A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ANB019 in the Treatment of Subjects With Ichthyosis
Phase: PHASE2
Conditions: Ichthyosis
Sponsor: Vanda Pharmaceuticals

 
 
 
 
 
 
16.1.1 
Protocol and Protocol Amendments 
16.1.1.1 
Clinical Study Protocol: ANB019-206 Original ...................................................................... 2 
 
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AnaptysBio, Inc., ANB019 
Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

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1 
 
 
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of ANB019 in the Treatment of Subjects with 
Ichthyosis 
 
Protocol Number: ANB019-206 
Investigational New Drug (IND) Number: 136145 
European Clinical Trials Database (EudraCT) Number: 2020-003476-41 
 
 
 
Sponsor Name: AnaptysBio, Inc. 
Sponsor Address: 10421 Pacific Center Court, Suite 200 
San Diego, CA 92121, United States 
 
Sponsor Medical Expert and Signatory:
 
 
 
 
Original Protocol (Version 1.0) 
30 October 2020 
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AnaptysBio, Inc., ANB019 
Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020  
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
6 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
Investigator Global Assessment 
IgG4 
immunoglobulin G4 
IgE 
immunoglobulin E 
IL 
Interleukin 
IL-36R 
interleukin 36 receptor 
IL-36Ra 
IL-36R antagonist 
IND 
Investigational New Drug  
iQoL-32 
Ichthyosis Quality of Life- 32 items 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IWRS 
Interactive Web Response System 
KD 
dissociation constant 
LMW 
low molecular weight 
LSM 
least-squares means 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MCH 
mean cell hemoglobin 
MCHC 
mean cell hemoglobin concentration 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute 
MMRM 
mixed effects model for repeated measures 
NaCl 
sodium chloride 
NASA 
Netherton Area and Severity Assessment 
NOAEL 
no observed adverse effect level 
NRS 
Numeric Rating Scale 
NSAID 
nonsteroidal anti-inflammatory drugs 
PASI 
Psoriasis Area and Severity Index 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PCV 
packed cell volume 
PD 
pharmacodynamic 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetic 
PPP 
palmoplantar pustulosis 
PT 
preferred term 
QC 
quality control 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RNA-seq 
RNA sequencing 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
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Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020  
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
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SAS 
statistical analysis system 
SC 
subcutaneous/subcutaneously 
SD 
standard deviation 
SoA 
Schedule of Activities 
SOC 
system organ class 
SOP 
standard operating procedure 
t1/2 
terminal half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TEWL 
transepidermal water loss 
Th-17 
T-helper 17 
TK 
toxicokinetic 
Tmax 
time to maximum observed concentration 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
W 
week 
WBC 
white blood cell 
WHO 
world health organization 
WOCBP 
woman of childbearing potential 
 
 
 
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Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020  
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
9 
6.5 
Concomitant Therapy ........................................................................................................................... 45 
6.5.1 
Permitted Therapies................................................................................................................ 45 
6.5.2 
Prohibited Medications or Procedures ................................................................................. 45 
6.5.3 
Rescue Medication ................................................................................................................. 47 
6.6 
Dose Modification .................................................................................................................................. 47 
6.7 
Treatment After the End of the Study ................................................................................................. 47 
7 
STUDY TREATMENT DISCONTINUATION AND SUBJECT DISCONTINUATION/WITHDRAWAL . 48 
7.1 
Discontinuation of Study Treatment ................................................................................................... 48 
7.1.1 
Temporary Interruption ........................................................................................................... 48 
7.1.2 
Re-Challenge ........................................................................................................................... 48 
7.2 
Subject Discontinuation/Withdrawal from the Study ........................................................................ 48 
7.3 
Lost to Follow-Up .................................................................................................................................. 49 
8 
STUDY ASSESSMENTS AND PROCEDURES.......................................................................................... 50 
8.1 
Efficacy Assessments ........................................................................................................................... 50 
8.1.1 
Subject Assessments of Pruritus and Pain ......................................................................... 50 
8.1.2 
Ichthyosis Quality of Life- 32 Items ....................................................................................... 50 
8.1.3 
Dermatology Life Quality Index / Children’s Dermatology Life Quality Index 
Questionnaires......................................................................................................................... 51 
8.1.4 
Patient Global Impression of Severity .................................................................................. 51 
8.1.5 
Patient Global Impression of Change .................................................................................. 51 
8.1.6 
Body Surface Area .................................................................................................................. 51 
8.1.7 
Investigator Global Assessment ........................................................................................... 52 
8.1.8 
Ichthyosis Area Severity Index .............................................................................................. 52 
8.1.9 
Netherton Area and Severity Assessment .......................................................................... 52 
8.1.10 Transepidermal Water Loss .................................................................................................. 52 
8.2 
Safety Assessments ............................................................................................................................. 52 
8.2.1 
Adverse Events and Serious Adverse Events .................................................................... 52 
8.2.1.1 
Definition of Adverse Events ............................................................................ 52 
8.2.1.1.1 
Events Meeting the Adverse Event Definition ......................................... 53 
8.2.1.1.2 
Events Not Meeting the Adverse Event Definition .................................. 53 
8.2.1.2 
Definition of Serious Adverse Events ............................................................... 53 
8.2.1.3 
Classification of an Adverse Event .................................................................. 54 
8.2.1.3.1 
Severity of Event ..................................................................................... 54 
8.2.1.3.2 
Relationship to Study Treatment............................................................. 54 
8.2.1.3.3 
Expectedness ......................................................................................... 55 
8.2.1.4 
Time Period and Frequency for Event Assessment and Follow-Up ................ 55 
8.2.1.5 
Adverse Event Reporting ................................................................................. 56 
8.2.1.6 
Serious Adverse Event Reporting .................................................................... 57 
8.2.1.6.1 
Reporting via an Electronic Data Collection Tool ................................... 57 
8.2.1.6.2 
Reporting via Paper Case Report Form ................................................. 58 
8.2.1.7 
Reporting Events to Subjects ........................................................................... 58 
8.2.1.8 
Reporting of Pregnancy ................................................................................... 58 
8.2.1.9 
Treatment of Overdose .................................................................................... 58 
8.2.2 
Height and Weight ................................................................................................................... 59 
8.2.3 
Chest X-ray .............................................................................................................................. 59 
8.2.4 
Physical Examinations............................................................................................................ 59 
8.2.5 
Vital Signs ................................................................................................................................ 59 
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Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020  
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
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8.2.6 
Electrocardiograms ................................................................................................................. 60 
8.2.7 
Clinical Safety Laboratory Assessments ............................................................................. 60 
8.2.8 
Telephone Contact .................................................................................................................. 60 
8.3 
Other Assessments ............................................................................................................................... 61 
8.3.1 
Photography ............................................................................................................................. 61 
8.3.2 
Pharmacokinetics .................................................................................................................... 61 
8.3.3 
Immunogenicity Assessments ............................................................................................... 62 
8.3.4 
Immunoglobulin E Levels Evaluation ................................................................................... 63 
8.3.5 
Biomarkers Analysis ............................................................................................................... 63 
8.3.5.1 
Tape Stripping .................................................................................................. 63 
8.3.5.2 
Optional Skin Biopsy ........................................................................................ 63 
9 
STATISTICAL CONSIDERATIONS............................................................................................................... 65 
9.1 
Statistical Hypotheses .......................................................................................................................... 65 
9.2 
Sample Size Determination ................................................................................................................. 65 
9.3 
Populations for Analyses ...................................................................................................................... 65 
9.4 
Statistical Analyses ............................................................................................................................... 66 
9.4.1 
General Approach ................................................................................................................... 66 
9.4.2 
Subject Disposition ................................................................................................................. 66 
9.4.3 
Baseline Descriptive Statistics .............................................................................................. 66 
9.4.4 
Concomitant Medication ......................................................................................................... 67 
9.4.5 
Analysis of the Primary Efficacy Endpoint ........................................................................... 67 
9.4.6 
Analysis of the Secondary Efficacy Endpoints .................................................................... 67 
9.4.6.1 
Categorical Endpoints ...................................................................................... 67 
9.4.6.2 
Continuous Endpoints ...................................................................................... 67 
9.4.7 
Analysis of the Exploratory Efficacy Endpoints .................................................................. 68 
9.4.8 
Safety Analyses ....................................................................................................................... 69 
9.4.8.1 
Adverse Events and Serious Adverse Events ................................................. 70 
9.4.8.2 
12-Lead Electrocardiogram, Vital Signs, and Clinical Safety Laboratory 
Tests................................................................................................................. 70 
9.4.9 
Pharmacokinetic Analyses ..................................................................................................... 70 
9.4.9.1 
Derivation of Pharmacokinetic Parameters...................................................... 70 
9.4.9.2 
Pharmacokinetic Concentration Data Analysis ................................................ 71 
9.4.9.3 
Pharmacokinetic Parameter Data Analysis...................................................... 71 
9.4.9.4 
Population Pharmacokinetics Analysis ............................................................ 71 
9.4.10 Immunogenicity Analyses ...................................................................................................... 71 
9.4.11 Immunoglobulin E level Analyses ......................................................................................... 71 
9.4.12 Biomarker Analyses ................................................................................................................ 71 
9.4.13 Planned Interim Analysis ........................................................................................................ 72 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................. 73 
10.1 Regulatory, Ethical, and Study Oversight Considerations .............................................................. 73 
10.1.1 Informed Consent Process .................................................................................................... 73 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided to Subjects ... 73 
10.1.1.2 
Consent Procedures and Documentation ........................................................ 73 
10.1.2 Study Discontinuation and Closure ...................................................................................... 74 
10.1.3 Confidentiality and Privacy .................................................................................................... 74 
10.1.4 Future Use of Stored Specimens and Data ........................................................................ 75 
10.1.5 Medical Monitor ....................................................................................................................... 75 
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Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020 
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
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For scheduled on-site study visits, subjects will come to the study center 
on 13 occasions to monitor changes in disease activity, PK (if applicable), 
safety, and tolerability: screening and Days 1, 8, 29, 57, 85, 113, 141, 169, 
197, 225, 253, and 281 (end of study [EOS]/early termination [ET]). The 
subjects will leave the study center following study treatment 
administration when all postdose assessments have been completed and 
with the Investigator’s approval. In addition, during the 
placebo-controlled period, the subjects will also be contacted via 
telephone by study staff on Days 3, 15, 43, and 71 to inquire about 
potential adverse events (AEs) they experienced and any changes in 
concomitant medications. All procedures will be conducted in accordance 
with the Schedule of Activities (SoA) in Section 1.3. 
Of note, all predose assessments performed on Day 113 (Week 16) will 
be used to evaluate the primary and secondary efficacy endpoints, as 
well as the safety, tolerability, and immune response of ANB019 
compared with placebo.  
Safety assessments will include AE/serious adverse event (SAE) 
monitoring, vital signs, physical examination, electrocardiograms (ECGs), 
and clinical laboratory tests (hematology, biochemistry, and urinalysis). 
Disease activity will be evaluated for all subjects using the Ichthyosis Area 
Severity Index (IASI), IASI erythema (IASI-E) subscore, IASI scaling (IASI-S) 
subscore, Netherton Area and Severity Assessment (NASA) for subjects 
with Netherton Syndrome only, Investigator Global Assessment (IGA), 
and body surface area (BSA) involved with ichthyosis. Quality of life will 
be evaluated using Ichthyosis Quality of Life- 32 items (iQoL-32) in 
subjects ≥ 15 years of age only, Dermatology Life Quality Index (DLQI) for 
subjects ≥ 16 years of age, and Children’s DLQI (CDLQI) for subjects <16 
years of age. Subjects will also be evaluated for disease-associated 
characteristics, such as worst and average pruritus and pain using a 
Numeric Rating Scale (NRS), impression of severity using the Patient 
Global Impression of Severity (PGI-S) and impression of change using the 
Patient Global Impression of Change (PGI-C), as well as changes in 
transepidermal water loss (TEWL).  
Blood samples to determine PK, immunogenicity (presence of anti-drug 
antibodies [ADA] to ANB019), and immunoglobulin E (IgE) levels (for 
subjects with Netherton Syndrome only) will be collected on Day 1 before 
the administration of the study treatment and at the other time points 
specified in the SoA (see Section 1.3). Tape strips and optional skin 
biopsies for biomarker analysis will be collected at the time points 
specified in the SoA. All subjects randomized in the study will be asked to 
participate in skin biopsy collection; however, the subject’s participation 
is optional. In addition, photographs will be taken at selected study 
centers only to document skin lesions at the time points specified in the 
SoA. 
Interim analyses (IAs) may be performed during the treatment periods 
(placebo-controlled period and/or open-label extension period) for 
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Protocol No: ANB019-206 
Synoptic Clinical Study Report 
CSR Final, 11 July 2022 
 
 

Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020 
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
15 
assessment of all primary and secondary efficacy endpoints, and 
evaluation of all safety data available. 
Objectives: 
Primary Objective:   
 To determine the effect of ANB019 compared with placebo as 
measured by IASI total score  
 
Secondary Objectives:  
 To evaluate the effect of ANB019 compared with placebo on 
ichthyosis signs and symptoms, and quality of life in subjects with 
ichthyosis 
 To determine the safety of ANB019 in the treatment of ichthyosis 
 
Exploratory Objectives:  
 To further evaluate the effect of ANB019 on ichthyosis signs and 
symptoms, and quality of life in subjects with ichthyosis 
 To explore the effect of ANB019 on cutaneous biomarkers 
 To explore ichthyosis-associated mutations and additional 
pharmacogenomic analysis 
 To test for immunogenicity to ANB019 
 To evaluate IgE levels in subjects with Netherton Syndrome 
 To describe the PK profile of ANB019 in subjects with ichthyosis 
Endpoints: 
Primary Efficacy Endpoint: 
 Change from Baseline in IASI total score at Week 16 
 
Secondary Endpoints:  
 Percent change from Baseline in IASI total score at Week 16 
 Proportion of subjects achieving an improvement of 50% from 
Baseline in IASI (IASI50) at Week 16 
 Change and percent change from Baseline in IASI-E and IASI-S 
subscores at Week 16 
 Incidence of AEs, SAEs, and AEs leading to withdrawals, as well as 
changes in vital signs, clinical laboratory parameters (hematology, 
biochemistry, and urinalysis), and 12-lead ECGs 
 
Exploratory Endpoints:  
 Change and percent change from Baseline in IASI total score at Weeks 
1, 4, 8 and 12 
 Proportion of subjects achieving IASI50 at Weeks 1, 4, 8, and 12 
 Proportion of subjects achieving an improvement of 75% from 
Baseline in IASI (IASI75) at Weeks 1, 4, 8, 12, and 16 
 Change and percent change from Baseline in IASI-E and IASI-S 
subscores at Weeks 1, 4, 8, and 12 
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Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020 
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 Change and percent change from Baseline in NASA at Weeks 1, 4, 8, 
12, and 16 (for subjects with Netherton Syndrome only)  
 Proportion of subjects achieving an improvement of 50% from 
Baseline in NASA (NASA50) at Weeks 1, 4, 8, 12, and 16 (for subjects 
with Netherton Syndrome only) 
 Change and percent change from Baseline in IGA at Weeks 1, 4, 8, 12, 
and 16 
 Proportion of subjects achieving an IGA of clear (0) or almost clear (1) 
at Weeks 1, 4, 8, 12, and 16 
 Proportion of subjects with at least 2-point decrease in IGA at 
Weeks 1, 4, 8, 12, and 16 
 Change and percent change from Baseline in worst and average 
pruritus NRS at Weeks 1, 4, 8, 12, and 16 
 Change and percent change from Baseline in worst and average pain 
NRS at Weeks 1, 4, 8, 12, and 16 
 Proportion of subjects with at least 3-point decrease in worst pruritus 
NRS at Weeks 1, 4, 8, 12, and 16 for subjects with a Baseline worst 
pruritus NRS of at least 3 
 Proportion of subjects with at least 4-point decrease in worst pruritus 
NRS at Weeks 1, 4, 8, 12, and 16 for subjects with a Baseline worst 
pruritus NRS of at least 4 
 Proportion of subjects with at least 3-point decrease in worst pain 
NRS at Weeks 1, 4, 8, 12, and 16 for subjects with a Baseline worst 
pain NRS of at least 3 
 Proportion of subjects with at least 4-point decrease in worst pain 
NRS at Weeks 1, 4, 8, 12, and 16 for subjects with a Baseline worst 
pain NRS of at least 4 
 Change from Baseline in BSA at Weeks 1, 4, 8, 12, and 16 
 Change from Baseline in DLQI and CDLQI scores at Weeks 1, 4, 8, 12, 
and 16 
 Proportion of subjects in each response category for the PGI-S and 
PGI-C at Weeks 1, 4, 8, 12, and 16 
 Change from Baseline in iQoL-32 score at Weeks 4, 8, 12, and 16 
 Change from Baseline in TEWL at Weeks 4, 8, 12, and 16 
 Proportion of subjects receiving rescue medication at Weeks 4, 8, 12, 
and 16 
 Proportion of subjects achieving IASI50 from Week 20 through 
Week 40 
 Proportion of subjects achieving IASI75 from Week 20 through 
Week 40 
 Change and percent change from Baseline in IASI total score from 
Week 20 through Week 40 
 Change and percent change from Baseline in IASI-E and IASI-S 
subscores from Week 20 through Week 40 
 Change and percent change from Baseline in NASA from Week 20 
through Week 40 (for subjects with Netherton Syndrome only) 
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Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
Protocol ANB019-206 
30 October 2020 
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 Proportion of subjects achieving NASA50 from Week 20 through 
Week 40 (for subjects with Netherton Syndrome only) 
 Change and percent change from Baseline in IGA from Week 20 
through Week 40 
 Proportion of subjects achieving an IGA of clear (0) or almost clear (1) 
from Week 20 through Week 40 
 Proportion of subjects with at least 2-point decrease in IGA from 
Week 20 through Week 40 
 Change and percent change from Baseline in worst and average 
pruritus NRS from Week 20 through Week 40 
 Proportion of subjects with at least 3-point decrease in worst pruritus 
NRS from Week 20 through Week 40 for subjects with a Baseline 
worst pruritus NRS of at least 3 
 Proportion of subjects with at least 4-point decrease in worst pruritus 
NRS from Week 20 through Week 40 for subjects with a Baseline 
worst pruritus NRS of at least 4 
 Change and percent change from Baseline in worst and average pain 
NRS from Week 20 through Week 40 
 Proportion of subjects with at least 3-point decrease in worst pain 
NRS from Week 20 through Week 40 for subjects with a Baseline 
worst pain NRS of at least 3 
 Proportion of subjects with at least 4-point decrease in worst pain 
NRS from Week 20 through Week 40 for subjects with a Baseline 
worst pain NRS of at least 4 
 Change from Baseline in BSA from Week 20 through Week 40 
 Change from Baseline in iQoL-32 score from Week 20 through 
Week 40 
 Change from Baseline in DLQI and CDLQI scores from Week 20 
through Week 40 
 Proportion of subjects in each response category for the PGI-S and 
PGI-C from Week 20 through Week 40 
 Change from Baseline in TEWL from Week 20 through Week 40 
 Proportion of subjects receiving rescue medication from Week 20 
through Week 40 
 Skin tape strip biomarkers analysis including, but not limited to, IL-36 
and Th-17 
 Optional skin biopsy biomarkers analysis including, but not limited to, 
IL-36 and Th-17 
 Presence of anti-drug antibodies to ANB019 
 IgE levels evaluation (for subjects with Netherton Syndrome only) 
 Serum concentration following ANB019 administration and other 
parameters as appropriate will be determined to describe the PK 
profile of ANB019 
Study Population: 
Approximately 24 male and female subjects, aged 12 to 75 years, with 
clinically confirmed diagnosis of ichthyosis (as described in Section 5.1) 
will be enrolled in this study. To be eligible for the study, the subjects will 
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Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
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30 October 2020 
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need to have a diagnosis of their ichthyosis subtype confirmed by genetic 
testing. In addition, the subjects will have the following characteristics at 
Day 1: IASI total score of at least 18, erythema score of at least 2 
(moderate severity) in at least 1 body region and scaling score of at least 
2 (moderate severity) in at least 1 body region as evaluated by IASI, and 
BSA involved with ichthyosis of at least 50%.  
Phase: 
2 
Description of Study 
Centers Enrolling 
Subjects: 
Approximately 20 study centers located globally are expected to 
participate in this study.   
Description of Study 
Treatments: 
ANB019 will be provided in a glass vial as a sterile, colorless to yellow, 
and clear to slightly opalescent solution for injection. The placebo 
contains no active ingredient and will be provided as a sterile, colorless to 
slightly yellowish, and clear to very slightly opalescent solution for 
injection. 
During the placebo-controlled period, eligible subjects will be 
randomized (2:1) to receive either ANB019 or placebo, SC administered 
on 4 occasions: 
 Day 1: 400-mg dose of ANB019 or placebo (administered as 2 SC 
injections of ANB019 at 200 mg each or placebo) 
 Days 29, 57, and 85: 200-mg dose of ANB019 or placebo 
During the open-label extension, all subjects will receive ANB019, SC 
administered on 4 occasions. Subjects assigned to ANB019 during the 
placebo-controlled period will continue to receive a 200-mg dose of 
ANB019 on Days 113, 141, 169, and 197. Subjects assigned to placebo 
during the placebo-controlled period will receive a 400-mg dose of 
ANB019 on Day 113, followed by a 200-mg dose of ANB019 on Days 141, 
169, and 197. 
The blind will be maintained throughout the study. To keep the blind, the 
following measures will be taken on Day 113: 
 Subjects assigned to ANB019 during the placebo-controlled period will 
receive 2 SC injections on Day 113: 1 of ANB019 at 200 mg and 1 of 
placebo.   
 Subjects assigned to placebo during the placebo-controlled period will 
receive 2 SC injections on Day 113 of ANB019 at 200 mg each. 
Rescue Medication: 
Rescue medications (topical only) may be used starting at Week 4 
provided that the criteria for rescue defined in Section 6.5.3 are met. 
Study Duration: 
The estimated study duration is approximately 25 months from first 
subject screened until completion of data analyses. 
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Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
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30 October 2020 
Confidential and proprietary. Permission should be obtained before any reproduction.  
 
19 
Subject Duration: 
The maximum study duration per subject is approximately 44 weeks from 
screening to last visit (including up to 30 days for the screening period, 
followed by a 16-week placebo-controlled period, a 16-week open-label 
extension period, and an 8-week safety follow-up period). 
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Efficacy and Safety of ANB019 in Subjects with Ichthyosis 
Version 1.0 
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30 October 2020 
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Table 1: Schedule of Activities (Continued) 
 
b The ET visit will include all procedures to be done at the ET/EOS visit (Day 281/Week 40 visit). 
c Adolescent subjects who reach 18 years of age during the study must be reconsented as adults.  
d Height to be measured at screening only for subjects ≥ 18 years of age, and at screening, Day 113 (Week 16), and Day 281 (Week 40)/ET for 
subjects < 18 years of age. 
e Refer to Section 8.1 for details and instructions regarding pain and pruritus NRSs (worst and average), iQoL-32 (subjects ≥ 15 years of age only), DLQI 
(subjects ≥ 16 years of age), CDLQI (subjects < 16 years of age), PGI-S, PGI-C, BSA, IGA, IASI, NASA, and TEWL. PGI-C is not to be performed at Day 1.  
f Refer to Section 8.2.4 for details regarding the complete physical examination.   
g Refer to Section 8.2.6 for details and instructions regarding the ECG. In addition to the time points specified in the SoA, ECGs may be performed at any time 
during the study if in the opinion of the Investigator it is clinically warranted. 
h Bidirectional posterior-anterior view and lateral view chest X-ray, or as indicated by local treatment guidelines or practice, will be performed at screening. If 
a chest X-ray was performed within 6 months of screening and no clinically significant abnormality was observed, it can be skipped at screening. 
i Refer to Section 8.2.5 for details and instructions regarding vital signs. 
j If a negative QuantiFERON®-TB test result was obtained within 6 months of screening, it can be skipped at screening. The FSH testing is performed for 
women not of childbearing potential who are postmenopausal (at least 12 months of amenorrhea without an alternative medical cause). An adolescent 
subject who experiences menarche during the trial will be considered a WOCBP (refer to Appendix 1 for definition of WOCBP) and will be required to follow 
the contraceptive guidance in Appendix 1 and undergo scheduled pregnancy testing. Additional pregnancy testing may be performed whenever a menstrual 
cycle is missed or when pregnancy is otherwise suspected. Refer to Appendix 10 for details and instructions regarding clinical laboratory parameters.  
k On Day 1, samples for PK will be collected at predose and 2 hours (± 10 min) post SC administration. In addition, samples for PK will also be collected at the 
time points specified in Table 4. 
l On these days, blood for PK and ADA will only be collected from adult subjects (≥ 18 years). Adolescent subjects who reach 18 years of age during the study 
and are reconsented as adults will follow the adult schedule for PK and ADA assessments (refer also to Table 4 and Table 5). 
m For subjects with Netherton syndrome only. 
n All randomized subjects will be asked to participate in the skin biopsy test; however, the subject’s participation is optional. Subjects should provide their 
consent to participate in the skin biopsies. Tape stripping will be performed for all randomized subjects as part of this study (not optional). Tape strips and 
punch biopsies will be collected from the same location (if applicable) on Day 1, 29, 113, and 169 (from lesional skin).  
o At selected study centers only. 
p Subjects will be contacted by phone on Days 3, 15, 43, and 71, to assess for AEs and concomitant medications. 
q During the placebo-controlled period, subjects will receive either ANB019 or placebo SC administered as follows: a 400-mg dose of ANB019 or placebo on 
Day 1; a 200-mg dose of ANB019 or placebo on Days 29, 57, and 85. The placebo-controlled period ends on Day 113 (Week 16) visit, before study treatment 
administration. All subjects will receive ANB019 on Day 113 (Week 16) visit. Subjects assigned to ANB019 during the placebo-controlled period will continue 
to receive a 200-mg dose of ANB019 on Days 113, 141, 169, and 197. Subjects assigned to placebo during the placebo-controlled period will receive a 
400-mg dose of ANB019 on Day 113, followed by a 200-mg dose of ANB019 on Days 141, 169, and 197. 
r Type/frequency of emollient application (if applicable) must be recorded by the subject in a diary throughout the study. Bath/shower time and duration 
must be recorded by the subject in a diary throughout the study. 
s At screening, prior medications should be reviewed and documented. Refer to Section 6.5. 
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should not receive further doses of the monoclonal antibody. Symptoms of an apparent allergic reaction 
to the drug, also known as ‘cytokine release syndrome’, vary dramatically but can include:  
 Mild to moderate fever, chills, headache, nausea, and vomiting 
 Moderate to severe symptoms such as edema, hypotension, and pulmonary infiltrates (eg, blood 
and mucus in the lung) 
Such reactions should be managed as clinically indicated and according to standard clinical practice. 
2.3.2 
KNOWN POTENTIAL BENEFITS  
Subjects with ichthyosis may or may not receive direct benefit from participating in this study. An 
improvement in the condition as a result of participating in the study may be observed since all subjects 
will receive the active treatment at some point during the study.  
Participation in this study also may help generate future benefit for larger groups of patients with 
ichthyosis if ANB019 proves to be successful in treating this disease.  
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
All quality, pharmacology and toxicology data, and satisfactory safety and tolerability data 
demonstrated in nonclinical and clinical studies are considered sufficient to expect a positive 
benefit/risk ratio for the treatment of ichthyosis with ANB019, and therefore to initiate this study. 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, proper study 
design, and close monitoring. 
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9. 
Known or suspected autoimmune disorder, including but not limited to rheumatoid arthritis, 
systemic lupus erythematosus, polymyalgia rheumatica, giant cell arteritis, Bechet’s disease, 
dermatomyositis, multiple sclerosis, moderate to severe asthma, or other severe forms of atopy, 
any autoimmune vasculitis, autoimmune hepatitis, or any other active autoimmune disease for 
which a subject requires medical follow-up or medical treatment. 
10. History of known or suspected congenital or acquired immunodeficiency state, or condition that 
would compromise the subject’s immune status (eg, history of splenectomy). 
11. Any major surgery within 4 weeks of Day 1. 
12. History of cancer or lymphoproliferative disease within 5 years prior to Day 1. Subjects with 
successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or 
localized carcinoma in situ of the cervix are not to be excluded. 
13. History of any significant drug allergy or reaction (such as anaphylaxis or hepatotoxicity) and 
reactivity to polysorbate-20, a component of ANB019 formulation, or the inactive ingredients 
(excipients). 
14. Subject has taken the following drugs within the specified period prior to Day 1: 
a) 
Topical medications (including, but not limited to, corticosteroids, keratolytics, retinoids, 
crisaborole, and other phosphodiesterase 4 inhibitors) within 2 weeks prior to Day 1. 
b) 
Topical agents or systemic agents that could affect pruritus (such as topical antipruritic agents, 
gabapentin, pregabalin, doxepin, and aprepitant) within 2 weeks prior to Day 1. 
Note: Other drugs that may have an effect on pruritus and that are used to treat other 
conditions may be allowed if started at least 4 weeks before Day 1 and are on a stable dose 
during the entire study. 
Note: Over the counter topical products containing pramoxine 1% are allowed during the 
entire study. 
c) 
Oral sedative H1 antihistaminic (including but not limited to diphenhydramine) within 2 weeks 
prior to Day 1. 
Note: Oral nonsedative H1 antihistaminic to treat allergies will be permitted during the study 
only if the subject has been on a stable dose for at least 2 weeks prior to Day 1 and continues 
to use the same agent at the same frequency throughout the study. 
d) 
Systemic therapy (including, but not limited to retinoids, cyclosporin, methotrexate, 
corticosteroids) or any other immunosuppressant or immunomodulation drugs within 4 weeks 
prior to Day 1. 
e) 
Previous treatment with anti-IL-36R, anti-IL-36, anti-tumor necrosis factor (TNF)/ 
IL-12/IL-23/ IL-17, or any other mAbs within 12 weeks or 5 half-lives (whichever is longer) prior 
to Day 1. 
f) 
Any nonbiologic investigational drug within 4 weeks or 5 half-lives, whichever is longer prior to 
Day 1. 
g) 
Marketed or investigational biological agent within 12 weeks or 5 half-lives (whichever is 
longer) prior to Day 1. 
h) 
Antibiotic medication within 4 weeks (topical 1 week and systemic 4 weeks) prior to Day 1. 
i) 
Systemic antiviral medication within 4 weeks prior to Day 1. 
j) 
Live attenuated vaccine within 12 weeks prior to Day 1. 
15. Active TB or latent TB infection as indicated by a positive QuantiFERON®-TB Gold test at screening 
or within 6 months prior to screening (if the test is indeterminate, it can be repeated only once), 
chest X-ray, and/or clinical examination, or has had active TB disease at any time in the past. 
16. Clinically significant drug or alcohol abuse in the last year prior to Day 1, or other factors limiting 
the ability to cooperate and to comply with the study protocol, as determined by the Investigator. 
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6.1.2 
DOSING AND ADMINISTRATION 
Study treatment dosing and administration details are provided in Table 2. 
Table 2: Study Treatment Details 
Study 
Treatment 
Name: 
ANB019 
Anti-interleukin 36 receptor monoclonal 
antibody 
Placebo 
 
Dosage Form: 
Solution for injection 
Solution for injection 
Source of 
procurement: 
AnaptysBio, Inc. 
AnaptysBio, Inc. 
Study 
Treatment 
Description 
ANB019 will be provided as a sterile, colorless 
to yellow, and clear to slightly opalescent 
solution supplied in a single use, 2R, Type I 
glass vial with a fill volume of 1.2 mL. Each 
vial contains 120 mg of ANB019 at a 
concentration of 100 mg/mL. 
The placebo contains no active ingredient and 
will be provided as a sterile, colorless to slightly 
yellowish, and clear to very slightly opalescent 
solution supplied in a single use, 2R, Type I 
glass vial with a fill volume of 1.2 mL. 
Dosage 
Formulation: 
 
ANB019 study treatment is formulated as: 
100 mg/mL ANB019 in 25 mM-histidine, 
60 mM-NaCl, 145 mM sorbitol, and 0.02% v/v 
polysorbate-20 at pH 6.0.  
The Placebo is formulated as: 25 mM-histidine, 
60 mM-NaCl, 145 mM sorbitol, and 0.02% v/v 
polysorbate-20, at pH 6.0. 
Unit Dose 
Strength(s)/ 
Dosage 
Level(s): 
Placebo-controlled period: 
Subjects assigned to ANB019 during the 
placebo-controlled period will receive the 
following doses: 
 Day 1: 400-mg dose, administered as 
2 mL × 2 SC injections of ANB019 at 200 
mg each. 
 Days 29, 57, and 85: 200-mg dose, 
administered as 2 mL × 1 SC injection of 
ANB019 at 200 mg. 
Open-label extension period: 
 Day 113 for subjects assigned to 
placebo during the placebo-controlled 
period: 400-mg dose, administered as 2 
mL x 2 SC injections of ANB019 at 200 
mg each. 
 Day 113 for subjects assigned to 
ANB019 during the placebo-controlled 
period: 200-mg dose, administered as 2 
mL x 2 SC injections; 1 SC injection of 
ANB019 at 200 mg and 1 SC injection of 
placebo. 
 Days 141, 169, and 197 for all subjects: 
200-mg dose, 2 mL × 1 SC injection. 
Placebo-controlled period: 
Subjects assigned to placebo during the 
placebo-controlled period will receive an 
equivalent volume of placebo SC administered 
on Days 1, 29, 57, and 85. 
 Day 1: 2mL × 2 SC injections of placebo. 
 Days 29, 57, and 85: 2 mL × 1 SC injection 
of placebo. 
 
 
Open-label extension period: 
There will be no placebo administration during 
the open-label extension period.  
Route of 
Administration:  
SC injection (4 doses during the 
placebo-controlled period and 4 doses during 
the open-label extension period) 
SC injection (4 doses during the 
placebo-controlled period, none during the 
open-label extension period) 
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expected. If in any doubt, Investigator is advised to discuss medications with the Medical Monitor. In 
addition, the Investigator must notify the Medical Monitor in order to make a decision as to whether the 
subject will be withdrawn from the study.  
All treatments likely to have efficacy in ichthyosis need to be discontinued prior to treatment initiation 
(prior to Day 1) with washout periods as stipulated in Table 3. All medications listed in Table 3 are also 
restricted during the study period. If treatment with any of these prohibited treatments is essential, 
then the subject must notify the study team. 
Table 3: List of Prohibited Medications 
Treatment 
Washout period 
Topical medications (including, but not limited to, corticosteroids, 
keratolytics, retinoids, other medicated topical agents)  
2 weeks prior to Day 1 
Topical agents or systemic agents that could affect pruritus (such 
as topical antipruritic agents, gabapentin, pregabalin, doxepin, 
and aprepitant) within 2 weeks prior to Day 1. 
Note: Other drugs that may have an effect on pruritus and that 
are used to treat other conditions may be allowed if started at 
least 4 weeks before Day 1 and are on a stable dose during the 
entire study. 
Note: Over the counter topical products containing pramoxine 1% 
are allowed during the entire study. 
2 weeks prior to Day 1 
Oral sedative H1 antihistaminic (including but not limited to 
diphenhydramine) 
Note: Oral nonsedative H1 antihistaminic to treat allergies will be 
permitted during the study only if the subject has been on a 
stable dose for at least 2 weeks prior to Day 1 and continues to 
use the same agent at the same frequency throughout the study. 
2 weeks prior to Day 1 
Systemic therapy (including but not limited to retinoids, 
cyclosporin, methotrexate, corticosteroids) or any other 
immunosuppressant or immunomodulation drugs 
4 weeks prior to Day 1 
Anti-IL-36R, anti-IL-36, anti-TNF/IL-12/IL-23/IL-17, or any other 
mAbs 
12 weeks or 5 half-lives (whichever is 
longer) prior to Day 1 
Any nonbiologic investigational drugs  
4 weeks or 5 half-lives (whichever is longer) 
prior to Day 1 
Marketed or investigational biological agent 
12 weeks or 5 half-lives (whichever is 
longer) prior to Day 1 
Antibiotic medication 
Topical: 1 week prior to Day 1 
Systemic: 4 weeks prior to Day 1  
Systemic antiviral medication 
4 weeks prior to Day 1 
Live attenuated vaccine 
12 weeks prior to Day 1 
Abbreviations: IL, interleukin; IL-36R, IL-36 receptor; mAb, monoclonal antibody; TNF, tumor necrosis factor. 
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The aim of this subject-reported questionnaire is to measure how much ichthyosis has affected the 
subject’s quality of life during the past 4 weeks. The iQoL-32 will be completed by the subject on a 
worksheet prior to any safety and efficacy evaluations. The questionnaire is self-explanatory and handed 
to the subject who is asked to fill it in without the need for a detailed explanation. The iQoL-32 is 
presented in Appendix 3. 
8.1.3 
DERMATOLOGY LIFE QUALITY INDEX / CHILDREN’S DERMATOLOGY LIFE QUALITY 
INDEX QUESTIONNAIRES 
The DLQI/CDLQI questionnaires will be assessed at the visits specified in the SoA (see Section 1.3). They 
are simple 10-question validated questionnaires (Finlay 1994; Lewis-Jones 1995). The DLQI/CDLQI score 
ranges from 0 (no effect on the subject’s life) to 30 (extremely large effect on the subject’s life). The aim 
of these subject-reported questionnaires is to measure how much the skin condition has affected the 
subject’s quality of life during the previous week.  
The CDLQI will be administered to subjects < 16 years old and the DLQI will be administered to subjects 
≥ 16 years old. Subjects will be administered the same questionnaire during the entire study based on 
their age at Day 1. 
The DLQI/CDLQI will be completed by the subject on a worksheet prior to any safety and efficacy 
evaluations. The questionnaires are self-explanatory and will be filled in by the subjects without the 
need for a detailed explanation. The DLQI and CDLQI are presented in Appendix 4 and Appendix 5, 
respectively. 
8.1.4 
PATIENT GLOBAL IMPRESSION OF SEVERITY  
The PGI-S will be assessed at the visits specified in the SoA (see Section 1.3). It is a single-item question, 
which asks the subject to rate the current severity of ichthyosis. The response options are “Clear skin”, 
“Mild”, “Moderate”, “Severe”.  
The PGI-S will be completed by the subject on a worksheet prior to any safety and efficacy evaluations. 
The questionnaire is self-explanatory and handed to the subject who is asked to fill it in without the 
need for a detailed explanation. The PGI-S (modified from Yalcin 2003) is presented in Appendix 6. 
8.1.5 
PATIENT GLOBAL IMPRESSION OF CHANGE  
The PGI-C will be assessed at the visits specified in the SoA (see Section 1.3). The PGI-C is a single-item, 
self-administered questionnaire, which ask the subject to rate the change in their symptom severity 
(“Very much better” to “Very much worse”). 
The PGI-C will be completed by the subject on a worksheet prior to any safety and efficacy evaluations. 
The questionnaire is self-explanatory and handed to the subject who is asked to fill it in without the 
need for a detailed explanation. The PGI-C (modified from Yalcin 2003) is presented in Appendix 7. 
8.1.6 
BODY SURFACE AREA  
The overall BSA affected by ichthyosis will be evaluated (from 0% to 100%) at the visits specified in the 
SoA (see Section 1.3). The palmar surface of one hand (using the subject’s hand and including the 
fingers) represents 1% of his or her total BSA (Thomas 2007). To be eligible, subjects must have a 
BSA ≥ 50% at Day 1. 
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8.2.1.1.1 EVENTS MEETING THE ADVERSE EVENT DEFINITION 
Events meeting the AE definition include: 
 Any abnormal laboratory test results (hematology, biochemistry, or urinalysis) or other safety 
assessments (eg, ECG, vital signs measurements), including those that worsen from Day 1, 
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 fulfill the definition 
of an AE or SAE. 
8.2.1.1.2 EVENTS NOT MEETING THE ADVERSE EVENT DEFINITION 
Events not meeting the AE definition include: 
 Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which 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. 
8.2.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS  
An AE or suspected adverse reaction is considered "serious" if, in the view of either the Investigator or 
Sponsor, it results, at any dose, in any of the following outcomes:  
 Death 
 Life-threatening adverse event – 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, which hypothetically might have caused death, if it were more severe. 
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 Inpatient hospitalization or prolongation of existing hospitalization – In general, hospitalization 
signifies that the subject has been admitted (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. 
 Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions – 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. 
 Congenital anomaly/birth defect 
 Other important medical events – Events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
Examples of such medical events include invasive or malignant cancers, allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.  
8.2.1.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1.3.1 SEVERITY OF EVENT 
The intensity of an AE is an estimate of the relative severity of the event. The Investigator will make an 
assessment of intensity for each AE and SAE reported during the study based on his or her clinical 
experience and familiarity with the literature. The following definitions are to be used to rate the 
severity of an AE: 
• Mild – Events require minimal or no treatment, is easily tolerated by the subject, causing minimal 
discomfort, and do not interfere with the subject’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning and sufficient 
discomfort to the subject. 
• Severe – Events interrupt a subject’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, 
the term “severe” does not necessarily equate to “serious”. 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. 
8.2.1.3.2 RELATIONSHIP TO STUDY TREATMENT 
All AEs must have their relationship to study treatment assessed by the Investigator who examines and 
evaluates the subject based on temporal relationship and his or her clinical judgment. Alternative 
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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. The Investigator will also consult the IB in his or her assessment. The degree of certainty 
about causality will be graded using the categories below. In a clinical study, the study treatment must 
always be suspect.  
 
Unrelated – Clinical event incontrovertibly not related to the study treatment.  
• 
Unlikely to be related – Clinical event with an incompatible time relationship to study treatment 
administration which makes a causal relationship improbable, and in which an underlying 
condition or other drugs or chemicals provides plausible explanations.  
• 
Possibly related – Clinical event with a reasonable time relationship to study treatment 
administration, and that is unlikely to be attributed to concurrent condition or other drugs or 
chemicals.  
• 
Related – Clinical event with plausible time relationship to study treatment administration and 
that cannot be explained by concurrent condition or other drugs or chemicals.  
For each AE/SAE, the Investigator must document in the medical notes that he or 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 the pharmacovigilance unit. 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 the pharmacovigilance unit within 24 hours of awareness of the event. 
The Investigator may change his or her opinion of causality in light of follow-up information and send a 
SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
8.2.1.3.3 EXPECTEDNESS  
The pharmacovigilance unit will be responsible for determining whether an AE is expected or 
unexpected as interpreted through the IB. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the study 
treatment. 
8.2.1.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study subject presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions will be captured on the appropriate eCRF. Information to 
be collected includes event description, date of onset, clinician’s assessment of severity, seriousness, 
relationship to study treatment (assessed only by those with the training and authority to make a 
diagnosis), action taken, and outcome of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship (see Section 8.2.1.3.2). All AEs will be followed to 
adequate resolution. 
Study site personnel will note the occurrence and nature of each subject’s medical condition(s) present 
prior to the informed consent signature in the appropriate section of the source document and eCRF. 
During the study, site personnel will note any change in the condition(s) and the occurrence and nature 
of any AE. Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE occurrences. 
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Should a subject experience an AE at any time after the screening visit informed consent signature until 
the end of participation in the study, the event will be recorded as an AE in the source document and 
eCRF. Any SAE related to the study participation (eg, screening procedure) will be recorded in the source 
document and eCRF from the time consent is given to participate in the study until the end of 
participation in the study (EOS/ET visit).  
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the 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 or she considers the event to be reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the pharmacovigilance unit.  
Any medical condition that is present at the time that the subject is screened will be considered as 
medical history and not reported as an AE. However, if the study subject’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE/SAE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The Investigator is responsible for appropriate medical care of subjects during the study. After the initial 
AE/SAE report, the Investigator is required to proactively follow each subject at subsequent 
visits/contacts. The Investigator also remains responsible for following through with an appropriate 
health care option for all AEs that are ongoing at the end of the study. The subject should be followed 
until the event is resolved or stable. If an AE is ongoing at the end of study, the follow-up duration is left 
to the discretion of the Investigator. Follow-up frequency will be performed at the discretion of the 
Investigator.  
Whenever possible, clinically significant abnormal laboratory results are to be reported using the 
diagnostic that resulted in the clinically significant abnormal laboratory results and not the actual 
abnormal test. 
8.2.1.5 ADVERSE EVENT REPORTING  
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 (including event term, start and stop 
dates, severity, relationship to study treatment, outcome, if serious or non-serious) in the eCRF. Each 
event must be recorded separately. 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to the 
pharmacovigilance unit in lieu of completion of the AE/SAE eCRF page. 
There may be instances when copies of medical records for certain cases are requested by the 
pharmacovigilance unit. 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 the pharmacovigilance unit. 
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. 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the pharmacovigilance unit to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
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tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
New or updated information will be recorded in the originally completed eCRF. 
8.2.1.6 SERIOUS ADVERSE EVENT REPORTING  
Prompt notification by the Investigator to the pharmacovigilance unit 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. All SAEs will be recorded and reported to the 
pharmacovigilance unit within 24 hours of awareness. The Investigator will submit any updated SAE data 
to the pharmacovigilance unit within 24 hours of receipt of the information as outlined in the Safety 
Reporting Instructions that will be provided to the sites and in the study Safety Management Plan. 
The pharmacovigilance unit will inform the Medical Monitor, the Sponsor, and Innovaderm within 
1 business day of awareness of a new SAE. The pharmacovigilance unit will process and evaluate all SAEs 
as soon as the reports are received. For each SAE received, the pharmacovigilance unit, in consultation 
with the Sponsor if needed, will make a determination as to whether the criteria for expedited reporting 
to relevant regulatory authorities have been met. 
The Sponsor or designee 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 or 
designee will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/EC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected SAEs according to local 
regulatory requirements and pharmacovigilance unit policy, and forwarded to 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 pharmacovigilance unit will review and then file it 
along with the IB and will notify the IRB/EC, if appropriate according to local requirements.  
If a subject dies while participating in the study, the Investigator will provide the pharmacovigilance unit 
with a copy of any postmortem findings.  
8.2.1.6.1 REPORTING VIA AN ELECTRONIC DATA COLLECTION TOOL  
The primary mechanism for reporting an SAE to the pharmacovigilance unit will be the EDC clinical 
database. 
If the electronic system is unavailable, then the study center will use the back-up paper SAE Report 
Form. The study center will then enter the SAE data into the EDC system as soon as it becomes available. 
After the study is completed and the database is locked, the tooled system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
If a study center receives a report of a new SAE from a subject or receives updated data on a previously 
reported SAE after the EDC system is locked, then the study center can report this information on a 
paper SAE form and email the form to the pharmacovigilance unit. 
Contacts for SAE reporting can be found in SAE form and Safety Reporting Instructions that will be 
provided to the sites. 
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8.2.1.6.2 REPORTING VIA PAPER CASE REPORT FORM  
In rare circumstances, and in the absence of EDC or email, notification by facsimile or telephone is 
acceptable for notifying the pharmacovigilance unit of an SAE. Once the EDC is available, the SAE must 
be reported in the system within 24 hours of it becoming available. 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE CRF pages within the designated reporting time frames. 
Contacts for SAE reporting can be found in Safety Reporting Instructions that will be provided to the 
sites. 
8.2.1.7 REPORTING EVENTS TO SUBJECTS  
Not applicable. 
8.2.1.8 REPORTING OF PREGNANCY  
If a female subject or a female partner of a male subject becomes pregnant during the study and up to 
28 days after the end of the study, the subject should inform the study center as soon as possible. 
If a pregnancy is reported, the Investigator should inform the pharmacovigilance unit within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 1. 
If a pregnancy occurs, it will be followed up to determine the outcome, but no longer than 6 to 8 weeks 
after the estimated delivery date, where consent has been obtained to do so. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
and ectopic pregnancy) are considered SAEs and must be reported in 24 hours of awareness as 
described in Section 8.2.1.6. 
8.2.1.9 TREATMENT OF OVERDOSE  
For this study, any dose of ANB019 or placebo administered in a volume exceeding the planned dosing 
detailed in Table 2 (Dose Strength[s]/Dosage Level[s]) will be considered an overdose. For ANB019, this 
means a dose greater than 400 mg received within a 24-hour time period on Day 1 and Day 113 (for 
subjects assigned to placebo during the placebo-controlled period) and greater than 200 mg on Days 29, 
57, 85, 113 (for subjects assigned to ANB019 during the placebo-controlled period), 141, 169, and 197. 
In the improbable event of a suspected overdose, the following procedures should be executed: 
• Administration is to be discontinued. 
• The subject is to be monitored clinically. 
• Supportive measures are to be undertaken as clinically indicated. 
• Electrocardiography and clinical laboratory evaluations (ie, blood glucose, hepatic enzymes, 
creatinine, blood urea nitrogen, creatine kinase (CK), and complete blood count) are to be 
performed and followed until all values return to Baseline levels and AEs subside, if applicable. 
No information on overdose, maximum tolerated dose, or dose-limiting toxicities for ANB019 has been 
established at this time and since there are no known antidotes for ANB019, the treatment of overdose 
is at Investigator’s discretion. 
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In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities and follow-up until 
resolution. 
3. Obtain a serum sample for PK analysis soon after the dose for SC administration. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the eCRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the Medical 
Monitor based on the clinical evaluation of the subject. 
8.2.2 
HEIGHT AND WEIGHT 
Height (cm) and weight (kg) will be collected to calculate the BMI. Height and weight will be measured 
at the time points specified in the SoA (see Section 1.3). 
8.2.3 
CHEST X-RAY 
Bidirectional posterior-anterior and lateral view chest X-ray, or as indicated by local treatment 
guidelines or practice, will be performed at screening (see Section 1.3). If a chest X-ray was performed 
within 6 months of screening and no clinically significant abnormality was observed, it can be skipped 
at screening. 
8.2.4 
PHYSICAL EXAMINATIONS 
Complete physical examinations will be performed at the time points indicated in the SoA (see 
Section 1.3). 
A complete physical examination will include assessments of general appearance; skin; head/neck; 
pulmonary, cardiovascular, gastrointestinal, lymphatic, and musculoskeletal system; extremities; eyes; 
nose; throat; and neurologic status. 
A detailed examination of the skin should be performed at the time points indicated in the SoA for the 
efficacy assessments (eg, IASI). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.5 
VITAL SIGNS 
Body temperature (°C), pulse rate (bpm), blood pressure (mmHg), and respiratory rate (breath/min) will 
be assessed at the time points specified in SoA (see Section 1.3). 
Blood pressure and pulse rate will be assessed in a seated position with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for the 
subject in a quiet setting without distractions (eg, television, cell phones). 
Vital signs including body temperature, respiratory rate, and pulse rate (after at least 5 minutes rest) 
should be measured once. Arterial blood pressure should be measured twice (at intervals of at least 
5 minutes), using a validated device.  
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8.2.6 
ELECTROCARDIOGRAMS 
A single 12-lead ECG will be obtained at the time points specified in the SoA (see Section 1.3) using a 
validated ECG machine that automatically calculates the heart rate and measures RR, PR, QRS, QT, and 
QTcF intervals. 
Additional information will be provided in a separate manual. 
The ECG will be reviewed by the Investigator or an authorized representative who is experienced in the 
evaluation of ECGs and assessed for clinical significance. 
The ECG individual data (including clinical significance that will be reported as AE) will be entered into 
the electronic data capture (EDC). 
8.2.7 
CLINICAL SAFETY LABORATORY ASSESSMENTS 
See Appendix 10 for the list of clinical laboratory tests to be performed and the SoA (see Section 1.3) for 
the timing and frequency of the tests. 
A central laboratory will be used to perform all laboratory tests except urine pregnancy dipstick which 
will be assessed by the study center staff. However, local laboratory tests will be allowed in the event 
that the central laboratory results will not be available immediately and the Investigator needs to make 
an immediate decision for any safety concerns based on laboratory results. If a local sample is required, 
it is important that the sample for central analysis is obtained at the same time. 
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 more severe than 
expected for the subject’s condition. 
For screening laboratory assessments, if any laboratory results are outside of the upper or lower limits 
listed in Section 5.1, final determination of eligibility will be at the Investigator’s discretion following 
consultation with the Medical Monitor and Sponsor. 
All laboratory tests with values considered clinically significantly abnormal during the study and 
including the subject’s last study visit (EOS) should be repeated until the values return to normal or 
Baseline or are no longer considered clinically significant or judged medically stabilized by the 
Investigator or Medical Monitor. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 10, must be conducted in 
accordance with the Laboratory Manual and the SoA. 
If laboratory values from nonprotocol 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 or AE), then the results must be recorded in the eCRF. 
8.2.8 
TELEPHONE CONTACT 
At Days 3, 15, 43 and 71, subjects will be contacted by phone to assess for safety. Study staff will review 
for any new AEs or changes in concomitant medications. Any new/changed AEs and concomitant 
medications will be recorded on the eCRF.   
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Table 4: Pharmacokinetic Sample Collection and Time Points 
Study Visit 
Pharmacokinetic Sample Time Point 
(Serum) 
Adults (≥ 18 years) 
Adolescents  
(≥ 12 to < 18 years)a 
Day 1 
Predose  
X 
X 
2 hrs ( 10 min) postdose 
X 
X 
Day 8 
Anytime 
X 
 
Day 29 
Predose 
X 
X 
Day 57 
Predose 
X 
X 
Day 85 
Predose 
X 
 
Day 113 
Predose 
X 
X 
Day 141 
Predose 
X 
 
Day 169 
Predose 
X 
 
Day 197 
Predose 
X 
 
Day 225 
Anytime 
X 
X 
Day 253 
Anytime 
X 
 
Day 281 
Anytime 
X 
X 
Abbreviations: hrs, hours; min, minutes. 
a Adolescent subjects who reach 18 years of age during the study and are reconsented as adults will follow the 
adult schedule of assessments. 
8.3.3 
IMMUNOGENICITY ASSESSMENTS 
Anti-drug antibodies (ADA) to ANB019 will be evaluated in serum samples collected from all subjects 
according to the SoA (see Section 1.3) and Table 5. Additionally, serum samples should also be collected 
at the final visit from subjects who discontinued study treatment or were withdrawn from the study. 
These samples will be tested by the Sponsor or Sponsor’s designee. Each serum sample will be divided 
into 2 aliquots (1 each for primary and a back-up). 
The detection and characterization of antibodies to ANB019 will be performed using a validated assay 
method by or under the supervision of the Sponsor.  
Serum samples will be tested in a multi-tiered approach. A validated screening assay for antibodies 
binding to ANB019 will be initially used to assess serum samples. Samples that are determined putative 
positive in the screening assay will then be subjected to a confirmatory assay to demonstrate that 
antibodies are specific to ANB019. Samples that are identified as positive in the confirmatory assay will 
be further characterized in a validated titer assay and the titer of confirmed positive samples will be 
reported. Other analyses may be performed to verify the stability of antibodies to study treatment 
and/or to further characterize the immunogenicity of study treatment.  
Samples that are confirmed positive for antibodies binding to ANB019 may be further characterized for 
their ability to neutralize the activity of the study treatment using a validated neutralizing antibody 
assay method and the presence and/or titer of ADA may be correlated to safety and PK data.  
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Table 5: Anti-Drug Antibodies Sample Collection and Time Points 
Study Visit 
Anti-Drug Antibodies Sample Time Point 
(Serum) 
Adults (≥ 18 years) 
Adolescents  
(≥ 12 to < 18 years)a 
Day 1 
Predose  
X 
X 
Day 29 
Predose 
X 
X 
Day 57 
Predose 
X 
X 
Day 85 
Predose 
X 
 
Day 113 
Predose 
X 
X 
Day 141 
Predose 
X 
 
Day 225 
Anytime 
X 
X 
Day 281 
Anytime 
X 
X 
a Adolescent subjects who reach 18 years of age during the study and are reconsented as adults will follow the 
adult schedule of assessments. 
8.3.4 
IMMUNOGLOBULIN E LEVELS EVALUATION 
Whole blood will be obtained from subjects with Netherton Syndrome for the evaluation of IgE levels. 
Samples will be collected according to the SoA (see Section 1.3). The quantification of IgE will be 
performed by the Sponsor or Sponsor’s designee using a validated method. Samples collected for IgE 
levels evaluation may also be used to correlate with safety or efficacy results. 
The actual date and time of the sample collection will be recorded in the subject’s eCRF. The details of 
blood sample collection, sample tube labeling, sample preparation, storage, and shipping procedures 
will be described in a separate manual. 
8.3.5 
BIOMARKERS ANALYSIS 
8.3.5.1 TAPE STRIPPING 
Tape strips samples will be collected according to the SoA (see Section 1.3) to measure cutaneous 
biomarkers including but not limited to IL-36R, Th-17 cytokines such as IL-17A, and markers of 
neutrophils and dendritic cells infiltration. 
The actual date and time of the sample collection will be recorded in the subject’s eCRF. The details of 
tape strips collection, sample tube labeling, sample preparation, storage, and shipping procedures will 
be described in a separate Laboratory Manual. 
The measurement of tape strips biomarkers may be performed by an additional third party (eg, a 
university Investigator) designated by the Sponsor. 
8.3.5.2 OPTIONAL SKIN BIOPSY 
Optional skin biopsy samples will be collected according to the SoA (see Section 1.3) to measure skin 
biopsy biomarkers including but not limited to IL-36R, Th-17 cytokines such as IL-17A, and markers of 
neutrophils and dendritic cells infiltration. 
The actual date and time of the sample collection will be recorded in the subject’s eCRF. The details of 
skin biopsy collection, sample tube labeling, sample preparation, storage, and shipping procedures will 
be described in a separate Laboratory Manual. 
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The measurement of skin biopsy biomarkers may be performed by an additional third party (eg, a 
university Investigator) designated by the Sponsor. 
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9.4.4 
CONCOMITANT MEDICATION 
All medications will be coded using the World Health Organization (WHO) Drug Dictionary and 
Anatomical Therapeutic Chemical (ATC) system. Each medication will be classified as prior medication if 
it is stopped prior to the first dose of study treatment, or as concomitant medication if it is ongoing at 
the time of the first dose or is started after the first dose of study treatment. Prior, concomitant, and 
rescue medications will be summarized descriptively with a by-subject listing. 
9.4.5 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the change from Baseline in IASI total score at Week 16. 
A general linear mixed model repeated measures (MMRM) analysis will be used to estimate the 
least-squares means (LSM) and associated standard errors for the change from Baseline in IASI total 
score to Week 16. The model will include change from Baseline in IASI total score at Week 16 as the 
dependent variable, fixed effects for treatment arm, categorical time point, and the treatment by time 
point interaction, and the Baseline IASI total score as a covariate. An appropriate covariance structure 
will be described in the SAP prior to database lock. Should the initial model not converge, alternate 
covariance structures or inclusion of fewer postBaseline visits (eg, Week 8 and Week 16 only) will be 
considered. Full details will be described in the SAP. The difference between LSMs (ANB019 – placebo) 
at Week 16 will be presented along with the associated 95% CI and p-value. 
Possible effect of any other covariates as well as investigation of variables through sub-group analysis 
may also be investigated. Details of such analyses will be described in the SAP. Details of specific 
alternative statistical methods will be documented in the SAP. 
In addition, descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented by 
visit. 
9.4.6 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS 
Following are the secondary efficacy endpoints: 
 Percent change from Baseline in IASI total score at Week 16 
 Proportion of subjects achieving IASI50 at Week 16 
 Change and percent change from Baseline in IASI-E and IASI-S subscores at Week 16 
9.4.6.1 CATEGORICAL ENDPOINTS 
Frequency and percentages for each response Yes/No for categorical endpoints related to IASI will be 
presented separately by visit for both treatment arms. Subjects with missing scores at a given visit will 
be considered to have not met the criteria of interest (ie, nonresponse). Estimates of the difference 
between treatments (ANB019 – placebo) will be presented along with exact 95% CIs. Treatment arms 
will be compared using an exact test, as described in the SAP. 
9.4.6.2 CONTINUOUS ENDPOINTS 
Summary statistics will be provided for absolute scores of IASI, IASI-E, and IASI-S, , as well as for change 
from Baseline by visit and treatment arm. A by-subject listing will be presented for each assessment, by 
visit. 
Summary statistics will be provided for TEWL scores as well as for change from Baseline by visit and 
treatment arm. 
Analyses involving endpoints of percent change will be implemented descriptively. 
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9.4.7 
ANALYSIS OF THE EXPLORATORY EFFICACY ENDPOINTS  
Following are the exploratory efficacy endpoints: 
 
Change and percent change from Baseline in IASI total score at Weeks 1, 4, 8 and 12 
 
Proportion of subjects achieving IASI50 at Weeks 1, 4, 8, and 12 
 
Proportion of subjects achieving IASI75 at Weeks 1, 4, 8, 12, and 16 
 
Change and percent change from Baseline in IASI-E and IASI-S subscores at Weeks 1, 4, 8, and 12 
 
Change and percent change from Baseline in NASA at Weeks 1, 4, 8, 12, and 16 (for subjects 
with Netherton Syndrome only) 
 
Proportion of subjects achieving NASA50 at Weeks 1, 4, 8, 12, and 16 (for subjects with 
Netherton Syndrome only)  
 
Change and percent change from Baseline in IGA at Weeks 1, 4, 8, 12, and 16 
 
Proportion of subjects achieving an IGA of clear (0) or almost clear (1) at Weeks 1, 4, 8, 12, and 
16 
 
Proportion of subjects with at least 2-point decrease in IGA at Weeks 1, 4, 8, 12, and 16 
 
Change and percent change from Baseline in worst and average pruritus NRS at Weeks 1, 4, 8, 
12, and 16 
 
Change and percent change from Baseline in worst and average pain NRS at Weeks 1, 4, 8, 12, 
and 16 
 
Proportion of subjects with at least 3-point decrease in worst pruritus NRS at Weeks 1, 4, 8, 12, 
and 16 for subjects with a Baseline worst pruritus NRS of at least 3 
 
Proportion of subjects with at least 4-point decrease in worst pruritus NRS at Weeks 1, 4, 8, 12, 
and 16 for subjects with a Baseline worst pruritus NRS of at least 4 
 
Proportion of subjects with at least 3-point decrease in worst pain NRS at Weeks 1, 4, 8, 12, and 
16 for subjects with a Baseline worst pain NRS of at least 3 
 
Proportion of subjects with at least 4-point decrease in worst pain NRS at Weeks 1, 4, 8, 12, and 
16 for subjects with a Baseline worst pain NRS of at least 4 
 
Change from Baseline in BSA at Weeks 1, 4, 8, 12, and 16 
 
Change from Baseline in DLQI and CDLQI scores at Weeks 1, 4, 8, 12, and 16 
 
Proportion of subjects in each response category for the PGI-S and PGI-C at Weeks 1, 4, 8, 12, 
and 16 
 
Change from Baseline in iQoL-32 score at Weeks 4, 8, 12, and 16 
 
Change from Baseline in TEWL at Weeks 4, 8, 12, and 16 
 
Proportion of subjects receiving rescue medication at Weeks 4, 8, 12, and 16 
 
Proportion of subjects achieving IASI50 from Week 20 through Week 40 
 
Proportion of subjects achieving IASI75 from Week 20 through Week 40 
 
Change and percent change from Baseline in IASI total score from Week 20 through Week 40 
 
Change and percent change from Baseline in IASI-E and IASI-S subscores from Week 20 through 
Week 40 
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 
Change and percent change from Baseline in NASA from Week 20 through Week 40 (for subjects 
with Netherton Syndrome only)  
 
Proportion of subjects achieving NASA50 from Week 20 through Week 40 (for subjects with 
Netherton Syndrome only) 
 
Change and percent change from Baseline in IGA from Week 20 through Week 40 
 
Proportion of subjects achieving an IGA of clear (0) or almost clear (1) from Week 20 through 
Week 40 
 
Proportion of subjects with at least 2-point decrease in IGA from Week 20 through Week 40 
 
Change and percent change from Baseline in worst and average pruritus NRS from Week 20 
through Week 40 
 
Proportion of subjects with at least 3-point decrease in worst pruritus NRS from Week 20 
through Week 40 for subjects with a Baseline worst pruritus NRS of at least 3 
 
Proportion of subjects with at least 4-point decrease in worst pruritus NRS from Week 20 
through Week 40 for subjects with a Baseline worst pruritus NRS of at least 4 
 
Change and percent change from Baseline in worst and average pain NRS from Week 20 through 
Week 40 
 
Proportion of subjects with at least 3-point decrease in worst pain NRS from Week 20 through 
Week 40 for subjects with a Baseline worst pain NRS of at least 3 
 
Proportion of subjects with at least 4-point decrease in worst pain NRS from Week 20 through 
Week 40 for subjects with a Baseline worst pain NRS of at least 4 
 
Change from Baseline in BSA from Week 20 through Week 40 
 
Change from Baseline in iQoL-32 score from Week 20 through Week 40 
 
Change from Baseline in DLQI and CDLQI scores from Week 20 through Week 40 
 
Proportion of subjects in each response category for the PGI-S and PGI-C from Week 20 through 
Week 40 
 
Change from Baseline in TEWL from Week 20 through Week 40 
 
Proportion of subjects receiving rescue medication from Week 20 through Week 40 
Methods for analyzing the above categorical and continuous efficacy endpoints will mirror the methods 
described in Section 9.4.6.1 and 9.4.6.2, respectively. 
9.4.8 
SAFETY ANALYSES 
Following are the primary safety and tolerability endpoints: 
 Assessment of AEs, SAEs, and AEs leading to withdrawal. 
 Vital signs. 
 12-Lead ECG. 
 Clinical safety laboratory tests (hematology, biochemistry, and urinalysis). 
All safety analyses will be performed on the safety analysis set. 
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9.4.8.1 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
A TEAE is defined as: 
 A new event that occurs during or after first dose of study treatment or, 
 Any event present at Baseline that worsens in either intensity or frequency after first dose of 
study treatment. 
Adverse events will be coded using the MedDRA and only TEAEs will be summarized. Number of events 
and percentage will be tabulated by preferred term (PT) and system organ class (SOC). Multiple 
occurrences of an AE for a subject will only be counted once per SOC and PT. Percentages will be 
determined relative to the subjects in the safety analysis set for the given treatment arm. 
If the intensity or seriousness of the AE changes, the overall intensity or seriousness will be the 
maximum intensity or seriousness of the multiple occurrences. The TEAEs, SAEs, TEAEs leading to 
treatment discontinuation, and TEAEs leading to withdrawal of subject will be tabulated for each 
treatment arm. 
All AE data will be listed for each subject. 
Summaries over SOC and PT of TEAEs, TEAEs leading to death, SAEs, and TEAEs that led to 
discontinuation from the study or study treatment will be presented by treatment. Summaries will also 
be presented by relatedness to the study treatment and the severity of the TEAE. 
9.4.8.2 12-LEAD ELECTROCARDIOGRAM, VITAL SIGNS, AND CLINICAL SAFETY LABORATORY 
TESTS 
Summaries and listings of data for vital signs and safety laboratory tests result (hematology, 
biochemistry, and urinalysis) will be presented. Appropriate descriptive statistics will be summarized for 
the observed value at each scheduled assessment and for the corresponding change from Baseline. 
For hematology and biochemistry tests, listings of subject data will also flag up any abnormal or 
out-of-range values. Clinically significant changes in the laboratory test parameters will be summarized 
and listed. Hematology and biochemistry data will be reported in System International units. 
Descriptive statistics will be used to present the safety outcomes including, weight, BMI, 12-Lead ECG, 
vital signs, and clinical laboratory test results. 
Change from Baseline will also be summarized for vital signs, and clinical laboratory tests results. 
All ECG data results (normal/abnormal) will be summarized using frequency and percentage, and 
parameter values will be summarized descriptively. Clinically significant abnormalities will be presented 
in by-subject listings. 
9.4.9 
PHARMACOKINETIC ANALYSES 
Limited ANB019 PK parameter analysis will be evaluated by assessment of drug concentrations in serum. 
These drug concentrations will be listed and summarized for each sampling time point using appropriate 
descriptive statistics. The PK parameters will be summarized using appropriate descriptive statistics. 
9.4.9.1 DERIVATION OF PHARMACOKINETIC PARAMETERS 
Where possible, PK parameters will be derived using noncompartmental methods. The actual sampling 
times will be used in the PK parameter calculations. Further details of PK analysis, data handling, analysis 
procedures, and data reporting will be detailed in a separate analysis plan. 
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9.4.9.2 PHARMACOKINETIC CONCENTRATION DATA ANALYSIS 
A subject listing of all concentration-time data following SC injections will be presented by subject and 
scheduled sample collection time. 
Concentration data of ANB019 will be summarized by day and nominal time point using the number of 
observations, arithmetic mean, SD, CV, minimum, median, maximum, and geometric mean. 
Graphs for mean concentration-time data following SC administration will be presented. Individual 
subject concentration-time plots will also be presented. 
Mean trough concentrations-time data will be graphically displayed for samples collected at the visits 
specified in the SoA (see Section 1.3) to visually assess time to attainment of steady state. Time to 
steady state may also be explored by using inferential statistics, if deemed appropriate. Other 
presentations of data may be added at the discretion of the PK scientist, as appropriate, and will be 
described in detail in a separate analysis plan. 
9.4.9.3 PHARMACOKINETIC PARAMETER DATA ANALYSIS 
Where possible, PK parameters will be summarized using number of observations, arithmetic mean, SD, 
CV, minimum, median, maximum, geometric mean, and geometric CV, with the exception of time to 
maximum observed concentration (Tmax), which should be reported with n, minimum, median, and 
maximum only. 
Graphs of parameters may be added at the discretion of the PK scientist, as appropriate, and will be 
described in detail in a separate analysis plan. 
9.4.9.4 POPULATION PHARMACOKINETICS ANALYSIS 
Pharmacokinetic data from the study may also be used for population PK and PK/response analyses. If 
done, a separate analysis plan will be prepared, and results will be reported separately from the Clinical 
Study Report (CSR). 
9.4.10 IMMUNOGENICITY ANALYSES 
Observed values for ADA levels/status will be listed by-subject and summarized with descriptive 
statistics based on the safety analysis set. If data permits, correlation will be analyzed between ADA 
levels, serum concentration, and safety and efficacy endpoints. 
Frequency and percentage of ADA response will be presented and listed and correlated to safety and PK 
endpoints. 
9.4.11 IMMUNOGLOBULIN E LEVEL ANALYSES 
Observed values for IgE levels will be listed by-subject (for subjects with Netherton Syndrome only) and 
summarized with descriptive statistics based on the safety analysis set. If data permits, correlation will 
be analyzed between IgE levels, serum concentration, and safety and efficacy endpoints. 
9.4.12 BIOMARKER ANALYSES 
Tape strip and optional skin biopsy biomarkers (including but not limited to IL-36R and Th-17 cytokine) 
analysis will be performed by a third party designated by the Sponsor. A separate analysis plan will be 
created for the biomarker analyses. 
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9.4.13 PLANNED INTERIM ANALYSIS  
Interim analyses (IA) may be performed during the treatment periods (placebo-controlled period and/or 
open-label extension period) for assessment of all primary and secondary efficacy endpoints, and 
evaluation of all safety data available.  
The rationale for these analyses is to assist in making decisions for potential future development of this 
treatment. No adjustments to the current protocol are planned as a result of the interim analyses; 
therefore, overall alpha in the analyses of the primary analysis is expected to be maintained at 0.05, 
two-sided. 
Full details of the interim analysis, including procedures for maintaining the study blind for key 
personnel and the confidentiality of the results will be described in the SAP. 
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10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study subjects, Investigator, the IND Sponsor, and 
regulatory authorities, as applicable. If the study is prematurely terminated or suspended, the 
Investigator will promptly inform study subjects and the IRB/EC and will provide the reason(s) for the 
termination or suspension. Study subjects will be contacted, as applicable, and be informed of changes 
to study visit schedule.  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to subjects 
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Scientific or corporate reasons 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the Sponsor, IRB/EC and/or regulatory authorities. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Subject confidentiality and privacy are strictly held in trust by the participating Investigators, their staff, 
and the Sponsor and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to subjects. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the Sponsor.  
All research activities will be conducted in a setting as private as possible. The Investigator must assure 
that the subjects’ anonymity will be maintained and that subjects’ identities are protected from 
unauthorized parties. On CRFs or other documents submitted to the Sponsor, subjects should not be 
identified by their names, but by an identification code. The Investigator should keep a subject log 
relating codes with the names of subjects. The Investigator should maintain in strict confidence 
documents not for submission to the Sponsor (eg, subjects’ written consent forms). 
The study monitor, other authorized representatives of the Sponsor, and representatives of the IRB/EC, 
regulatory agencies, or pharmaceutical company supplying study treatment may inspect all documents 
and records required to be maintained by the Investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the subjects in this study. The clinical study site will 
permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the applicable legal or regulatory requirements, the reviewing IRB/EC, 
Institutional policies, or Sponsor requirements. 
Study subject research data, which are for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the data management company responsible for data management, 
analysis, and reporting. This will not include the subject’s contact or identifying information. Rather, 
individual subjects and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical study centers and by data 
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management research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived by the Sponsor.  
All information generated in this study must be considered highly confidential and must not be disclosed 
to any persons not directly concerned with the study without written prior permission from the 
Sponsor. Authorized regulatory officials and Sponsor personnel (or their representatives) will be allowed 
full access to inspect and copy the records. All study investigational product, subject bodily fluids, and/or 
other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed 
to in writing by the Sponsor. Subjects will only be identified by unique subject numbers on eCRFs. Every 
subject will be given a copy of each version of the ICF that he or she signs before and during the study. 
Each ICF may also include authorization allowing the institution, Investigator, and Sponsor to use and 
disclose personal health information in compliance with the Health Information Portability and 
Accountability Act (HIPAA). 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
With the subject’s approval and approval by IRB/EC, de-identified biological samples will be stored at a 
certified, licensed central laboratory. During the conduct of the study, a subject may choose to withdraw 
consent to have biological specimens stored for future research. Once samples have been analyzed 
specimens will be destroyed. If no analyses have been completed within 5 years following EOS, samples 
will be destroyed.  
10.1.5 MEDICAL MONITOR 
Medical monitoring will be conducted to ensure the early recognition, identification and reporting of 
issues impacting on subjects’ health and well-being throughout the trial. Details of medical monitoring 
with contact information of the Medical Monitors will be documented in a Medical Monitoring Plan. 
10.1.6 SAFETY OVERSIGHT 
No Data and Safety Monitoring Board is required as part of this study. 
10.1.7 CLINICAL MONITORING 
All aspects of the study will be monitored by the Sponsor or authorized representatives of the Sponsor 
according to GCP and Standard Operating Procedures (SOPs) for compliance with applicable government 
regulations, (ie, Informed Consent Regulations [US 21CFR, Part 50] and Institutional Review Board 
regulations [US 21CFR, Part 56.103]).  
Access to all records, both during the study and after study completion, should be made available to the 
Sponsor at any time for review and audit to ensure the integrity of the data. The Investigator must notify 
Sponsor immediately if the responsible IRB/EC has been disqualified or if proceedings leading to 
disqualification have begun.  
The Investigator must conduct the protocol in accordance with applicable GCP regulations and 
guidelines; applicable informed consent regulations (US 21CFR, Part 50); and in compliance with the 
Declaration of Helsinki. Every attempt must be made to follow the protocol and to obtain and record all 
data requested for each subject at the specified times. If data are not recorded per protocol, the reasons 
must be clearly documented on the eCRF/records.  
Before study initiation, at a study center initiation visit or at a meeting with the Investigator(s), a 
representative from the Sponsor will review the protocol and study eCRFs with the Investigator(s) and 
their staff. During the study, the study monitor will visit the study center regularly to check the 
completeness of subject records, the accuracy of entries on the eCRFs, the adherence to the protocol 
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and to GCP, the progress of enrollment, and to ensure that consent is being sought and obtained in 
compliance with applicable regulations, and that the study drug is being stored, dispensed and 
accounted for according to specifications.  
The Investigator and key study personnel must be available to assist the monitor during these visits. The 
Investigator must give the monitor access to relevant hospital or clinical records, to confirm their 
consistency with the eCRF entries. No information in these records about the identity of the subjects will 
leave the study center.  
Monitoring standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of primary efficacy and safety 
variables. Additional checks of the consistency of the source data with the eCRFs will be performed 
according to the study-specific Monitoring Plan.  
The Investigator must promptly complete the eCRFs after the subject’s visit. The monitor is responsible 
for reviewing them and clarifying and resolving any data queries. A copy of the eCRFs will be retained by 
the Investigator who must ensure that it is stored in a secure place with other study documents, such as 
the protocol, the IB, and any protocol amendments.  
The Investigator must provide the Sponsor and the responsible IRB/EC with a study summary shortly 
after study completion, or as designated by the Sponsor. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.   
Quality control (QC) procedures will be implemented beginning with the data entry system, and data QC 
checks, which will be run on the database, will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, ICH GCP, and applicable regulatory requirements (eg, GLP, Good Manufacturing 
Practices [GMP]).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the Sponsor, and inspection by IRB/EC and local 
and regulatory authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
All protocol-specified data will be recorded in site source documents. Study data will be entered within 
the clinical database eCRFs from the original source documents. Upon each subject’s completion of the 
study, the Investigator is required to sign and affirm the data entered in the subject CRF along with a 
statement attesting that all pages of the subject’s case report have been reviewed. All Investigator data 
attestation signatures will be made through the 21 CFR Part11 compliant EDC system. Signature stamps 
and “per signatures” are not acceptable. 
It is the Sponsor’s policy that study data be verifiable with the source data which necessitates access to 
all original recordings, laboratory reports, and other records for each subject. The Investigator must 
therefore agree to allow access to subjects’ records, and source data must be made available for all 
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study data. Subjects (or their legal representatives) must also allow access to their medical records. 
Subjects will be informed of the importance of increased record access and permission granted by 
signature on the informed consent document prior to screening.  
Checks will be performed to ensure quality, consistency, and completeness of the data. Instances of 
missing or uninterpretable data will be resolved with the Investigator or study coordinator. Data 
queries, documented within the clinical database, will be accessible to the research facility through the 
EDC system. Study center personnel will be responsible for providing resolutions to the data queries and 
for correcting the eCRFs, as appropriate. 
The Investigator must keep written or electronic source documents for every subject participating in the 
clinical study. for the appropriate document retention period. The subject file that identifies the study in 
which the subject is participating must include the subject’s available demographic and medical 
information including:  
 Name 
 Contact information 
 Year of birth 
 Sex 
 Medical history 
 Concomitant therapies/medication 
 Study visit dates 
 Performed examinations, evaluations, and clinical findings 
 Investigational product administration 
 AEs, SAEs, or pregnancy (as applicable)  
Additionally, any other documents with source data, especially original printouts of data that were 
generated by technical equipment must be included in the subject’s source document (eg, laboratory 
value listings). All these documents must have at least the subject’s study number, and the date of the 
evaluation.  
The data recorded during the course of the study will be documented in the eCRF and/or the 
study-specific forms. Before or at study termination, all data must be forwarded to the Sponsor. The 
data will then be recorded, evaluated, and stored in anonymous or coded form in accordance with 
data-protection regulations.  
Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements. Subjects who deny permission to use 
and disclose protected health information will not be eligible to participate in the study.  
The Investigator will ensure that the study documents forwarded to the Sponsor, and any other 
documents, contain no mention of subject names. Any amendments and corrections necessary will be 
undertaken in both the source documents and eCRFs (as appropriate), and countersigned by the 
Investigator, or documented designee, stating the date of the amendment/correction. Errors must 
remain legible and may not be deleted with correction aids. The Investigator must state his/her reason 
for the correction of any data. In the case of missing data/remarks, the entry spaces provided in the 
eCRF should be cancelled out so as to avoid unnecessary follow-up inquiries.  
Electronic CRFs will be kept by the Sponsor or an authorized designee in a secured area. Clinical data will 
be recorded in a computer format for subsequent statistical analyses. Data files will be stored on 
electronic media with a final master data file kept by the Sponsor after descriptive and statistical 
analyses and reports have been generated and are complete.  
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It is the responsibility of the Investigator to ensure that the study center file is maintained in accordance 
with the ICH Guidance for Industry E6(R2) GCP: Consolidated Guidance, Section 8 – Essential Documents 
for the Conduct of a Clinical Trial. 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region, and until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study treatment. These documents should be retained for a longer period, however, 
if required by local regulations or as specified in the study agreement, whichever retention period is 
longer.  
If the Investigator withdraws from the study (eg, relocation, retirement) all study-related records should 
be transferred to a mutually agreed upon designee. Notice of such transfer will be provided to the 
Sponsor in writing. No records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the Sponsor to inform the Investigator when these documents no 
longer need to be retained.  
10.1.10 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP requirements. The 
noncompliance may be either on the part of the subject, the Investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
Protocol deviations related to COVID-19 pandemic will be identified and documented accordingly. 
These practices are consistent with ICH GCP:  
 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
 5.1 Quality Assurance and Quality Control, Section 5.1.1  
 5.20 Noncompliance, Sections 5.20.1, and 5.20.2.  
It is the responsibility of the Investigator to use continuous vigilance to identify and report deviations as 
soon as possible. All deviations must be addressed in study source documents, and applicable deviations 
must be sent to the reviewing IRB/EC per their policies. The Investigator is responsible for knowing and 
adhering to the reviewing IRB/EC requirements. Further details about the handling of protocol 
deviations will be included in the Protocol Deviation Plan, Data Management Plan, Medical Monitoring 
Plan, blind data review documentation, and SAP.  
This study will be conducted as described in this protocol, except for an emergency situation in which 
the protection, safety, and well-being of the subject requires immediate intervention, based on the 
judgment of the Investigator (or a designee, appropriately trained professional designated by the 
Investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake, the Investigator or designee must contact the Medical Monitor and the Sponsor at the earliest 
possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in 
the study. This decision will be documented by the Investigator and the Medical Monitor. Please refer to 
Section 4.2 for allowable, as necessary, modifications to the protocol due to COVID-19 restrictions. 
The monitor must ensure that a prompt action is taken to secure compliance. If a noncompliance that 
significantly affects or has the potential to significantly affect human subject protection or reliability of 
trial results is discovered, the CRO and the Sponsor should perform a root cause analysis and implement 
appropriate corrective and preventive actions. 
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authorities and/or regional IRB/EC before implementation. The only exception is when an Investigator 
considers that a subject may be harmed, and immediate action is necessary. Under these circumstances, 
approval of the chairman of the IRB/EC, or an authorized designee, must be sought immediately. The 
Investigator should inform the Sponsor, and the full IRB/EC, no later than 5 working days after the 
emergency occurs. Protocol-specified safety reporting requirements must be adhered to, independent 
of any other variables.  
10.2.3 INSURANCE  
Sponsor will provide insurance in accordance with local guidelines and requirements for the subjects in 
this study. The terms of the insurance will be kept in the study files. 
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duration of the study and for 220 days (which includes the duration of relevant exposure plus the 
duration of sperm cycle) after the last dose of study treatment. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use highly effective 
methods of contraception consistently and correctly as described in the table below and during the 
protocol-defined time frame in Section 5.1, and refrain from donating oocytes for assisted reproduction 
during this period. 
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Highly Effective Contraceptive Methods: 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation 
 
Oral.  
 
Intravaginal.  
 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral. 
 
Injectable.  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
 
Intrauterine device (IUD). 
 
Intrauterine hormone-releasing system (IUS). 
 
Implants inserted beneath the skin 
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.  
 
Pregnancy Testing: 
Women of childbearing potential should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test at screening and urine pregnancy test on Day 1 (prior to 
study treatment administration). 
Additional pregnancy testing should be performed as mentioned in the SoA (see Section 1.3). 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected. Positive urine pregnancy test result should be confirmed with serum test. 
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Collection of Pregnancy Information 
Male subjects with partners who become pregnant  
The Investigator will attempt to collect pregnancy information on any male subject’s female partner 
who becomes pregnant while the male subject is in this study. This applies only to male subjects who 
receive study treatment. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, the 
Investigator will record pregnancy information on the appropriate pregnancy form and submit it to the 
pharmacovigilance unit within 24 hours of learning of the partner’s pregnancy. The female partner will 
also be followed to determine the outcome of the pregnancy. Information on the status of the mother 
and child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure.  
Any SAEs associated with the pregnancy in the male subject’s partner should also be reported to the 
pharmacovigilance unit within 24 hours of the event using the back-up Paper Report Form. 
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 
pharmacovigilance unit 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 after the 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 poststudy pregnancy related SAE considered reasonably related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 8.2.1.8. 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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89 
14. has your scalp bothered you (combing, hair care, pain, or 
itching)?  
 
 
 
 
 
15. have you changed your vacation plans or the places you go 
because the planning required by your ichthyosis was too 
complicated? 
 
 
 
 
 
16. have you felt that your ichthyosis was a handicap (aesthetic or 
physical), even if you do not consider yourself a handicapped 
person? 
 
 
 
 
 
17. have you experienced mood swings because of ichthyosis? 
 
 
 
 
 
18. Have you felt sad, discouraged or powerless in the face of your 
disease? 
 
 
 
 
 
19. have you felt lonely or withdrawn because of the disease?  
 
 
 
 
 
20. have you experienced a feeling of anger, being ‘fed up’, a 
sense of injustice because of your disease?   
 
 
 
 
 
21. have you felt afraid of the future (treatments losing their 
effectiveness, worsening, difficulty applying the creams with 
age)? 
 
 
 
 
 
22. have you felt afraid that the disease could restrain a 
romantic/sexual relationship? 
 
 
 
 
 
23. have you had the unpleasant feeling of being stared at or 
avoided by others? 
 
 
 
 
 
24. have you been afraid of being rejected or humiliated by 
others? 
 
 
 
 
 
25. have you felt afraid that others find your skin oily, sticky or 
rough? 
 
 
 
 
 
26. have you had bothersome side effects because of the 
medications? 
 
 
 
 
 
27. has the disease hampered you in performing your work or 
going about your studies? 
 
 
 
 
 
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90 
28. has your ichthyosis influenced the way you dress? 
 
 
 
 
 
29. have you had a surplus of household chores because of your 
ichthyosis (skin flakes, oily clothes)? 
 
 
 
 
 
30. have you found caring for your skin difficult and unpleasant?  
 
 
 
 
 
31. has the care taken too much of your time each day? 
 
 
 
 
 
32. has the ichthyosis caused you significant expenses or 
inconvenient administrative procedures?  
 
 
 
 
 
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30 October 2020 
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91 
Appendix 4: Dermatology Life Quality Index 
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER 
THE LAST WEEK. Please tick  one box for each question. 
 
1. Over the last week, how itchy, sore, painful or stinging has your skin 
been? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
2. Over the last week, how embarrassed or self-conscious have you been 
because of your skin? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
3. Over the last week, how much has your skin interfered with you going 
shopping or looking after your home or yard? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
4. Over the last week, how much has your skin influenced the clothes 
you wear? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
5. Over the last week, how much has your skin affected any social or 
leisure activities? 
 
 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
6. Over the last week, how much has your skin made it difficult for you 
to do any sport? 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
7. Over the last week, has your skin prevented you from working or 
studying? 
Yes 
No 
 
 
 
 
Not relevant 
 
If “No,” over the last week how much has your skin been a problem at 
work or studying? 
A lot 
A little 
Not at all  
 
 
 
 
 
 
 
8. Over the last week, how much has your  skin created problems with 
your partner or any of your close friends or relatives?   
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
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92 
9. Over the last week, how much has your  skin 
caused 
any 
sexual 
difficulties? 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
10. Over the last week, how much of a problem has the treatment for your 
skin been, for example by making your home messy, or by taking up 
time? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant 
 
©AY Finlay, GK Khan, April 1992 www.dermatology.org.uk. 
Please check you have answered EVERY question. Thank you. 
If two or more questions are left unanswered the questionnaire is not scored. If two or more response 
options are ticked, the response option with the highest score should be recorded. If there is a response 
between two tick boxes, the lower of the two score options should be recorded. 
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30 October 2020 
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93 
Appendix 5: Children’s Dermatology Life Quality Index 
The aim of this questionnaire is to measure how much your skin problem has affected you OVER THE 
LAST WEEK.  Please tick  one box for each question. 
 
1. 
Over the last week, how itchy, "scratchy", 
 
 
Very much 
 
 
 
sore or painful has your skin been? 
 
 
  
Quite a lot 
 
 
 
 
  
 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
2. 
Over the last week, how embarrassed  
 
 
Very much 
 
 
 
or self conscious, upset or sad have you  
 
 
Quite a lot 
 
 
 
been because of your skin? 
 
  
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
3. 
Over the last week, how much has your  
 
 
Very much 
 
 
 
skin affected your friendships?   
 
 
 
Quite a lot 
 
 
 
 
 
 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
4. 
Over the last week, how much have you changed 
 
Very much 
 
 
 
or worn different or special clothes/shoes 
 
 
Quite a lot 
 
 
 
because of your skin? 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
5. 
Over the last week, how much has your  
 
 
Very much 
 
 
 
skin trouble affected going out, playing, 
 
 
Quite a lot 
 
 
 
or doing hobbies? 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
6. 
Over the last week, how much have you   
 
 
Very much 
 
 
 
avoided swimming or other sports because 
 
 
Quite a lot 
 
 
 
of your skin trouble? 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
7. 
Last week, 
 
If school time: Over the  
 
Prevented school 
 
 
was it     
 
 last week, how much did 
 
Very much 
 
 
 
school   
 
your skin affect your 
 
 
Quite a lot 
 
 
time?  
 
school work? 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
 
   OR 
 
 
 
 
 
 
 
 
 
 
was it  
 
If vacation time: How much 
 
Very much 
 
 
 
vacation  
 
over the last week, has your 
 
Quite a lot 
 
 
time?     
skin problem interfered with 
 
 
Only a little 
 
 
 
 
 
 
your enjoyment of the vacation? 
Not at all 
 
 
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94 
8. 
Over the last week, how much trouble   
 
 
Very much 
 
 
 
have you had because of your skin with  
 
 
Quite a lot 
 
 
 
other people calling you names, teasing, 
 
 
Only a little 
 
 
 
bullying, asking questions or avoiding you? 
 
 
Not at all 
 
 
 
9. 
Over the last week, how much has your sleep   
 
Very much 
 
 
 
been affected by your skin problem? 
 
 
 
Quite a lot 
 
 
 
 
 
 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
10. 
Over the last week, how much of a  
 
 
 
Very much 
 
 
 
problem has the treatment for your  
 
 
 
Quite a lot 
 
 
 
skin been? 
 
 
 
 
 
 
Only a little 
 
 
 
 
 
 
 
 
 
 
  
Not at all 
 
 
 
Please check that you have answered EVERY question. Thank you.  
 
©M.S. Lewis-Jones, A.Y. Finlay, May 1993. This must not be copied without the permission of the authors. 
 
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30 October 2020 
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95 
Appendix 6: Patient-Global Impression of Severity 
Overall, how would you rate the severity of your ichthyosis now? 
1. 
 
Clear Skin 
2. 
 
Mild 
3. 
 
Moderate 
4. 
 
Severe 
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96 
Appendix 7: Patient-Global Impression of Change 
Overall, how would you rate the change in severity of your ichthyosis compared with how it was before 
you started taking the medication in this study? 
1. 
 
Very much better 
2. 
 
Much better 
3. 
 
A little better 
4. 
 
No change 
5. 
 
A little worse 
6. 
 
Much worse 
7. 
 
Very much worse 
 
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100 
Appendix 10: Clinical Laboratory Tests  
The tests detailed in Table 7 will be performed by the central laboratory. The time points are specified in 
the SoA (see Section 1.3). 
Local laboratory tests will be allowed in the event that the central laboratory results will not be available 
immediately, and the Investigator needs to take an immediate decision for any safety concerns. If a local 
sample is required, it is important that the sample for central analysis is obtained at the same time. 
Urine pregnancy dipstick will be performed at the study center prior to study treatment administration. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 5 of the 
protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 7: Protocol-required Safety Laboratory Assessments by Central Laboratory 
Laboratory 
Assessments 
Parameters 
Hematology 
Hemoglobin 
Red blood cell (RBC) count 
Hematocrit 
White Blood Cell (WBC) count with 
Differential: 
Packed cell volume (PCV) 
Neutrophils 
Mean cell hemoglobin (MCH) 
Lymphocytes 
Mean cell volume (MCV) 
Monocytes 
Mean cell hemoglobin concentration 
(MCHC) 
Eosinophils 
Basophils 
Platelet count  
 
Biochemistry 
Alanine aminotransferase (ALT) 
Creatinine 
Albumin 
Gamma glutamyl transferase (GGT) 
Alkaline phosphatase (ALP) 
Glucose 
Aspartate aminotransferase (AST) 
Potassium 
Bicarbonate 
Phosphate (Inorganic) 
Bilirubin (Total) 
Protein (Total) 
Bilirubin (Direct-only if total is 
elevated) 
Sodium 
Calcium 
Blood urea nitrogen (urea) 
Chloride 
Creatine kinase (CK) 
Uric acid 
Triglycerides 
Lactate dehydrogenase 
human C-reactive protein (hsCRP) 
Troponin 
Total cholesterol (fractions) 
Serum pregnancy 
Human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) 
Follicle stimulating 
hormone (FSH) 
In women of nonchildbearing potential only (postmenopausal woman with at least 
12 months of amenorrhea without an alternative medical cause) 
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101 
Laboratory 
Assessments 
Parameters 
Urinalysis 
Bilirubin  
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Urobilinogen 
Leukocytes 
 
 
 
Nitrites 
 
Microscopy (At discretion of Investigator 
based on urinalysis results) 
 
 
Viral serology 
Antibodies to hepatitis B core antigens 
Hepatitis B surface antigen 
Hepatitis C antibody 
 
Human immunodeficiency virus 
antibodies 
 
Tuberculosis (TB) 
screening 
QuantiFERON-TB Gold® In-Tube, the third-generation test (If the test indeterminate 
it can be retested only once) 
NOTES: Please see SoA for laboratory tests time points. 
All blood samples must be drawn prior to administration of the study treatment, unless otherwise specified. 
The date and exact time of sample collection must be recorded. 
 
 
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