Clinical trial NCT03173547
Conditions: Ichthyosis Vulgaris
Sponsor: Crown Laboratories, Inc.
Start date: 2017-04-25; Completion date: 2019-07-31
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to determine and compare the safety and efficacy of topical 146-9251 cream and vehicle cream applied twice daily for 6 weeks in subjects with moderate to severe ichthyosis vulgaris (IV).

Detailed description:

Arms: arm 1: Topical cream to be applied two times daily to specified treatment areas for 6 weeks. arm 2: Topical cream to be applied two times daily to specified treatment areas for 6 weeks.
Interventions: intervention 1: 146-9251 cream intervention 2: Vehicle cream
Intervention descriptions: intervention 1: 146-9251 cream contains an active drug and is applied topically. intervention 2: Vehicle cream does not contain an active drug and is applied topically.

Protocol documents:
Prot_SAP_000.pdf: 
Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 1 of 8 
PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Vehicle-Controlled Study To Evaluate The Safety 
And Efficacy Of 146-9251 Cream Applied Twice-Daily For Six Weeks In Subjects 
With Ichthyosis Vulgaris 
Study Type 
Phase 2 
Test Articles 
1. 
146-9251 Cream (Crown Laboratories) 
2. 
Vehicle Cream 
Study Objective 
The objective of this study is to determine and compare the safety and efficacy of 
topical 146-9251 Cream and vehicle cream applied twice daily for up to 6 weeks in 
subjects with moderate to severe ichthyosis vulgaris (IV).  
Study Design 
Double-blind, randomized, multicenter, vehicle-controlled study. 
Treatment Groups 
Eligible subjects will be randomized (1:1) to one of two treatment groups:  
1. 146-9251 Cream 
2. Vehicle cream 
The assigned test article will be applied by the subjects twice daily for up to 6 
weeks. 
Duration of Treatment 
Up to 6 weeks 
Duration of Study 
Up to 6 weeks for an individual subject 
Study Population 
Male or female subjects at least 12 years of age with moderate to severe IV. 
Total Number of Subjects 
Approximately 88 subjects will be enrolled (44 per treatment arm). 
Number of Sites 
Approximately 5 sites will participate in the study. 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
 
1. Subject is a male or female and is at least 12 years of age at the time of 
enrollment.  
2. Subject has provided written informed consent/assent. A subject under 18 years 
of age must provide written informed assent and be accompanied by the parent 
or legal guardian at the time of assent/consent signing. The parent or legal 
guardian must provide informed consent for the subject. If a subject becomes 
18 years of age during the study, the subject must provide written informed 
consent at that time to continue study participation. 
3. Subject and parent/guardian (if applicable) are willing and able to apply the 
test article(s) as directed, comply with study instructions, and commit to all 
follow-up visits for the duration of the study. 
4. Subject has a clinical diagnosis of IV involving a minimum of 5% body surface 
area (BSA) within the Treatment Area.1  The Treatment Area is defined as the 
entire body exclusive of the a) head and neck and b) mucosal areas.   
                                                 
1 1% BSA is approximately equal to the surface area of the subject’s palm and fingers, with the fingers extended yet 
grouped together, creating a flat oval-like surface area. 


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 2 of 8 
5. Subject has an Investigator’s Global Assessment (IGA) score of at least three 
(3 = moderate) at the Baseline Visit. 
6. Subject is in good general health and free of any disease state or physical 
condition that might impair evaluation of IV or which, in the investigator’s 
opinion, exposes the subject to an unacceptable risk by study participation.  
7. Females must be post-menopausal,2 surgically sterile,3 or use an effective 
method of birth control.4,5 Women of childbearing potential (WOCBP) must 
have a negative urine pregnancy test (UPT)6 at the Baseline Visit.  
Exclusion Criteria 
A subject is ineligible to enter the study if he/she meets one or more of the following 
criteria:  
 
1. Subject is pregnant, lactating, or is planning to become pregnant during the 
study. 
2. Subject is currently enrolled in an investigational drug or device study. 
3. Subject has used an investigational drug or investigational device treatment 
within 30 days prior to first application of the test article. 
4. Subject has used any topical therapy, including urea products, topical 
corticosteroids, or retinoids, in the Treatment Area within 2 weeks prior to the 
initiation of treatment.  Note: a bland emollient may be used in the Treatment 
Area up to 3 days prior to the initiation of treatment. 
5. Subject has used systemic corticosteroids within 4 weeks or retinoids within 
24 weeks prior to the initiation of treatment. 
6. Subject has stable use of vitamin or herbal supplements for less than 2 weeks 
prior to the initiation of treatment. 
7. Subject has a history of sensitivity to any of the ingredients in the test articles. 
8. Subject is known to be noncompliant or is unlikely to comply with the 
requirements of the study protocol (e.g., due to alcoholism, drug dependency, 
mental incapacity) in the opinion of the investigator.  
9. Subject has a physical condition or other dermatologic disorders (e.g., atopic, 
seborrheic or contact dermatitis, psoriasis, tinea infections, etc.) which, in the 
investigator’s opinion, might impair evaluation of IV, or which exposes the 
subject to unacceptable risk by study participation. 
Study Procedures 
Subjects can be screened for the study up to 45 days before Visit 1. During 
screening, the study requirements will be reviewed, written informed 
consent/assent obtained, and eligibility confirmed. If applicable, the washout from 
prohibited medications or treatments will be determined and implemented. These 
procedures may be combined with the Baseline Visit if medication washout is not 
required. The following procedures will take place according to the visit schedule: 
 
                                                 
2 Defined as amenorrhea greater than 12 consecutive months in women 50 years of age and older. 
3 Hysterectomy, bilateral tubal ligation (at least six months prior to initiation of treatment), or bilateral oophorectomy. 
4 Effective forms of birth control include a) hormonal contraceptives [e.g., oral, transdermal, injectable, or vaginal 
ring] (see footnote 5), b) intrauterine device (IUD) for at least one week prior to test article application, c) barrier 
methods [condom and spermicidal or diaphragm/cervical cap and spermicidal], d) monogamous relationship with a 
partner who is sterile [e.g., vasectomy performed at least six months prior to study entry], or e) total abstinence for 
subjects who are not sexually active. Subjects who become sexually active or begin to have relations with a partner 
who is not sterile during the study must agree to use an effective form of birth control for the duration of the study.  
5 WOCBP taking hormonal therapy must be on treatment prior to study entry, continued per label, and must not change 
their dosing regimen during the study; treatment must be for (1) oral: at least one complete cycle (e.g., four to eight 
weeks); (2) transdermal, injectable (e.g., Depo-Provera), or vaginal ring (e.g., NuvaRing): at least one week.  
6 UPT must have a minimum sensitivity of 25 mIU ß-hCG/mL. 


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 3 of 8 
1. Visit 1 (Day 1) - Screening/Baseline Visit: At Visit 1, study staff will explain 
the study procedures and an informed consent/assent must be signed prior to 
the 
initiation 
of 
any 
study-related 
procedures. 
At 
this 
visit, 
consenting/assenting subjects will have their medical history and 
demographics, concomitant medications and procedures/therapies, and 
inclusion/exclusion (I/E) criteria reviewed to determine subject eligibility. 
Subjects that require a “washout” period prior to enrollment into the treatment 
phase to meet I/E criteria requirements will be required to return to the clinic 
within 45 days to complete the remaining activities. Subjects who require 
“washout” for longer than 45 days will be re-consented. All WOCBP must 
have a negative UPT. A brief physical exam, vital signs (including height, and 
weight), clinical laboratory testing, photography, which is optional, at select 
site(s) per a photo guide provided by the Sponsor, and clinical evaluations will 
be performed prior to test article application. The Treatment Area will be 
defined as the entire body exclusive of a) the head and neck and b) mucosal 
areas*. The location of the IV to be treated and the percent BSA with IV in the 
Treatment Area will be recorded prior to test article application. Subjects who 
meet all inclusion criteria and no exclusion criteria will be randomized and 
assigned to the next available (lowest) subject number in ascending order. The 
test article will be weighed prior to dispensing to subjects. Test article, Subject 
Instruction Sheet, and Subject Diary with completion instructions will be 
dispensed. At this visit, study personnel will review the Subject Instruction 
Sheet and the subject and parent/guardian (if applicable) will be instructed on 
how and where to dispense and apply test article to all affected skin in the 
Treatment Area and to record applications in the Subject Diary. Subjects will 
apply the first dose of the assigned test article to all affected skin in the 
Treatment Area under staff supervision. Any adverse events (AEs) post-
application will be recorded. Subjects will apply the assigned test article to all 
affected skin in the Treatment Area twice daily for up to 6 weeks. The subject 
will then be scheduled for Visit 2. 
 
* Note disease on the neck and face if present may be treated with a bland 
moisturizer, but shall not be evaluated. 
 
2. Visit 2 (Week 2, Day 15 ± 2) and Visit 3 (Week 4, Day 29 ± 2): Subjects 
enrolled into the study will return to the clinic at Weeks 2 and 4 for the study 
staff to perform the clinical evaluations, record percent BSA with IV in the 
Treatment Area, collect, review and dispense a new Subject Diary for test 
article compliance, update concomitant medications and procedures/therapies, 
record AEs, collect and weigh used test article and dispense test article if 
necessary. Photography, which is optional, will be performed at select site(s) 
per a photo guide provided by the Sponsor.  Subjects whose IV is completely 
clear (IGA score = 0 and all clinical signs of IV = 0 [scaling = 0, fissuring = 0, 
and erythema = 0]) at Day 15 or Day 29 will complete the end of study (EOS) 
procedures. These subjects will have completed the study. Subjects whose IV 
is NOT completely clear will be instructed to continue twice daily treatment 
until the next visit and to record all applications in the Subject Diary. The 
subject will be scheduled for the next visit. 
 
3. Visit 4 (Week 6, Day 43 ± 3 [OR Day 15 ± 2 or Day 29 ± 2 for subjects who 
are clear]) – End of Treatment/End of Study or Early Discontinuation: These 
activities may occur as scheduled at the end of the 43-day treatment period or 
earlier if (a) the subject is to be dropped from the study or (b) the subject’s IV 
within the Treatment Area is completely clear at Day 15 or Day 29. At this 
visit, the study staff will perform the clinical evaluations, record percent BSA 


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 4 of 8 
with IV in the Treatment Area, perform clinical laboratory testing, perform 
photography, which is optional, at select site(s) per a photo guide provided by 
the Sponsor, update concomitant medications and procedures/therapies, record 
AEs, collect and review the Subject Diary for test article compliance and 
collect and weigh used test article. A UPT will be performed on all WOCBP. 
All subjects will exit the study. 
Study Measurements 
At each visit, the skin affected with IV in the Treatment Area defined at the 
Baseline Visit will be assessed as follows: 
 
Efficacy: 
Investigator’s Global Assessment 
The IGA score is a static evaluation of the overall or “average” degree of severity of a 
subject’s disease, taking into account all of the subject’s scaling, erythema, and 
fissuring in the Treatment Area by the investigator or designee as the subject appears 
on the day of the evaluation. This evaluation takes into consideration the three 
individual characteristics of IV (scaling, fissuring, and erythema) as well as 
hyperpigmentation with the IGA score at each visit representing the average degree of 
scaling, fissuring, and erythema (± hyperpigmentation, if present) that is eligible for 
treatment. IGA will be assessed using the following 5-point scale: clear (0), almost 
clear (1), mild (2), moderate (3), or severe (4). 
 
Clinical Signs of Ichthyosis Vulgaris 
Scaling, fissuring, and erythema in the Treatment Area will be graded using the 
following 5-point scale: clear (0), almost clear (1), mild (2), moderate (3), or severe 
(4). 
 
The degree of hyperpigmentation relative to the subject’s normal skin color 
associated with the disease affected skin in the Treatment Area will be graded using 
the following 5-point scale: none (0), minimal (1), mild (2), moderate (3), or severe 
(4). 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 5 of 8 
 
Pruritus 
At the Baseline Visit, prior to the first application of the test article, the subject’s 
overall experience of pruritus within the previous two weeks will be assessed using 
a questionnaire (5-D Pruritus Scale). At all follow-up visits, the overall experience 
of pruritus, in the previous two weeks, will be scored using the same questionnaire. 
Pruritus assessed by this evaluation should be reported as an AE only if therapy is 
required. 
 
Percent Body Surface Area with Active Ichthyosis Vulgaris in the Treatment Area 
The percent BSA with active IV within the designated Treatment Area will be 
calculated at Baseline and at all follow-up visits.  
 
Safety: 
Test Article Compliance 
Subjects will apply the first dose of test article to skin affected with IV within the 
Treatment Area under staff supervision. Subjects will be instructed to record the 
date and time that each dose was applied. At each visit, subject diaries will be 
reviewed and subjects will be counseled regarding compliance, if necessary. All 
dispensed test article will be weighed at each visit and will be recorded.   
 
Adverse Events 
All AEs will be recorded. At each visit after the Baseline Visit/Day 1, subjects will 
also be questioned specifically about the status of any ongoing AEs. 
 
Clinical Laboratory Testing and Pregnancy Testing 
Chemistries, hematology, and urinalysis and UPTs will be performed at Baseline 
and EOS. 
Study Endpoints 
Efficacy Endpoint(s): 
IGA scores and the clinical signs and symptoms of IV will be dichotomized to 
“treatment success” or “treatment failure” where “treatment success” is defined as 
at least a two grade decrease in severity score relative to Baseline. Dichotomization 
of scores for clinical signs and symptoms of IV will exclude subjects with Baseline 
scores of 0 or 1 unless the corresponding sign score at follow-up visits is >1. 
 
The primary efficacy endpoint will be the proportion of subjects with IGA 
“treatment success” at EOS, where EOS is the subjects last completed post-
Baseline visit. 
 
Secondary efficacy endpoints (observed data only) include: 
• 
The proportion of subjects with IGA “treatment success” at Days 15 and 
29.  
• 
The proportion of subjects with a IGA score of 0 or 1 representing 
“cleared” or “almost cleared” at EOS. 
• 
The proportion of subjects rated “treatment success” for each of the 
clinical signs and symptoms of IV at Days 15, 29, and EOS. 
• 
Changes in percent BSA with IV in the Treatment Area at Days 15, 29, 
and EOS relative to Baseline. 
• 
Change from Baseline in 5-D pruritus score at Days 15, 29, and EOS. 
• 
Changes in 
 at Days 15, 29, and EOS relative to Baseline. 
 


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 6 of 8 
Safety Endpoint(s): 
Safety endpoints will include assessment of UPT (as applicable), clinical laboratory 
testing, and AEs, including serious adverse events (SAEs). 
Sample Size Calculations 
No formal power calculations were conducted to establish sample size. The sample 
size was selected empirically to enable sample size calculations for future pivotal 
studies. 
Statistical Methods 
All statistical analyses and summaries will be prepared using SAS® unless 
otherwise stated. All subjects enrolled in the study who were dispensed and applied 
test article at least once will be included in the analysis of safety and will be 
considered the Safety population. All randomized subjects who were dispensed the 
test article will be considered the intent-to-treat (ITT) population. The per-protocol 
(PP) population will be a subset of the ITT population consisting of subjects who 
have completed the study without significant protocol deviations. The statistical 
analysis plan will provide details regarding inclusion in the PP population. Missing 
values for the IGA score at EOS in the ITT population will correspond to IGA 
“treatment failure”. All other analyses for both ITT and PP populations will use 
observed data only. Efficacy analyses will be performed on both the ITT and PP 
populations with the ITT population considered primary.  
 
Demographic and baseline characteristics will be summarized by treatment group 
for the Safety, ITT, and PP populations. Frequency counts and percentages will be 
reported for categorical data and sample size, mean, median, standard deviation 
(SD), minimum and maximum will be reported for the continuous variables. 
 
Efficacy Analyses: 
For each of the efficacy endpoints (IGA and signs of IV), the following summaries 
will be prepared at Days 15, 29, and EOS: 
• 
Frequency distribution of observed scores 
• 
Frequency distribution of change from Baseline 
• 
Shift tables for changes from Baseline to Visits 2, 3, and 4 
• 
Frequency distribution of treatment success rates7 
 
At EOS, 95% confidence intervals will be calculated for the difference in 
proportions between treatment groups for rates of treatment success. The treatment 
groups will be compared with respect to “treatment success” rates for IGA and each 
sign of IV using Fisher’s Exact Test. The proportion of subjects with an IGA score 
of 0 or 1 will be analyzed likewise using Fisher’s Exact Test. 
 
Descriptive statistics (including mean, median, SD, minimum, and maximum) for 
observed and change from Baseline values in the percent BSA affected in the 
Treatment Area at each visit will be presented. 
 
For 5-D pruritus score and 
, descriptive statistics for observed and 
change from baseline values will be provided by treatment group at Baseline and 
at Days 15, 29, and EOS. The treatment groups will be compared with respect to 
the change from Baseline using mixed model of repeated measures (MMRM) 
including terms for treatment, visit, treatment by visit interaction, and the Baseline 
value serving as the covariate. 
 
                                                 
7 Subjects with Baseline scores of 0 or 1 will be excluded from summaries and analyses of success rates unless the 
corresponding sign score at follow-up visits is >1.  


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 7 of 8 
Safety Analyses: 
Dosing Compliance 
Descriptive statistics will be used to summarize test article compliance for the ITT 
population. Measures of test article compliance will include the duration of 
treatment (number of days dosed), the total number of applications (determined 
from the actual number of applications reported by the subject), and the percent of 
expected doses applied. A subject will be considered compliant with the dosing 
regimen if the subject applies at least 80% but no more than 120% of the expected 
number of applications. 
 
Extent of Exposure 
The total amount of test article used (grams of test article applied) will be calculated 
from the weights of the returned test articles. Descriptive statistics (mean, median, 
SD, minimum and maximum) will be determined for the total amount of test article 
used by each subject by treatment group. 
 
Clinical Laboratory Testing, and Urine Pregnancy Testing 
A listing of the clinical laboratory results and UPT results will also be prepared. 
 
Adverse Events 
All AEs reported during the study will be listed, documenting onset, whether 
therapy was required, any change in test article dosing, severity, possible 
relationship to test article, and outcome. Verbatim terms on the case report forms 
(CRFs) will be linked to preferred terms (PTs) and system organ class (SOC) using 
the Medical Dictionary for Regulatory Activities (MedDRA) mapping system. All 
reported AEs will be summarized by the number of subjects reporting AEs, SOC, 
PT, severity, and relationship to test article by treatment group. 
 


Product Name: 146-9251 Cream 
 
Protocol: 146-9251-201 
Sponsor Name: Crown Laboratories, Inc. 
 
Protocol Date: July 17, 2017, v3.0 
 
Page 8 of 8 
SCHEDULE OF EVENTS 
Study Day 
Visit 1 
Screening/ 
Baseline1 
Day 1 
Visit 2 
Week 2 
 
Day 15 (±2) 
Visit 3 
Week 4 
 
Day 29 (±2) 
Visit 4 
Week 6 
EOT/EOS 
Day 43 (±3)2 
Informed Consent/Assent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X3 
 
 
 
Urine Pregnancy Testing4 for WOCBP5 
X3 
 
 
X2 
Medical History/Demographics 
X 
 
 
 
Brief Physical Exam  
X 
 
 
 
Vital Signs, Height, & Weight 
X 
 
 
 
Clinical Evaluations (IGA, Clinical Signs 
of IV, 
, Pruritus) 
X3 
(prior to test article 
application) 
X 
X 
X 
Record percent BSA with IV in the 
Treatment Area 
X 
X 
X 
X 
Randomization to Treatment Regimen 
(Subject # Assignment) 
X 
 
 
 
Provide (or review) Instruction Sheet to 
Subject & Parent/Guardian (if applicable) 
and Demonstrate How to Apply the Test 
Article6 
X 
X 
X 
 
Provide Subject Diary to Subject & 
Parent/Guardian (if applicable) and 
Completion Instructions 
X 
 
 
 
Clinical Laboratory Assessments 
X7 
 
 
X2 
Photography (Select Sites) 
X 
X 
X 
X 
Review/Dispense/ 
Collect Subject Diary 
 
X 
X 
X 
Weigh/Dispense Test Articles 
X 
X 
X 
 
Weigh/Collect Test Articles 
 
X 
X 
X 
Instruct Subject to Continue Twice Daily 
Treatment 
X 
X 
X 
 
Record Concomitant Medications and 
Procedures/Therapies 
X 
X 
X 
X 
Record Adverse Events 
X 
X 
X 
X8 
1. 
Screening assessment may be performed up to 45 days prior to the Baseline Visit for those qualified subjects that 
are eligible to enroll in the study but require wash-out of medications prior to enrolling into the treatment phase 
of the study. Screening and Baseline activities may be combined into a single visit if the subject does not require 
washout. 
2. 
This activity may occur at an earlier visit if the subject is discontinued from the study. 
3. 
For those subjects that required a washout period related to exclusionary medications, need to reaffirm these 
subjects meet all protocol requirements at the Baseline Visit.  
4. 
UPTs must have a minimum sensitivity of 25 mIU ß-hCG/mL of urine. 
5. 
WOCBP include any female who has experienced menarche or is 10 years of age or older and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation (within six months of initiation 
of treatment), or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive 
months in women 50 years of age and older). 
6. 
See application guidelines per protocol and in the subject instruction sheet. 
7. 
Perform laboratory tests (blood chemistries, hematology, and urinalysis). 
8. 
Any treatment related AEs that are ongoing at EOS must be followed until resolution or stabilization.