters With at Least 
One Clinically Significant Result 
14.3.5 Vital Signs  
Table 14.3.5.1 
Summary of Vital Signs (Heart Rate) by Position and Treatment 
Table 14.3.5.2 
Summary of Vital Signs (Systolic Blood Pressure) by Position and 
Treatment 
Table 14.3.5.3 
Summary of Vital Signs (Diastolic Blood Pressure) by Position and 
Treatment 
Table 14.3.5.4 
Summary of Vital Signs (Respiratory Rate) by Position and Treatment 
Table 14.3.5.5 
Summary of Vital Signs (Temperature) by Position and Treatment 
Figure 14.3.5.6 
Mean Vital Signs Over Time by Position and Treatment 
14.3.6 Other Measurements  
Table 14.3.6.1 
Summary of Local Skin Reactions by Treatment 


 
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Table 14.3.6.2 
Physical Examination