Clinical trial NCT03743038
Conditions: Acne Vulgaris
Sponsor: Vyne Therapeutics Inc.
Start date: 2018-11-20; Completion date: 2019-02-11
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Evaluator-Blinded, Bilateral Comparison Study to Evaluate the Safety and Efficacy of Two Topicals in the Treatment of Subjects With Acne Vulgaris (Study FX2018-23).

Detailed description:
A Randomized, Evaluator-Blinded, Bilateral Comparison Study to Evaluate the Safety and Efficacy of Two Topicals in the Treatment of Subjects With Acne Vulgaris. Eligible subjects will be randomized (1:1) to treatment with Test Article A to one side of the face versus Test Article B on the contralateral side.

Arms: arm 1: FMX101 hydrophobic oil based vehicle (Test Article A) topically applied daily for six weeks on one side of the face (in a split-face model) arm 2: Hydro-alcohol solution based vehicle (Test Article B) topically applied daily for six weeks on the contralateral side of the face (in a split-face model)
Interventions: intervention 1: FMX101 vehicle intervention 2: Hydro-alcohol solution
Intervention descriptions: intervention 1: FMX101 vehicle - hydrophobic oil based vehicle (Test Article A) intervention 2: Hydro-alcohol solution based vehicle (Test Article B)

Protocol documents:
Prot_000.pdf: 
A Randomized, Evaluator-Blinded, Bilateral Comparison Study of Two 
Topicals in the Treatment of Subjects with Acne Vulgaris 
ClinicalTrials.gov Identifier: NCT03743038 
Date of Protocol: 13 November 2018 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Report for Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
Report Date: June 4, 2019, v1.0 
 
 
 
 
 
CONTROLLED & CONFIDENTIAL 
Appendix 16.1.1 Protocol and Protocol Amendments 
 


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December 19,2018
IntegReview IRB
3815 S. Capital of Texas Highwa¡i, Suite 320
Austin, TX78704
Administrative letter for study FX20I8-23
Administrative Amendment#2 to Protocol FX2018-23: ARandomized, Evaluator-Blinded,
Bilateral Comparison Study of two Topicals in the Treatment of Subjects with Acne Vulgaris
To whom it may concern:
The purpose of this administrative letter is to clarify the test articles used in this study do not
contain minocycline.
Sincerely,
 
VP, Clinical Development
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TI 305-A Protocol Template, Version 07 
 
Page 1 of 57 
Template Effective Date: 31 OCT 2016 
CONTROLLED & CONFIDENTIAL 
 
A RANDOMIZED, EVALUATOR-BLINDED, BILATERAL COMPARISON 
STUDY OF TWO TOPICALS IN THE TREATMENT OF SUBJECTS WITH 
ACNE VULGARIS  
 
PROTOCOL NUMBER: 
FX2018-23 
TI PROJECT NUMBER: 
152-11051-401 
ORIGINAL PROTOCOL:  
October 18, 2018 
PROTOCOL VERSION: 
2.0 
PROTOCOL AMENDMENT #1 
November 13, 2018 
FILENAME: 
152-11051-401_protocol_13Nov2018_v2.0 
SPONSOR: 
Foamix Pharmaceuticals 
520 US Highway 22, Suite 204 
Bridgewater, NJ USA 
SPONSOR REPRESENTATIVE: 
 
  
MEDICAL MONITOR: 
 
Therapeutics, Inc. 
 
 
 
 
 
 
PROJECT MANAGER: 
 
 
 
 
 
 
 
 
24 Hour Emergency Telephone Number 
 
 
Therapeutics, Incorporated 
 
 
The information contained in this document is confidential and proprietary 
property of Foamix Pharmaceuticals. 
PPD
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Product Name: FMXI 01 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foam ix Pharmaceuticals 
Protocol Date: November 13, 2018, v2.0 
PROTOCOL APPROVAL 
The following individuals approve version 2.0 of the FX2018-23 protocol dated 
November 13, 2018. All changes to this version of the protocol must have prior written 
approval and require an amendment or administrative letter. 
Signature: -
Senior Vice President, R
 
Signature: -----
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Director, Clinical Trials
Therapeutics, Inc. Representative(s): 
Signatu
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Medical Monitor 
Signature: 
  
 
 
Vice-President, Clinical Development 
Signature 
 
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Senior Principal B -c: 
CONTROLLED & CONFIDENTIAL 
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Page 2 of 57 
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Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 3 of 57 
 
CONTROLLED & CONFIDENTIAL 
STUDY ACKNOWLEDGEMENT 
I understand this protocol contains information that is confidential and proprietary to 
Foamix Pharmaceuticals. 
 
I have read this protocol, agree that it contains all the details necessary to conduct the 
study as described, and will conduct this study following this protocol. 
 
I will provide the contents of this protocol to study staff under my direct supervision that 
need to know the contents to conduct the study. I will discuss this information with the 
study staff to ensure they are fully informed about the study and the test articles. I will 
provide the contents of the protocol to the responsible Institutional Review Board(s). 
These disclosures may be made; providing the contents are not used in any other clinical 
study and they are not disclosed to any other person or entity without prior written 
consent from Foamix Pharmaceuticals. This condition does not apply to disclosure 
required by government regulations or laws; however, I agree to give prompt notice to 
Foamix Pharmaceuticals of any such disclosure. 
 
I understand the study may be terminated or enrollment suspended at any time by 
Foamix Pharmaceuticals, with or without cause, or by me if it becomes necessary to 
protect the interests of the study subjects. 
 
Any additional information added to this protocol is also confidential and proprietary to 
Foamix Pharmaceuticals and must be treated in the same manner as the contents of this 
protocol. 
 
____________________________________ 
Printed Name of Principal Investigator 
 
____________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
 
Date 
 
Protocol number: FX2018-23  
 
 
 
Site number:                  
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 4 of 57 
 
CONTROLLED & CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Title 
A Randomized, Evaluator-Blinded, Bilateral Comparison Study of Two 
Topicals in the Treatment of Subjects with Acne Vulgaris 
Study Type 
Phase 4 
Test Articles 
1. FMX101 hydrophobic oil based vehicle (Test Article A) 
2. Hydro-alcohol solution based vehicle (Test Article B) 
Study Objective 
To evaluate the safety and efficacy of two topicals in the treatment of acne 
vulgaris. 
Study Design 
Randomized, evaluator-blinded, bilateral comparison 
Treatment Groups 
Eligible subjects will be randomized (1:1) to treatment with Test Article A 
to one side of the face versus Test Article B on the contralateral side. 
Duration of Treatment 
Once daily for six weeks. 
Duration of Study 
Each subject will participate for approximately seven weeks. 
Study Population 
Healthy male or female subjects 9 years of age or older with a clinical 
diagnosis of symmetric moderate facial acne vulgaris (Grade 3 on the 
Investigator’s Global Assessment [IGA]), ≥16 inflammatory lesions (i.e., 
papules and pustules) on the face, and no more than two active nodules on 
the face. 
Total Number of 
Subjects 
Approximately 12 subjects will be enrolled to obtain at least 10 evaluable 
subjects.  
Number of Sites 
One to two sites will participate in the study. 
Inclusion Criteria 
 
To enter the study, a subject must meet the following criteria:  
 
1. 
Subject is a healthy male or non-pregnant, non-breastfeeding female 
9 years of age or older at the time of consent/assent.  
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 has a clinical diagnosis of moderate facial acne vulgaris, with 
an identical IGA score (IGA Grade 3) on both the right and left side 
of the face at Visit 1/Baseline. 
NOTE: Right or Left side of the face refers to the subject’s 
Right or Left side of his/her face. 
4. 
Subject must have a minimum of 16 inflammatory lesions (papules 
and pustules) on the face at Visit 1/Baseline. The inflammatory lesion 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 5 of 57 
 
CONTROLLED & CONFIDENTIAL 
count on the right and left side of the face should be similar (defined 
as within ~ 50% of each other based on the side with the higher lesion 
count; e.g., if the left side of the face has 17 lesions, then 50% of 17 
is 8.5, rounding up to nine (9) lesions; this means that the right side 
can have as few as eight lesions [17 minus 9]) and have a minimum 
of eight lesions on each side. 
5. 
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. 
6. 
Subject must be willing and able to refrain from use of all other 
topical products in the Treatment Area, all acne medications other 
than test article, and all antibiotics during the study period. 
7. 
Subject, in the investigator’s opinion, is in good general health and 
free of any disease state or physical condition that might impair 
evaluation of facial acne vulgaris or otherwise impact the integrity of 
the study, or exposes the subject to an unacceptable risk by study 
participation. 
8. 
Females must be surgically sterile1 or use an effective method of birth 
control.2,3 Women of childbearing potential (WOCBP) must have a 
negative urine pregnancy test (UPT)4 at Visit 1/Baseline.  
9. 
Subject is willing to use only the supplied non-medicated cleanser and 
to refrain from use of any other acne medication, medicated cleanser, 
excessive sun exposure, and tanning booths for the duration of the 
study. 
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 has active nodulocystic acne or acne conglobata, acne 
fulminans, or other forms of acne (e.g., acne mechanica). 
                                                 
 
1 Hysterectomy, bilateral tubal ligation (at least six months prior to initiation of treatment), or bilateral 
oophorectomy. 
2 Effective forms of birth control include a) hormonal contraceptives [e.g., oral, transdermal, injectable, 
implantable, or vaginal ring] (see next footnote), b) intrauterine device 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.  
3 WOCBP who are currently taking and want to remain on hormonal therapy (e.g., oral, transdermal, 
injectable, implantable, vaginal ring) must continue treatment per label and must not change their dosing 
regimen during the study. In addition, WOCBP taking hormonal therapy for any reason (e.g., as 
contraception, etc.) must be on the same treatment for at least three months prior to study entry. For subjects 
that do not meet the above requirements; the washout period for hormonal therapy is discontinuation of use 
at least eight weeks prior to the start of the study. 
4 UPT must have a minimum sensitivity of 25 mIU ß-hCG/mL. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 6 of 57 
 
CONTROLLED & CONFIDENTIAL 
3. 
Subject has more than two facial nodules/cysts (where nodule/cyst is 
defined as an inflammatory lesion greater than or equal to 0.5 cm in 
size with or without cystic changes) in total with no more than one 
nodule/cyst per the right or left side of the face.   
4. 
Subject has any skin condition that, in the investigator’s opinion, 
could interfere with the diagnosis or assessment of acne vulgaris (e.g., 
on the face: rosacea, dermatitis, psoriasis, squamous cell carcinoma, 
eczema, acneiform eruptions caused by medications, steroid acne, 
steroid folliculitis, or bacterial folliculitis).  
5. 
Subject has folliculitis on the face. 
6. 
Subject has excessive facial hair (e.g., beards, sideburns, moustaches) 
or other facial attributes that, in the investigator’s opinion, would 
interfere with diagnosis or assessment of acne vulgaris. 
7. 
Subject has a history of hypersensitivity or allergy to any of the test 
articles and/or any of the ingredients in the test articles. 
8. 
Subject has used the following medications: 
Within one week prior to randomization: 
• 
Medicated facial cleansers on the face. 
• 
Any topical acne treatments on the face.  
Within four weeks prior to randomization: 
• 
Topical retinoids on the face. 
• 
Topical anti-inflammatories and/or corticosteroids on the face. 
• 
Topical corticosteroids on body areas other than the face for 
more than 15 consecutive days and on more than 10% of the 
body surface area (BSA). In body folds, such as axillary and 
inguinal regions, only mild topical steroids are allowed for short 
term use (≤15 consecutive days). 
• 
Systemic antibiotics. 
• 
Systemic acne treatments. 
Within 12 weeks prior to randomization: 
• 
Systemic retinoids. 
• 
Systemic corticosteroids (Note: Intranasal and inhaled 
corticosteroids may be used throughout the trial if the subject is 
on a stable dose [i.e., consistent use over a 4-week period]). 
9. 
Subject has used oral contraceptives or estrogen for less than three 
continuous months prior to Visit 1/Baseline. 
10. 
Subject has used a sauna during the two weeks prior to randomization. 
11. 
Subject has had epilation of the face within two weeks prior to 
randomization. 
12. 
Subject is planning surgery during the study. 
13. 
Subject has the need or plans to be exposed to artificial tanning 
devices or excessive sunlight during the study. 
14. 
Subject is currently enrolled in an investigational drug, device, or 
biologic study. 
15. 
Subject has used an investigational drug or investigational device 
treatment within 30 days prior to first application of the test article. 
16. 
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.  


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 7 of 57 
 
CONTROLLED & CONFIDENTIAL 
17. 
Subject and parent/guardian (if applicable) are unable to 
communicate or cooperate with the investigator due to language 
problems, poor mental development, or impaired cerebral function. 
18. 
Subject has a documented drug addiction or alcohol abuse within the 
last two years. Heavy drinking levels defined by The Substance 
Abuse and Mental Health Services Administration 13 as drinking five 
or more alcoholic drinks on the same occasion on each of five or more 
days in the past 30 days. 
19. 
Subject has a documented history of depression that is not, in the 
opinion of the investigator, currently adequately controlled with 
medication.  
Study Procedures 
NOTE: Clinical evaluations (Right and Left Facial IGA and lesion 
counts) will be performed by a Blinded Evaluator who is not involved in 
randomization, test article application instructions, or documentation of 
test article compliance. The same Blinded Evaluator should evaluate a 
subject over the course of the study.  
 
Subjects can be screened for the study up to 45 days before Baseline. During 
screening, the study requirements will be reviewed, written informed 
consent/assent obtained, and eligibility confirmed. These procedures may be 
combined with the Baseline Visit if wash out from prohibited medications is 
not required. If applicable, qualified subjects can wash out from prohibited 
acne medications or treatments prior to their Baseline Visit once they have 
been consented/assented. Subjects who require washout for longer than 45 
days will be re-consented/assented.  
 
The study will consist of a Screening/Baseline Visit and follow-up visits at 
Weeks 1, 2, 4, 6, and 7. An unscheduled in-office visit may be done at the 
discretion of the investigator for subjects with tolerability issues or a material 
adverse event (AE) concern. 
 
Visit 1 (Day 1): Screening/Baseline. The study requirements and procedures 
will be reviewed and written informed consent/assent must be obtained prior 
to the initiation of any study-related procedures. Demographics, inclusion/ 
exclusion (I/E) criteria, medical history, and concomitant medications and 
procedures/therapies will be reviewed to determine eligibility. Subjects that 
require a “washout” period prior to enrollment into the study 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. The following procedures will be 
performed on Day 1: confirmation of eligibility, demographics, medical 
history, review of concomitant medications and procedures/therapies, 
dermatologic exam, a UPT for WOCBP, clinical evaluations (Right and Left 
Facial IGA and lesion counts) by a Blinded Evaluator, Right and Left Facial 
LSR assessment, and standardized photography of the face. Note: subjects 
must have identical IGA scores (IGA Grade 3) on both the Right and 
Left side of the face at Baseline with similar lesion counts (defined as 
within ~ 50% of each other and a minimum of eight lesions on each side). 
Prior to test article application, transepidermal water loss (TEWL) and 
sebum assessment will be performed as defined in a separate procedure 
manual on the Right and Left side of the face. Qualified subjects will be 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 8 of 57 
 
CONTROLLED & CONFIDENTIAL 
randomly assigned to one of two test articles on one side with the other test 
article on the contralateral side. Test article application will be demonstrated 
by the study staff using test article supplied to the site. Test article(s) will be 
dispensed along with application instructions, and a Subject Diary will be 
provided to document applied or missed doses. Subjects will apply the first 
doses of the test article in the clinic under staff supervision to ensure proper 
application. Subjects will be instructed to apply the test article once daily in 
the evening for six weeks. LSRs will be assessed 15 minutes following test 
article application. AEs will be documented; AEs on the face will be 
segmented by Right or Left, if applicable. The subject will be scheduled for 
their next follow-up visit. 
 
Visit 2 (Week 1): Follow-up 1, Visit 3 (Week 2): Follow-up 2, and Visit 4 
(Week 4): Follow-Up 3. The subject will return to the clinic for review of 
concomitant medications and procedures/therapies. Clinical evaluations 
(IGA and lesion counts for the Right and Left side of the face) will be 
performed by a Blinded Evaluator. LSRs will be assessed for the Right and 
Left side of the face. Visit 3 and Visit 4 only: standardized photographs 
will be taken. TEWL and sebum assessment will be performed as 
defined in a separate procedure manual on the Right and Left side of 
the face. The Subject Diary will be reviewed/collected/distributed as 
necessary and test article will be returned/weighed and compliance (Right vs 
Left) will be reviewed; the site staff will remind the subject to continue to 
apply test article daily (once in the evening) until the next clinic visit and to 
not apply test article or other products (including make-up and using a 
cleanser) to the face within four hours of the next clinic visit. Test article 
application will be demonstrated at each clinic visit – emphasizing the 
importance to properly apply the test articles to the correct side of the face. 
Additional test article will be dispensed as needed. AEs will be documented; 
AEs on the face will be segmented by Right or Left, if applicable. The subject 
will be scheduled for the next visit. 
 
Visit 5 (Week 6): End of Treatment (EOT). The subject will return to the 
clinic for review of concomitant medications and procedures/therapies. A 
UPT for WOCBP will be performed as applicable. Clinical evaluations (IGA 
and lesion counts for the Right and Left side of the face) will be performed 
by a Blinded Evaluator. LSRs will be assessed for the Right and Left side of 
the face. Standardized photos will be taken. TEWL and sebum assessment 
will be performed as defined in a separate procedure manual on the Right 
and Left side of the face. Test article accountability will be documented; all 
test articles and subject diaries will be collected. AEs will be documented; 
AEs on the face will be segmented by Right or Left, if applicable. The subject 
will be scheduled for the next visit. 
 
Visit 6 (Week 7): End of Study (EOS). The subject will return to the clinic 
for review of concomitant medications and procedures/therapies. Clinical 
evaluations (IGA and lesion counts for the Right and Left side of the face) 
and LSRs will be performed on the Right and Left side of the face. TEWL 
and sebum assessment will be performed as defined in a separate procedure 
manual on the Right and Left side of the face. AEs will be documented; AEs 
on the face will be segmented by Right or Left, if applicable. Any new or 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 9 of 57 
 
CONTROLLED & CONFIDENTIAL 
ongoing treatment emergent AEs (TEAEs) at the EOT visit (Visit 5) will also 
be evaluated. The subject will exit the study.  
 
Unscheduled Visit. The investigator may see the subject at an unscheduled 
visit to manage any AEs or LSRs (if applicable). The subject will return to 
the clinic for review of concomitant medications and procedures/therapies, 
LSRs, and AEs. Test article accountability will be documented. The Subject 
Diary and test article compliance will be reviewed. All assessments will take 
into account potential differences between the Right and Left side of the face. 
The subject’s next appointment will be confirmed. 
Study Measurements 
 
Dosing Compliance: 
Measures of test article compliance will include the duration (days) of 
treatment (defined as last dose date – first dose date +1), the total number of 
applications applied and missed (determined from the doses reported in the 
Subject Diary), and the percent of expected doses applied. A subject will be 
considered compliant with the dosing regimen if the subject applies at least 
 and no more than 
 of the expected test article applications for the 
specified duration of the study for all Test Articles and does not miss the 
scheduled applications for more than three consecutive days. 
 
Efficacy and safety measurements will be assessed according to the schedule 
of events. 
 
Efficacy: 
Investigator’s Global Assessment (Right and Left Face) 
Overall severity of acne will be assessed using a five-point scale where 
0=Clear, 1=Almost Clear, 2=Mild, 3=Moderate, and 4=Severe. This is a 
static morphological scale that refers to a point in time and not a comparison 
to Baseline. 
 
Acne Lesion Counts (Right and Left Face) 
The number of non-inflammatory lesions (open and closed comedones) and 
inflammatory lesions (papules and pustules) on the face (including those 
present on the nose) will be counted. Counts of nodules and cysts will be 
reported separately and are not to be included in the inflammatory or non-
inflammatory lesion counts. 
 
VISIA (Right and Left Face) 
Digital photographs will be taken of the face with the VISIA (Canfield 
Scientific) to document the progress of the subject (right vs left sides) in the 
study at Visit 1/Baseline, Visit 3, Visit 4, and Visit 5/EOT. At the election 
of the Sponsor, they may choose to perform an independent separate analysis 
of the photographs for clinical changes relative to Baseline.  
 
Bioinstrumentation Assessments (Right and Left Face) 
TEWL and sebum measurements will be taken as specified per protocol. 
 
Safety: 
Adverse Events (segmented to Right vs Left Face application area, as/if 
appropriate) 
CCI
CCI


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 10 of 57 
 
CONTROLLED & CONFIDENTIAL 
All reported or observed AEs will be recorded. At each visit, subjects will 
also be questioned specifically about the status of any ongoing AEs. 
Untoward events that occur prior to the first dose of test article will be 
captured in the Medical History section of the case report form (CRF) unless 
they are related to a study-specific procedure. 
 
Local Skin Reactions (Right and Left Face) 
At each visit, LSRs (erythema, edema, scaling/dryness, burning/stinging, 
pruritus, erosion, and pain) will be assessed. Erythema, edema, 
scaling/dryness, and erosion will be assessed by the investigator and 
burning/stinging, pain, and pruritus will be assessed by the subject. 
Assessments will be made using a 4-point ordinal scale where 0=absent, 
1=mild (slight, barely perceptible), 2=moderate (distinct presence), and 
3=severe (marked, intense). Only LSRs that require medical intervention 
(e.g., prescription medication), require withholding or discontinuation of the 
application of the test article, or extend 2 cm beyond the Treatment Area will 
be documented as AEs. Any LSRs that are not listed above will be recorded 
as an AE. 
 
Urine Pregnancy Tests 
A UPT will be performed at Visit 1/Baseline and at Visit 5/Week 6/EOT for 
WOCBP. 
Study Endpoints 
 
Efficacy Endpoints: 
• 
IGA Assessment 
o 
IGA within subject Test Article A versus Test Article B – 
at Week 6; Test Article A > Test Article B, Test Article A 
= Test Article B, Test Article A < Test Article B. 
o 
IGA scores will be dichotomized to “success” or “failure” 
where “success” is defined as at least a two-point 
improvement in IGA score relative to Baseline, Test 
Article A versus Test Article B. 
• 
Absolute and Percent Change from Baseline to Week 6 in the 
inflammatory (papules and pustules) lesion count, within subject 
Test Article A versus Test Article B. 
• 
Absolute and Percent Change from Baseline to Week 6 in the non-
inflammatory (open and closed comedones) lesion count, within 
subject Test Article A versus Test Article B. 
• 
Sebum and TEWL assessments relative to Baseline versus Weeks 
2, 4, 6 and 7, within subject Test Article A versus Test Article B.   
• 
VISIA Digital Photographs may undergo an independent separate 
analysis for clinical changes relative to Baseline. 
 
Safety Endpoints: 
• 
Incidence (severity and causality) of any reported or observed 
TEAEs, whether or not they are considered to be related to the test 
article [Note: all application site AEs will be analyzed for Test 
Article A vs Test Article B involvement].  
• 
Number of subjects with improved/same versus worsened 
severities compared to Baseline of the following LSRs: erythema, 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 11 of 57 
 
CONTROLLED & CONFIDENTIAL 
edema, scaling/dryness, burning/stinging, pruritus, erosion, and 
pain at each time point, Test Article A vs Test Article B. 
Sample Size 
Calculations 
This is a pilot proof of principle study, as such no specific power calculations 
were used to establish the sizing of this study. 
Statistical Methods 
All statistical processing will be performed using SAS® Version 9.4 unless 
otherwise stated.  
 
Study Populations: 
The Safety population will include all randomized subjects who received test 
article and applied at least one application.  
 
The modified intent-to-treat (mITT) population will include all randomized 
subjects who met all I/E criteria, applied at least one dose of test article, and 
returned for at least one post-Baseline evaluation visit.  
 
The per-protocol (PP) population will include all randomized subjects who met 
all mITT population criteria, were compliant with the assigned test articles 
based on the subject diaries (applied at least 
 and no more than 
 of 
the expected test article applications for the specified duration of the study), 
did not miss the scheduled test article applications for more than three 
consecutive days (i.e., three consecutive days with no test article application), 
have no other evidence of material dosing noncompliance, and completed the 
primary endpoint evaluation at Week 6 within the designated visit window (±3 
days) with no significant protocol violations and prohibited medications that 
would affect the treatment evaluation.  
 
Dosing Compliance: 
As appropriate, outcomes relative to Test Article A vs Test Article B will be 
tabulated. Descriptive statistics will be used to summarize test article 
compliance for each analysis population. Compliant subjects are defined as 
those who apply at least 
 and no more than 
 of the expected test 
article applications (Right and Left face), and did not miss scheduled 
applications for more than three consecutive days. The percentage of 
compliant subjects will also be presented. 
 
Efficacy Analyses: 
As appropriate outcomes relative to the Test Article A vs Test Article B will 
be tabulated for all visits. The efficacy analyses conducted on the mITT and 
PP populations will be compiled using descriptive statistics only for all 
efficacy variables.  
 
Safety Analyses:  
As appropriate, outcomes relative to the Test Article A vs Test Article B will 
be tabulated. All safety analyses will be performed in the Safety population 
unless otherwise stated. 
 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. The number and percent of unique 
subjects reporting each TEAE will be summarized by MedDRA system 
CCI
CCI
CCI
CCI


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 12 of 57 
 
CONTROLLED & CONFIDENTIAL 
organ class (SOC), MedDRA preferred term (PT), and treatment group. AEs 
will also be similarly summarized by SOC, PT, maximum severity, and 
treatment group as well as by SOC, PT, and closest relationship to test article. 
Application site AEs will be summarized separately by treatment group. All 
AEs reported during the study will be listed.  
 
Local Skin Reactions 
The frequency of the individual LSRs (erythema, edema, scaling/dryness, 
burning/stinging, pruritus, erosion, and pain) will be tabulated by severity 
and treatment group at each onsite clinic visit. Subject counts for 
improved/same versus worsened compared to Baseline value will be also 
presented for the post-baseline visits. 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 13 of 57 
 
CONTROLLED & CONFIDENTIAL 
SCHEDULE OF EVENTS 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Unscheduled 
Visit 
 
Screening/
Baseline 
Week 1 / 
Follow –
up 1 
Week 2 / 
Follow –
up 2 
Week 4 / 
Follow –
up 3 
Week 6 / 
EOT1 
Week 7 / 
EOS 
Days 
1 
8 ± 2 
15 ± 3 
29 ± 3 
43 ± 3 
50 ± 3 
Informed Consent/Assent2 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medications 
and Procedures/Therapies 
X 
X 
X 
X 
X 
X 
X 
Dermatological Exam 
X 
 
 
 
 
 
 
UPT3 for WOCBP4 
X 
 
 
 
X 
 
 
Clinical Evaluations (IGA 
and lesion counts, R vs 
L)5 
X 
X 
X 
X 
X 
X 
 
LSR Assessment, R vs L 
X6 
X 
X 
X 
X 
X 
X 
VISIA Photography 
X 
 
X 
X 
X 
 
 
TEWL/Sebum, R vs L 
X 
 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
 
 
Test Article 
Accountability, R vs L 
X 
X 
X 
X 
X 
 
X 
Demonstrate how to apply 
test articles7 
X 
X 
X 
X 
 
 
 
Apply test articles 
X 
 
 
 
 
 
 
Subject Diary and 
Compliance Review8: 
Dispense (D), Review 
(R), and/or Collect (C) 
D 
C+R+D C+R+D C+R+D 
C+R 
 
C+R+D, as 
necessary 
Adverse Events 
X9 
X 
X 
X 
X 
X 
X 
 
1 Or early termination from the study. 
2 Consent/assent may be performed up to 45 days prior to Baseline. Subjects who require “washout” for 
longer than 45 days will be re-consented. 
3 UPTs must have a minimum sensitivity of 25 mIU ß-hCG/mL. 
4 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, or bilateral 
oophorectomy). 
5 Clinical grading to be done by the same Blinded Evaluator. 
6 LSRs will be assessed both before and 15 minutes following test article application. 
7 Study staff will provide a Subject Instruction Sheet to the subject and parent/guardian (if applicable) and 
test article application will be demonstrated using the test article samples provided to the site.  
8 Review Subject Diary and amount of test article used since last visit to determine subject compliance. Re-
educate subject on use of the test article with particular attention to inappropriate prior use of test article – 
be it amount of product applied and/or frequency of use. 
9 Recorded under Medical History. 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 14 of 57 
 
CONTROLLED & CONFIDENTIAL 
ABBREVIATIONS 
AE 
Adverse Event 
β-hCG 
Beta-Human Chorionic Gonadotropin 
BSA 
Body Surface Area 
CLIA 
Clinical Laboratory Improvement Amendments 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
IB 
Investigator Brochure 
I/E 
Inclusion/Exclusion 
IGA  
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
L 
Left 
LSR 
Local Skin Reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
mIU 
Milli International Units 
mITT 
Modified Intent-to-Treat 
PP 
Per-Protocol 
PT 
Preferred Term 
R 
Right 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Events 
TEWL 
Transepidermal Water Loss 
TI 
Therapeutics, Incorporated 
UPT 
Urine Pregnancy Test 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
Protocol Date: November 13, 2018, v2.0 
Page 15 of 57 
CONTROLLED & CONFIDENTIAL 
TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis................................................................................................................ 4 
Schedule of Events ............................................................................................................ 13 
Abbreviations .................................................................................................................... 14 
Table of Contents .............................................................................................................. 15 
1.
Background ....................................................................................................... 18 
2.
Rationale ........................................................................................................... 18 
3.
Objective ........................................................................................................... 18 
4.
Study Design ..................................................................................................... 18 
5.
Study Population ............................................................................................... 19 
5.1 
Subject Eligibility ............................................................................................. 19 
5.1.1 
Inclusion Criteria ....................................................................................... 19 
5.1.2 
Exclusion Criteria ...................................................................................... 20 
5.1.3 
Subject Withdrawal Criteria ...................................................................... 22 
6.
Test Articles and Regimen ................................................................................ 22 
6.1 
Description ........................................................................................................ 22 
6.2 
Instructions for Use and Application ................................................................ 22 
6.3 
Warnings, Precautions, and Contraindications ................................................. 23 
7.
Randomization Assignment .............................................................................. 23 
8.
Prior and Concomitant Therapies ..................................................................... 23 
8.1 
Prohibited Medications or Therapies ................................................................ 24 
8.2 
Allowed Medications or Therapies ................................................................... 25 
9.
Study Procedures .............................................................................................. 25 
9.1 
Visit 1 (Day 1): Screening/Baseline ................................................................. 26 
9.2 
Visit 2 (Day 8 ± 2): Week 1/Follow-up 1, Visit 3 (Day 15 ± 3): Week 2/Follow-
up 2, and Visit 4 (Day 29 ± 3): Week 4/Follow-up 3 ....................................... 27 
9.3 
Visit 5 (Day 43 ± 3): Week 6/End of Treatment .............................................. 28 
9.4 
Visit 6 (Day 50 ± 3): Week 7/End of Study ...................................................... 28 
9.5 
Unscheduled Visit ............................................................................................. 29 
10.
Clinical Evaluations .......................................................................................... 29 
10.1 
Investigator’s Global Assessment ..................................................................... 29 
10.2 
Acne Lesion Counts .......................................................................................... 30 
10.3 
VISIA Photography .......................................................................................... 31 
10.4 
Bioinstrumentation Assessments ...................................................................... 31 
10.5 
Safety Evaluations ............................................................................................ 31 
10.5.1 
Adverse Events .......................................................................................... 31 
10.5.2 
Local Skin Reactions ................................................................................. 31 
10.5.3 
Urine Pregnancy Tests ............................................................................... 32 
10.5.4 
Concomitant Medications and Concurrent Procedures/Therapies ............ 32 
11.
Photography ...................................................................................................... 32 
12.
Laboratory Tests ............................................................................................... 32 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 16 of 57 
 
CONTROLLED & CONFIDENTIAL 
12.1 
Urine Pregnancy Tests ...................................................................................... 32 
13. 
End of Study Criteria ........................................................................................ 33 
13.1 
Completion of the Study ................................................................................... 33 
13.2 
Subject Discontinuation .................................................................................... 33 
13.3 
Study Termination ............................................................................................ 34 
14. 
Adverse Event Reporting .................................................................................. 34 
14.1 
Adverse Event Definitions ................................................................................ 34 
14.2 
Adverse Event Details....................................................................................... 35 
14.3 
Serious Adverse Event ...................................................................................... 37 
14.4 
Laboratory Test Abnormalities ......................................................................... 39 
14.5 
Pregnancy .......................................................................................................... 39 
15. 
Blinding/Unblinding ......................................................................................... 40 
16. 
Clinical Supplies ............................................................................................... 40 
16.1 
Test Article Information ................................................................................... 40 
16.2 
Supplies Provided by Therapeutics, Inc............................................................ 40 
16.3 
Supplies Provided by Investigator .................................................................... 40 
16.4 
Supplies Provided by Foamix Pharmaceuticals ................................................ 40 
17. 
Statistical Considerations .................................................................................. 40 
17.1 
Sample Size ....................................................................................................... 40 
17.2 
Endpoints .......................................................................................................... 41 
17.2.1 
Efficacy Endpoints .................................................................................... 41 
17.2.2 
Safety Endpoints ........................................................................................ 41 
17.3 
Statistical Methods ............................................................................................ 41 
17.3.1 
Dosing Compliance ................................................................................... 42 
17.3.2 
Efficacy Analyses ...................................................................................... 42 
17.3.3 
Safety Analyses ......................................................................................... 42 
17.3.3.1 
Adverse Events .................................................................................... 42 
17.3.3.2 
Local Skin Reactions ........................................................................... 42 
17.4 
Subgroup Analyses ........................................................................................... 43 
17.5 
Interim Analyses ............................................................................................... 43 
18. 
Ethical and Regulatory Considerations ............................................................. 43 
18.1 
Compliance with Good Clinical Practice .......................................................... 43 
18.2 
Institutional Review Board and Informed Consent .......................................... 43 
18.3 
Protocol Compliance ......................................................................................... 44 
18.4 
Protocol Revisions ............................................................................................ 44 
18.5 
Study Monitoring .............................................................................................. 44 
18.6 
Case Report Form Requirements ...................................................................... 44 
18.7 
Reports to Institutional Review Board .............................................................. 45 
18.8 
Quality Assurance Audits ................................................................................. 45 
18.9 
Records Retention ............................................................................................. 45 
18.10 Record Confidentiality ...................................................................................... 45 
19. 
References ......................................................................................................... 46 
Appendix 1 
Sample Subject Instruction Sheet .............................................................. 47 
Appendix 2 
Sample Subject Diary ................................................................................ 50 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 17 of 57 
 
CONTROLLED & CONFIDENTIAL 
Appendix 3 
Test Article Information ............................................................................ 52 
A 3.1 Test Article Packaging and Labeling ................................................................ 52 
A 3.2 Test Article Storage and Preparation ................................................................ 52 
A 3.3 Dispensing Test Article..................................................................................... 52 
A 3.4 Test Article Supply Records at Study Sites ...................................................... 53 
A 3.5 Dose Modifications ........................................................................................... 53 
A 3.6 Documentation of Application and Compliance............................................... 54 
A 3.7 Return and Destruction of Test Article Supplies .............................................. 54 
Appendix 4 
Protocol Amendments ............................................................................... 55 
 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 18 of 57 
 
CONTROLLED & CONFIDENTIAL 
1. 
BACKGROUND 
Acne vulgaris is a common disease of both males and females, usually manifesting initially 
during adolescence. The primary pathologic events are initiated in the pilosebaceous units, 
especially of sebaceous-gland-bearing areas of the face, chest, and back as a result of 
increased androgen stimulation initiated at adrenarche or puberty. As a result of both 
abnormal keratinization of the infra-infundibular portion of the pilosebaceous follicle and 
increased sebum produced in the gland, a blockage of the duct results in the unapparent 
clinical lesion of the microcomedone. Continued blockage, colonization of the follicle by 
Propionibacterium 
acnes, 
and 
generation 
of 
multiple 
chemoattractant 
and 
proinflammatory moieties may result in non-inflammatory clinical lesions, comedones, 
and inflammatory lesions: papules, pustules, nodules, and cysts [1]. 
 
FMX101 4% is a minocycline containing topical foam being developed as a treatment for 
acne vulgaris. Foamix has conducted three Phase 3 studies (FX2014-04; FX2014-05, and 
FX2017-22) to assess the safety and tolerability of FMX101 4%, which contains 
minocycline and the vehicle being studied. The treatment has been shown to be effective 
and well-tolerated. This Phase 4, Proof of Principle study (FX2018-23) will further 
evaluate the efficacy and safety of FMX101 hydrophobic oil based vehicle compared to a 
hydro-alcohol solution based vehicle for the treatment of moderate facial acne vulgaris. 
2. 
RATIONALE 
FMX101 vehicle is an oil-based formulation that may have a role in the effectiveness and 
tolerance of the FMX101 4% minocycline acne treatment. This Proof of Principle trial will 
study two formulations: the FMX101 vehicle versus a topical hydro-alcohol formulation, 
for safety and efficacy in the treatment of acne vulgaris.  
3. 
OBJECTIVE 
The objective of this study is to evaluate the safety and efficacy of the two topical 
formulations in acne vulgaris subjects. More specifically, the above formulations will be 
compared for their effect on facial sebum.  
4. 
STUDY DESIGN 
This is a randomized, evaluator-blinded, bilateral comparison study of FMX101 
hydrophobic oil based vehicle (Test Article A) and hydro-alcohol solution based vehicle 
(Test Article B) in healthy male or female subjects 9 years of age or older with facial acne 
vulgaris. Eligible subjects must have a clinical diagnosis of symmetric moderate facial acne 
vulgaris (Grade 3 on the Investigator’s Global Assessment [IGA]) and ≥16 inflammatory 
lesions (i.e., papules and pustules) on the face. Approximately 12 subjects will be enrolled 
to obtain about 10 evaluable subjects at one to two study sites. Subjects will be randomized 
(1:1) to treatment with Test Article A to one side of the face versus Test Article B on the 
contralateral side.  


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 19 of 57 
 
CONTROLLED & CONFIDENTIAL 
 
1. 
FMX101 hydrophobic oil based vehicle (Test Article A) 
2. 
Hydro-alcohol solution based vehicle (Test Article B) 
 
Subjects will be instructed to apply the assigned test articles once daily in the evening for 
six weeks to the appropriate sides of the face. The study will consist of a 
Screening/Baseline Visit, Visits at Week 1, Week 2, and Week 4, along with a Week 6/End 
of Treatment (EOT) Visit, and a Week 7/End of Study (EOS) Visit. An unscheduled in-
office visit may be completed at the discretion of the investigator for subjects with 
tolerability issues or a material adverse event (AE) concern. Efficacy measurements will 
include IGA, lesion counts, Transepidermal Water Loss (TEWL) and sebum 
measurements, and VISIA photographs. Safety measurements will include assessments of 
local skin reactions (LSRs), documentation of AEs, and a urine pregnancy test (UPT) for 
women of child-bearing potential (WOCBP).  
5. 
STUDY POPULATION 
5.1 
Subject Eligibility 
To be included in the study, subjects must meet the following inclusion and none of the 
exclusion criteria. 
5.1.1 Inclusion Criteria 
1. Subject is a healthy male or non-pregnant, non-breastfeeding female 9 years of age 
or older at the time of consent/assent.  
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 has a clinical diagnosis of moderate facial acne vulgaris, with an identical 
IGA score (IGA Grade 3) on both the right and left side of the face at 
Visit 1/Baseline. 
NOTE: Right or Left side of the face refers to the subject’s Right or Left 
side of his/her face. 
4. Subject must have a minimum of 16 inflammatory lesions (papules and pustules) 
on the face at Visit 1/Baseline. The inflammatory lesion count on the right and left 
side of the face should be similar (defined as within ~ 50% of each other based on 
the side with the higher lesion count; e.g., if the left side of the face has 17 lesions, 
then 50% of 17 is 8.5, rounding up to nine (9) lesions; this means that the right side 
can have as few as eight lesions [17 minus 9]) and have a minimum of eight lesions 
on each side. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 20 of 57 
 
CONTROLLED & CONFIDENTIAL 
5. 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. 
6. Subject must be willing and able to refrain from use of all other topical products in 
the Treatment Area, all acne medications other than test article, and all antibiotics 
during the study period. 
7. Subject, in the investigator’s opinion, is in good general health and free of any 
disease state or physical condition that might impair evaluation of facial acne 
vulgaris or otherwise impact the integrity of the study, or exposes the subject to an 
unacceptable risk by study participation. 
8. Females must be surgically sterile5 or use an effective method of birth control.6,7 
WOCBP must have a negative UPT8 at Visit 1/Baseline.  
9. Subject is willing to use only the supplied non-medicated cleanser and to refrain 
from use of any other acne medication, medicated cleanser, excessive sun exposure, 
and tanning booths for the duration of the study. 
5.1.2 
Exclusion Criteria 
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has active nodulocystic acne or acne conglobata, acne fulminans, or other 
forms of acne (e.g., acne mechanica). 
3. Subject has more than two facial nodules/cysts (where nodule/cyst is defined as an 
inflammatory lesion greater than or equal to 0.5 cm in size with or without cystic 
changes) in total with no more than one nodule/cyst per the right or left side of the 
face.   
4. Subject has any skin condition that, in the investigator’s opinion, could interfere 
with the diagnosis or assessment of acne vulgaris (e.g., on the face: rosacea, 
dermatitis, psoriasis, squamous cell carcinoma, eczema, acneiform eruptions 
caused by medications, steroid acne, steroid folliculitis, or bacterial folliculitis).  
                                                 
 
5 Hysterectomy, bilateral tubal ligation (at least six months prior to initiation of treatment), or bilateral 
oophorectomy. 
6 Effective forms of birth control include a) hormonal contraceptives [e.g., oral, transdermal, injectable, 
implantable, or vaginal ring] (see next footnote), b) intrauterine device 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.  
7 WOCBP who are currently taking and want to remain on hormonal therapy (e.g., oral, transdermal, 
injectable, implantable, vaginal ring) must continue treatment per label and must not change their dosing 
regimen during the study. In addition, WOCBP taking hormonal therapy for any reason (e.g., as 
contraception, etc.) must be on the same treatment for at least three months prior to study entry. For subjects 
that do not meet the above requirements; the washout period for hormonal therapy is discontinuation of use 
at least eight weeks prior to the start of the study. 
8 UPT must have a minimum sensitivity of 25 mIU ß-hCG/mL. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 21 of 57 
 
CONTROLLED & CONFIDENTIAL 
5. Subject has folliculitis on the face. 
6. Subject has excessive facial hair (e.g., beards, sideburns, moustaches) or other 
facial attributes that, in the investigator’s opinion, would interfere with diagnosis 
or assessment of acne vulgaris. 
7. Subject has a history of hypersensitivity or allergy to any of the test articles and/or 
any of the ingredients in the test articles. 
8. Subject has used the following medications: 
Within one week prior to randomization: 
• Medicated facial cleansers on the face. 
• Any topical acne treatments on the face.  
Within four weeks prior to randomization: 
• Topical retinoids on the face. 
• Topical anti-inflammatories and/or corticosteroids on the face. 
• Topical corticosteroids on body areas other than the face for more than 15 
consecutive days and on more than 10% of the body surface area (BSA). In 
body folds, such as axillary and inguinal regions, only mild topical steroids 
are allowed for short term use (≤15 consecutive days). 
• Systemic antibiotics. 
• Systemic acne treatments. 
Within 12 weeks prior to randomization: 
• Systemic retinoids. 
• Systemic corticosteroids (Note: Intranasal and inhaled corticosteroids may 
be used throughout the trial if the subject is on a stable dose [i.e., consistent 
use over a 4-week period]). 
9. Subject has used oral contraceptives or estrogen for less than three continuous 
months prior to Visit 1/Baseline. 
10. Subject has used a sauna during the two weeks prior to randomization. 
11. Subject has had epilation of the face within two weeks prior to randomization. 
12. Subject is planning surgery during the study. 
13. Subject has the need or plans to be exposed to artificial tanning devices or excessive 
sunlight during the study. 
14. Subject is currently enrolled in an investigational drug, device, or biologic study. 
15. Subject has used an investigational drug or investigational device treatment within 
30 days prior to first application of the test article. 
16. 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.  
17. Subject and parent/guardian (if applicable) are unable to communicate or cooperate 
with the investigator due to language problems, poor mental development, or 
impaired cerebral function. 
18. Subject has a documented drug addiction or alcohol abuse within the last two years. 
Heavy drinking levels defined by The Substance Abuse and Mental Health Services 
Administration 13 as drinking five or more alcoholic drinks on the same occasion 
on each of five or more days in the past 30 days. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 22 of 57 
 
CONTROLLED & CONFIDENTIAL 
19. Subject has a documented history of depression that is not, in the opinion of the 
investigator, currently adequately controlled with medication. 
5.1.3 Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 13.2. Subjects who are discontinued will not be replaced. 
6. 
TEST ARTICLES AND REGIMEN 
The test articles used in this study are described below. 
6.1 
Description 
Test Article A: 
FMX101 hydrophobic oil based vehicle  
Other ingredients: 
soybean oil, coconut oil, light mineral oil, cyclomethicone, 
cetostearyl alcohol, stearic acid, myristyl alcohol, hydrogenated 
castor oil, white wax (also known as beeswax), stearyl alcohol, and 
docosanol (also known as behenyl alcohol). The propellant is a 
mixture of butane, isobutane, and propane. 
 
Test Article B: 
Hydro-alcohol solution based vehicle 
Other ingredients: 
water, alcohol denatured, butylene glycol, poloxamer 124, lactic 
acid, PEG-40 hydrogenated castor oil, sodium hydroxide, glyceryl 
caprylate, phenoxyethanol, and fragrance. 
6.2 
Instructions for Use and Application  
At Visit 1/Baseline, subjects will be instructed on how to apply the test articles and will 
apply the first test article applications at the site under supervision of the study staff. 
Subjects will be instructed to apply the test articles to the appropriate sides of the face once 
daily in the evening at approximately the same time for six weeks. 
 
NOTE: Since this is a bilateral comparison study of two test articles, it is important 
that the same product be applied to the same side of the face over the six week 
treatment period. 
 
 
 
 
 
 
To minimize errors, at each clinic visit during the treatment period the study staff 
must review and emphasize the proper application of the test articles. 
 
CCI
CCI
CCI


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 23 of 57 
 
CONTROLLED & CONFIDENTIAL 
Subjects will be provided with a Subject Instruction Sheet detailing how to apply the test 
articles (see Appendix 1) and a Subject Diary (see Appendix 2) to record dates and times 
of applications. Subjects will be instructed to bring all test article containers (used and 
unused) and the Subject Diary to the study visits. At the appropriate study visits, test article 
containers will be weighed and the Subject Diary will be collected, reviewed, and a new 
one will be dispensed to the subject (as needed). Subjects will be instructed to store the test 
articles according to the directions on the label. Subjects will also be instructed not to apply 
the test articles four hours before any study visit. 
6.3 
Warnings, Precautions, and Contraindications 
These test articles are for topical use only. Care should be taken to avoid contact with eyes 
and all mucous membranes. If contact with eyes occurs, rinse thoroughly with water. 
 
Subjects with a known sensitivity to any of the ingredients in the test articles should not 
participate in this study. 
 
Should a significant skin irritation or rash develop, discontinue use. 
 
In case of accidental ingestion, subjects should contact the investigator immediately. 
 
The effects of the test article in nursing mothers, pregnant women, and their unborn 
children are unknown. WOCBP must not be pregnant or planning a pregnancy during the 
study period.  
7. 
RANDOMIZATION ASSIGNMENT 
Each subject will be randomized to the two treatment options on a 1:1 basis with one 
product (e.g. Test Article A) to one side of the face and the other product (e.g. Test Article 
B) to the contralateral side of the face. 
 
1. 
FMX101 hydrophobic oil based vehicle (Test Article A) 
2. 
Hydro-alcohol solution based vehicle (Test Article B)   
 
NOTE: Right or Left side of the face refers to the subject’s Right or Left side of 
his/her face with respect to which side of the face a given Test Article should be 
applied. 
8. 
PRIOR AND CONCOMITANT THERAPIES 
Current medications and any medications taken within 30 days prior to the start of the study 
(Visit 1/Baseline) will be recorded as prior/concomitant medications with the dose and 
corresponding indication. The medications to be recorded include prescription, over-the-
counter medications, and vitamins, minerals, and dietary supplements being taken for a 
therapeutic indication. Vitamins and mineral supplements are permitted at dosages 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 24 of 57 
 
CONTROLLED & CONFIDENTIAL 
considered by the investigator as reasonable for maintaining good health and will not be 
recorded in the case report forms (CRFs). All concomitant medications will be coded with 
the current version of the WHO Drug Dictionary. 
 
Any changes in concomitant medications and/or therapies/procedures during the study must 
be recorded. The reason for any changes in concomitant medications and/or 
therapies/procedures should be reported and should reflect either a baseline medical 
condition documented in the medical history or in conjunction with an AE. 
8.1 
Prohibited Medications or Therapies 
Prior to entry in the study or during the course of the study, subjects must not use the 
medications or procedures within the time frame prior to randomization as specified in 
Section 5.1.2. Subjects may washout from prohibited medications or treatments for acne 
vulgaris. The following medications and procedures/therapies are prohibited during the 
study from Visit 1/Baseline through Visit 6/EOS: 
 
• The use of oral contraceptives or estrogen when initiated during the study or when 
initiated for less than three continuous months prior to Visit 1/Baseline 
• Any investigational drug, device, or biologic within 30 days prior to first 
application of the test article 
• Any planned surgeries 
• Artificial tanning devices or excessive sunlight during the study 
 
Within one week prior to randomization: 
• Medicated facial cleansers on the face 
• Any topical acne treatments on the face  
 
Within two weeks prior to randomization 
• Epilation of the face 
• Use of a sauna 
 
Within four weeks prior to randomization: 
• Topical retinoids on the face 
• Topical anti-inflammatories and/or corticosteroids on the face 
• Topical corticosteroids on body areas other than the face for more than 15 
consecutive days and on more than 10% of the BSA. In body folds, such as axillary 
and inguinal regions, only mild topical steroids are allowed for short term use (≤15 
consecutive days) 
• Systemic antibiotics 
• Systemic acne treatments 
 


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Within 12 weeks prior to randomization 
• Systemic retinoids 
• Systemic corticosteroids (NOTE: Intranasal and inhaled corticosteroids use prior to 
Baseline may be used throughout the trial if the subject is on a stable dose, defined 
as continuous use in a dose regimen similar to the 4-week period prior to Baseline) 
8.2 
Allowed Medications or Therapies  
Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used during the study for the treatment or prevention of disease or to maintain good health. 
Non-prohibited chronic therapies being used at Visit 1/Baseline may be continued, but must 
be recorded. 
 
Effective methods of contraception for WOCBP are required per Inclusion Criterion #8, 
but subjects must be using the same method for at least three continuous months prior to 
Visit 1/Baseline. 
 
Estrogen therapy is allowed, but subjects must be on estrogen for at least three continuous 
months prior to Visit 1/Baseline.  
 
Vitamins and mineral supplements are permitted at dosages considered by the investigator 
as reasonable for maintaining good health; such vitamins and minerals will be recorded in 
the CRFs if taken for a therapeutic indication or in the source documents only if taken for 
general health.  
 
Minimal use of make-up (e.g., lip stick, mascara, eye shadow) is permitted after test article 
application and a one hour dry-down period. These do not need to be recorded in the CRFs. 
 
Intranasal, inhaled, and ophthalmic steroids used for the management of allergies, pulmonary 
disorders, or other conditions exclusive of acne are permitted. However, those using 
intranasal, inhaled steroid on a stable dose prior to Baseline shall continue dosing during the 
study. Medications not intended for or beneficial for the treatment of acne may be used unless 
specifically excluded or prohibited by this protocol (see Section 8.1), which includes non-
prohibited chronic therapies being used at Visit 1/Baseline. 
 
Sunscreens on the face are discouraged during the study given they can potentially affect 
skin disease. Ideally, wearing a hat is recommended. Nonetheless, when extenuating 
circumstances warrant sunscreen use, it may be used but should be recorded as a 
concomitant medication.  
9. 
STUDY PROCEDURES 
Responsibilities of the Unblinded and Blinded Evaluators are summarized in the Table 
below: NOTE: To preserve the blinding in the study the Blinded Evaluator must not 


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participate in any of the obligations of the Unblinded Evaluator. Similarly the Blinded 
Evaluator must not have access to CRFs for the activities of the Unblinded Evaluator: 
Table of Responsibilities 
Unblinded Evaluator 
Blinded Evaluator 
Tasks to be completed by the same person 
throughout the study1 
• AEs and serious AEs (SAEs) and any 
required management 
• All LSR Assessments 
Tasks to be completed by the same 
person throughout the study1 
• 
Clinical Evaluations (Right vs Left 
Facial IGA and lesion counts) 
Unblinded Evaluator or 
Qualified Designee2 
Study Staff 
• Concomitant Medications & Procedures / 
Therapies 
• Dermatological Exam 
• Urine Pregnancy Tests 
• VISIA Photography 
• TEWL/Sebum Assessment, Right vs Left 
• Randomization 
• Test Article Accountability 
• Demonstrate how to apply test articles 
• Subject Diary and Compliance Review 
General procedures that may be 
performed by either blinded or 
unblinded qualified members of the 
research staff 
• Informed Consent/Assent 
• Demographics 
• Eligibility 
• Medical History 
1 The same Blinded and Unblinded Evaluators should complete these evaluations for a 
given subject throughout the study. If this becomes impossible, an appropriately qualified 
evaluator with overlapping experience with the subject and the study should complete the 
evaluations. The same person may not complete the evaluations for both the Unblinded 
and Blinded Evaluator. 
2 Assessments can be performed by different unblinded, qualified individuals for a given 
subject, throughout the study. 
 
Specific activities for each study visit are listed below. 
9.1 
Visit 1 (Day 1): Screening/Baseline 
Prior to the start of this visit, Study Staff, the Unblinded Evaluator, and 
subjects will be reminded not to discuss the treatment, side effects, or study 
experience with the Blinded Evaluator.  
 
At Screening, the Unblinded Evaluator or designee will: 
• Obtain a signed, written informed consent/assent. 
• Record demographics. 
• Confirm I/E criteria. 


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• Record medical history. 
• Record prior and/or concomitant medications and procedures/therapies. 
 
If the subject requires washout from previous medications, the remaining activities will be 
performed after washout is complete. 
• Perform a dermatological exam of the head. Record abnormalities in medical 
history. 
• Perform a UPT for all WOCBP. The results must be negative for the subject to be 
enrolled. 
• Must be performed by a Blinded Evaluator: Perform clinical evaluations (IGA 
and lesion counts, R vs L). See Section 10.1 and Section 10.2. 
• Assess LSRs on the Right and Left sides of the face separately prior to first test 
article applications. See Section 10.5.2. 
• Perform VISIA photography. See Section 10.3. 
• Perform TEWL and sebum assessments. See Section 10.4. 
• Assign the subject the next available (lowest) subject number in ascending order 
and randomize the subject.  
• Review and dispense a Subject Instruction Sheet (see Appendix 1). 
• Dispense the Subject Diary and provide completion instructions (see Appendix 2). 
• Document Test Article Accountability. 
• Demonstrate proper test article applications and supervise the first applications in 
the clinic.  
• Assess LSRs on the Right and Left sides of the face separately 15 minutes after the 
first application of the test articles.  
• Record any AEs. 
• Schedule a follow-up visit. 
9.2 
Visit 2 (Day 8 ± 2): Week 1/Follow-up 1, Visit 3 (Day 15 ± 3): Week 2/Follow-
up 2, and Visit 4 (Day 29 ± 3): Week 4/Follow-up 3 
Prior to the start of this visit, Study Staff, the Unblinded Evaluator, and 
subjects will be reminded not to discuss the treatment, side effects, or study 
experience with the Blinded Evaluator.  
 
At this visit, the Unblinded Evaluator or designee will: 
• Query the subject for any changes in health status since the previous visit, including 
concomitant medications and procedures/therapies, and document the findings. 
• Must be performed by a Blinded Evaluator: Perform clinical evaluations (IGA 
and lesion counts, R vs L). See Section 10.1 and Section 10.2. 
• Assess LSRs on the Right and Left sides of the face separately. See Section 10.5.2. 
• At Visit 3 and Visit 4: 
o Perform VISIA photography. See Section 10.3. 
o Perform TEWL and sebum assessments. See Section 10.4. 


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• Document Test Article Accountability, weigh the test article, and collect/dispense 
the test article, as applicable. 
• Demonstrate proper application of the test articles. 
• Review compliance and collect/dispense the Subject Diary, as applicable. 
• Document any AEs. 
• Schedule the next visit. 
9.3 
Visit 5 (Day 43 ± 3): Week 6/End of Treatment 
Prior to the start of this visit, Study Staff, the Unblinded Evaluator, and 
subjects will be reminded not to discuss the treatment, side effects, or study 
experience with the Blinded Evaluator.  
 
At this visit, the Unblinded Evaluator or designee will: 
• Query the subject for any changes in health status since the previous visit, including 
concomitant medications and procedures/therapies, and document the findings. 
• Perform a UPT for all WOCBP. Any positive results must be followed. 
• Must be performed by a Blinded Evaluator: Perform clinical evaluations (IGA 
and lesion counts, R vs L). See Section 10.1 and Section 10.2. 
• Assess LSRs on the Right and Left sides of the face separately. See Section 10.5.2. 
• Perform VISIA photography. See Section 10.3. 
• Perform TEWL and sebum assessments. See Section 10.4. 
• Document Test Article Accountability, weigh the test article, and collect the test 
article. 
• Review compliance and collect the Subject Diary. 
• Document any AEs. 
• Schedule the next visit. 
9.4 
Visit 6 (Day 50 ± 3): Week 7/End of Study 
Prior to the start of this visit, Study Staff, the Unblinded Evaluator, and 
subjects will be reminded not to discuss the treatment, side effects, or study 
experience with the Blinded Evaluator.  
 
At this visit, the Unblinded Evaluator or designee will: 
• Query the subject for any changes in health status since the previous visit, including 
concomitant medications and procedures/therapies, and document the findings. 
• Must be performed by a Blinded Evaluator: Perform clinical evaluations (IGA 
and lesion counts, R vs L). See Section 10.1 and Section 10.2. 
• Assess LSRs on the Right and Left sides of the face separately. See Section 10.5.2. 
• Perform TEWL and sebum assessments. See Section 10.4. 
• Document any AEs. 
• The subject will exit the study. 


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9.5 
Unscheduled Visit 
Prior to the start of this visit, Study Staff, the Unblinded Evaluator, and 
subjects will be reminded not to discuss the treatment, side effects, or study 
experience with the Blinded Evaluator.  
 
At this visit, the Unblinded Evaluator or designee will: 
• Query the subject for any changes in health status since the previous visit, including 
concomitant medications and procedures/therapies, and document the findings. 
• Assess LSRs on the Right and Left sides of the face separately. See Section 10.5.2. 
• Document Test Article Accountability, weigh the test article, and collect/dispense 
the test article, as applicable. 
• Review compliance and collect/dispense the Subject Diary, as applicable. 
• Document any AEs. 
10. 
CLINICAL EVALUATIONS 
The following clinical evaluations will be performed according to the schedules indicated 
during the study. The same investigator should complete the evaluations for a given subject 
throughout the study. If this becomes impossible a sub-investigator with overlapping 
experience with the subject and the study should complete the evaluations. 
 
Clinical evaluations (Right and Left Facial IGA and lesion counts) will be performed 
by a Blinded Evaluator who is not involved in randomization, test article application 
instructions, or documentation of test article compliance. The same Blinded 
Evaluator should evaluate a subject over the course of the study. The study staff, the 
Unblinded Evaluator, and subjects will also be instructed not to discuss the treatment, 
AEs, SAEs, or any study experiences with the Blinded Evaluator. 
 
The Blinded Evaluator will only have access to the page in the CRF required to 
document the Right and Left Facial IGA and lesion counts; all other CRF content will 
be inaccessible. 
10.1 
Investigator’s Global Assessment 
The IGA score is a static evaluation of the overall severity or “average” degree of severity 
of a subject’s disease by the Blinded Evaluator, taking into account all of the subject’s 
facial acne lesions as the subject appears on the day of the evaluation. The investigator 
should NOT refer to any other assessments to assist with this evaluation and should 
complete the IGA score prior to performing lesion counts. This evaluation is NOT a 
comparison with the IGA at any other visit or a mathematical calculation based on counts 
of individual lesion types. Overall severity of acne will be assessed using a five-point scale 
from 0=Clear to 4=Severe. Subjects must have an identical IGA score of moderate severity 
(IGA Grade 3) on both the right and left side of the face at Baseline. 


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Grade 
Description 
0 
Clear; Normal, clear skin with no evidence of acne vulgaris 
1 
Almost clear; Rare non-inflammatory lesions may be present, with rare non-
inflamed papules (papules must be resolving and may be hyperpigmented, 
though not pink- red) 
2 
Mild; Some non-inflammatory lesions are present, with few inflammatory 
lesions (papules/pustules only; no nodulocystic lesions) 
3 
Moderate; Many non-inflammatory lesions. Multiple inflammatory lesions 
evident with several to many papules/pustules, and there may be one small 
nodulocystic lesion 
4 
Severe; Inflammatory lesions are more apparent, many comedones and 
papules/pustules, there may be a few nodulocystic lesions 
10.2 
Acne Lesion Counts 
The number of non-inflammatory lesions (open and closed comedones), inflammatory 
lesions (papules and pustules), and nodulocystic lesions (nodules and cysts) on the face 
(including those present on the nose) will be counted by the Blinded Evaluator. Subjects 
must have a minimum of 16 inflammatory lesions AND ≤ 2 nodulocystic lesions on the 
face in total (with no more than one nodule/cyst per the right or left side of the face) at 
Visit 1/Baseline.  
 
At Visit 1/Baseline, the inflammatory lesion count on the right and left side of the face 
should be similar (defined as within ~ 50% of each other). For example, if the left side of 
the face has 17 lesions, then 50% of 17 is 8.5, rounding up to nine (9) lesions; this means 
that the right side can have as few as eight lesions (17 minus 9). Subjects must have a 
minimum of eight lesions on each side. 
 
The entire face, vertically from the hairline to mandible rim and horizontally from ear to 
ear (not including any lesions on or in the ear), including the nose, will be examined. 
Lesions will be counted separately for the right and left side of the subject’s face. Lesions 
are defined as follows: 
 
Non-inflammatory lesions: 
• Comedones: open (blackheads) and closed (whiteheads). 
 
Inflammatory lesions: 
• Papules: raised inflammatory lesions with no visible purulent material. 
• Pustules: raised inflammatory lesions with visible purulent material. 
 


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Nodulocystic lesions: 
• Nodules and cysts: any circumscribed, inflammatory masses greater or equal to 
5 mm in diameter with or without cystic changes. 
10.3 
VISIA Photography 
Digital photographs will be taken of the face with the VISIA (Canfield Scientific) to 
document the progress of the subject (right vs left sides) in the study at Visit 1/Baseline, 
Visit 3, Visit 4, and Visit 5/EOT. At the election of the Sponsor, they may choose to 
perform an independent separate analysis of the photographs for clinical changes relative 
to Baseline.  
 
The investigator may also elect to photograph the subject to document AEs or other 
findings at any time during the study as they deem appropriate. 
10.4 
Bioinstrumentation Assessments 
TEWL and sebum measurements will be conducted on the right and left side of the face. 
Guidance regarding these measurements will be provided based upon additional details 
provided in a separate TEWL and Sebum Measurement Manual. 
10.5 
Safety Evaluations 
10.5.1 Adverse Events 
All reported or observed AEs will be recorded. At each visit, subjects will also be 
questioned specifically about the status of any ongoing AEs. Untoward events that occur 
prior to the first dose of test article will be captured in the Medical History section of the 
CRF unless they are related to a study-specific procedure. AEs in the face will be 
segmented to the right and/or left sides of the face. See Section 14 for details on Adverse 
Event Reporting.  
10.5.2 Local Skin Reactions 
At each visit, LSRs (erythema, edema, scaling/dryness, burning/stinging, pruritus, erosion, 
and pain) will be assessed. Erythema, edema, scaling/dryness, and erosion will be assessed 
by the investigator and burning/stinging, pain, and pruritus will be assessed by the subject. 
Assessments will be made using a 4-point ordinal scale where 0=absent, 1=mild (slight, 
barely perceptible), 2=moderate (distinct presence), and 3=severe (marked, intense). Only 
LSRs that require medical intervention (e.g., prescription medication), require withholding 
or discontinuation of the application of the test article, or extend 2 cm beyond the 
Treatment Area will be documented as AEs. LSRs will be segmented to the right and/or 
left sides of the face. Any LSR that are not listed above will be recorded as an AE. 


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10.5.3 Urine Pregnancy Tests 
A UPT will be performed at Visit 1/Baseline and at Visit 5/Week 6/EOT for WOCBP. 
10.5.4 Concomitant Medications and Concurrent Procedures/Therapies 
Concomitant medications and concurrent procedures/therapies will be reviewed at all visits 
and any changes will be recorded. 
11. 
PHOTOGRAPHY 
Photography documentation is required in this study so to participate in the study subjects 
must consent to photographs. Photographs taken as part of this study will be used to 
document the subject’s baseline disease, AEs, or other findings during the study. The site 
will be provided with suggested guidelines to assist them in taking standardized 
photographs using the VISIA Camera system at Baseline. All photographs taken as part of 
this study are for informational purposes only and are not to assist in grading or for any 
other assessment. Photographs will be compiled and reviewed and may be used to evaluate 
investigator/grader training needs, but no formal assessments will be performed. However, 
the Sponsor reserves the right to have these photos evaluated using a separate independent 
grader evaluation at its discretion. 
 
Note: Subjects who decline to have photographs taken during the conduct of study may 
continue to participate in the study. If a subject initially consents to photographs, then 
declines further photography as/if required, the Sponsor may use the photographs taken 
under consent for the purposes noted above. 
 
Additional details regarding photographic methods, uploading and labeling photos, etc. 
will be provided in a Photo Manual to the site.  
 
Photographic equipment will be provided by the Sponsor/Contract Research Organization 
(CRO) or the site may use its own photographic equipment if approved by the Sponsor or 
CRO.  
12. 
LABORATORY TESTS 
12.1 
Urine Pregnancy Tests 
The UPTs will be performed at the study site, if the site is registered and conforms to CLIA 
regulations for such testing (possesses a current valid CLIA Certificate of Waiver), or at 
an appropriately registered reference laboratory. The investigator will report the UPT 
results on the CRFs, in the subject’s medical records, and in independent records 
maintained at the study site. The UPT used must have a minimum sensitivity of 25 mIU of 
β-hCG/mL. 


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13. 
END OF STUDY CRITERIA 
At the end of each subject’s participation in the study, the investigator will complete an 
End of Study form for all completed and discontinued subjects.  
13.1 
Completion of the Study 
Subjects who complete the 6-week course of treatment and EOS visit as specified in this 
protocol will be considered to have completed the study. 
13.2 
Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any of the following 
reasons: 
• AEs 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject; NOTE: if the subject decides to withdraw from the study 
due to an AE then it should be classified as withdrawal due to an AE 
• Other (e.g., any reason that may affect the outcome of the study or safety of 
subjects) 
 
If a subject withdraws from the study prematurely for any reason, the site should make 
every effort to have the subject return to the clinic to perform all of the required visit 
activities and to collect and reconcile all test articles (if applicable). If the subject will not 
return to the clinic, the site should make every attempt to contact the subject; otherwise the 
subject will be considered lost to follow-up. 
 
When a subject is withdrawn from the study for a test article related AE (as defined in 
Section 14.2), when possible, the subject should be followed until resolution or 
stabilization of the AE. If the subject is discontinued from the study due to pregnancy, the 
pregnancy and its outcome should be followed. 
 
Subjects who are prematurely withdrawn or discontinued from the study will not be 
replaced. 


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13.3 
Study Termination 
The study may be terminated by the investigator or the Sponsor. If, in the opinion of the 
investigator, clinical observations made during the study suggest that it may be unwise to 
continue, he or she may stop the study. A study termination by the investigator will be 
reported to the Sponsor. 
 
In addition, a written statement fully documenting the reasons for this action will be 
submitted to the Sponsor by the investigator within five working days. 
 
In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 
14. 
ADVERSE EVENT REPORTING 
14.1 
Adverse Event Definitions 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
 
An AE (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a drug, without any judgment about causality. An AE can arise from any use of 
the drug (e.g., off-label use, use in combination with any drug) and from any route of 
administration, formulation, or dose, including an overdose. 
 
A suspected adverse reaction is any AE for which there is a reasonable possibility that 
the drug caused the event. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the AE. 
 
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any AE caused by a drug. For the purposes of 
prescription drug labeling, the term adverse reaction means an undesirable effect, 
reasonably associated with the use of a drug that may occur as part of its pharmacological 
action or may be unpredictable in its occurrence.  
 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator Brochure (IB) or is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, the event is considered “unexpected” if 
it is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the IB referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 


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CONTROLLED & CONFIDENTIAL 
would be unexpected (by virtue of greater specificity) if the IB listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to AEs or suspected adverse 
reactions that are mentioned in the IB as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
Timely and complete reporting of all AEs assists the Sponsor and/or their designee (e.g., 
Therapeutics, Inc. [TI]) in identifying any untoward medical occurrence, thereby allowing:  
1) protection of the safety of study subjects;  
2) a greater understanding of the overall safety profile of the test article;  
3) recognition of dose-related test article toxicity; 
4) appropriate modification of study protocols;  
5) improvements in study design or procedures; and  
6) adherence to worldwide regulatory requirements.  
14.2 
Adverse Event Details 
AEs may be either spontaneously reported or elicited during questioning and examination 
of a subject. All AEs must be recorded on the AE CRF. If known, the investigator should 
report the diagnosis of the underlying illness or disorder, rather than its individual 
symptoms. Subjects experiencing AEs that cause interruption or discontinuation of test 
article or those experiencing AEs that are present at the end of their participation in the 
study should receive follow-up as appropriate. AEs should be followed to resolution or 
stabilization (if possible) and, if they become serious, reported as SAEs (see Section 14.3). 
If possible, the outcome of any AEs that caused permanent discontinuation or that were 
present at the end of the study, especially those considered by the investigator to be related 
to the test article, should be reported. 
 
Information on the medical condition of subjects should begin following the subject’s 
written informed consent/assent (if applicable) to participate in the study and a medical 
history should be taken at screening. During any wash out and baseline periods, any 
changes in the health of subjects should be recorded as changes in medical history unless 
an event occurred as a result of a study-related procedure and is unanticipated; in such 
cases, the event should be recorded as an AE and reported to the Institutional Review Board 
(IRB) as an “unanticipated problem” in accordance with local procedures. Other changes 
in subject health information becomes AE data when the subject begins dosing with the 
test article; therefore AE data should be collected from the date of the first dose of test 
article until the date of the final study visit. These data are considered TEAEs. 
 
The investigator will instruct the subject to report any AEs that may occur during the study. 
At each visit, the investigator should ask the subject, in non-directive fashion, about any 
change in the subject’s overall health status since the previous visit. 
 


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The severity of each AE, as judged by the investigator, will be recorded on the appropriate 
AE CRF and will be graded according to the following scale: 
 
Mild - The AE is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
 
Moderate - The AE is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
 
Severe - The AE interrupts usual activities of daily living or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
The investigator must determine the relationship of the AE to the test article according to 
the following categories: 
 
Definitely Related - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; and that is confirmed by improvement on stopping or reducing 
the dosage, and reappearance of the event on repeated exposure (re-challenge). 
 
Probably Related - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; and that is confirmed by improvement on stopping or reducing 
the dosage of the test article; and that is unlikely to have been caused by 
concurrent/underlying illness or other drugs, procedures, or other causes. 
 
Possibly Related - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; but may have been caused by concurrent/underlying illness, other 
drug, procedure, or other causes. 
 
Unlikely Related - An event that does not follow a reasonable temporal sequence 
from administration of the test article; that does not follow a known or expected 
response pattern to the test article, or most likely was caused by 
concurrent/underlying illness, other drug, procedure, or other causes, because of 
their known effects.  
 
Not Related - An event almost certainly caused by concurrent/underlying illness, 
other drug, procedure, or other causes. 
 


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The investigator should categorize the outcome of the AE according to the following 
categories: 
 
Fatal - Termination of life as a result of an AE. 
 
Not Recovered/Not Resolved - AE has not improved or the subject has not 
recuperated. 
 
Recovered/Resolved - AE has improved or the subject has recuperated. 
 
Recovered/Resolved with Sequelae - subject recuperated but retained the 
pathological conditions resulting from the prior disease or injury. 
 
Recovering/Resolving - AE is improving or the subject is recuperating. 
 
Unknown - Not known, not observed, not recorded or subject refused. 
14.3 
Serious Adverse Event 
An event that is serious must be recorded on the AE CRF and on the TI SAE Report Form, 
and requires expeditious handling to comply with regulatory requirements. 
 
An AE or suspected adverse reaction is considered “serious” if, in the opinion of either the 
investigator or Sponsor, it results in any of the following outcomes: 
• Death; the event must be the cause of death for the SAE to meet this serious 
criterion. 
• Life-threatening event; an event in which the subject was at risk of death at the time 
of the event and not an event that hypothetically might have caused death if it had 
been more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization (for 
≥24 hours). 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect. 
• Important medical events; a medical event(s) that may not result in death, be life-
threatening, or require hospitalization but, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition above. Examples 
of such medical events include 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.  
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
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CONTROLLED & CONFIDENTIAL 
Events NOT considered to be SAEs are: 
• Hospitalizations for the treatment, which was elective or pre-planned, of a pre-
existing condition that did not worsen; and 
• Treatment on an emergency, outpatient basis, for an event not fulfilling any of the 
definitions of “serious” given above and not resulting in hospital admission. 
 
AEs classified as “serious” by either the investigator or the Sponsor require expeditious 
handling and reporting to TI to comply with regulatory requirements. All SAEs, whether 
related or unrelated to test article, must be immediately reported by telephone to the 
Medical Monitor and, in the event that he/she is unavailable, to the Project Manager 
listed on the first page of the protocol. Written notification of all SAEs should be sent to 
the Project Manager by email or confirmed facsimile transmission. These include those 
SAEs listed in the protocol or IB and must include an assessment of whether there is a 
reasonable possibility that the test article caused the event.  
 
Any suspected adverse reactions that are serious and unexpected represent especially 
important safety information that must be reported more rapidly to Health Authorities; 
therefore, it is important that the Investigator submit any information requested by the 
Sponsor or designee (e.g., TI) as soon as it becomes available. 
 
If only limited information is initially available, follow-up reports are required. Should the 
investigator become aware of an SAE (regardless of its relationship to test article) that 
occurs within 30 days after stopping the test article, the SAE must be reported in 
accordance with procedures specified in this protocol. In the event of death, if an autopsy 
is performed, a copy of the report should be sent to TI, if available. 
 
As required, the Sponsor or designee (e.g., TI) will notify participating investigators of all 
suspected adverse reactions that are serious and unexpected. This notification will be in the 
form of an IND safety report of potential serious risks as soon as possible but no later than 
15 calendar days after the Sponsor determines that the information is “reportable” 
according to the criteria listed in 21 CFR Section 312.32. These are: 
 
i) Serious and unexpected suspected adverse reactions; 
ii) Findings from other studies including epidemiological studies, pooled 
analyses, or other clinical studies that suggest a significant risk in humans 
exposed to the test articles; 
iii) Findings from animal or in vitro tests that suggest a significant risk to 
humans exposed to the test articles, or reports of significant organ toxicity 
at or near the expected human exposure; and 
iv) Clinically important increases in the rate of occurrence of serious suspected 
adverse reactions. 
 
Upon receiving such notices, the investigator must review and retain the notice with the IB 
and promptly submit a copy of this information to the responsible IRB according to local 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 39 of 57 
 
CONTROLLED & CONFIDENTIAL 
regulations. The investigator and IRB will determine if the informed consent/assent (if 
applicable) requires revision. The investigator should also comply with the IRB procedures 
for reporting any other safety information. Where required, submission of safety updates 
by the investigator to Health Authorities should be handled according to local regulations. 
 
The Sponsor or designee may be required to report certain SAEs to regulatory authorities 
(e.g., United States FDA) within seven calendar days of being notified about the event; 
therefore, it is important that investigators submit any information requested by the 
Sponsor or designee as soon as it becomes available. 
14.4 
Laboratory Test Abnormalities 
There are no specific laboratory tests, other than a UPT, required in this study. 
14.5 
Pregnancy 
WOCBP (see Schedule of Events for definition of WOCBP) must have a UPT prior to 
study enrollment. Prior to study enrollment, WOCBP must be advised of the importance 
of avoiding pregnancy during the study and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent/assent (if applicable) form 
documenting this discussion. 
 
WOCBP should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period). If a subject or investigator 
suspects that a subject may be pregnant at any time during the study, the test article must 
be withheld until the results of laboratory pregnancy testing are available. If pregnancy is 
confirmed, the subject must not receive or apply further test article and must be 
discontinued from the study unless the Sponsor or the Medical Monitor elects to keep the 
subject in the study for safety follow-up purposes. 
 
If following initiation of study treatment, it is subsequently discovered that a subject was 
pregnant or may have been pregnant at the time of test article exposure, the investigator 
must immediately notify the Medical Monitor of this event and record the pregnancy on 
the appropriate pregnancy surveillance form. The form will be sent to TI. The investigator 
must notify the IRB of any pregnancy associated with the study treatment and keep careful 
source documentation of the event. 
 
Protocol-required procedures for those subjects that are discontinued from the study must 
be performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated, 
including counseling of the subject by the investigator and her managing physician or 
health care provider (e.g., obstetrician). In addition, the investigator must report to TI, on 
the appropriate pregnancy surveillance form(s), any follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome. Although pregnancy 
itself is not an AE, any complications during pregnancy should be recorded as AEs or SAEs 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 40 of 57 
 
CONTROLLED & CONFIDENTIAL 
(if they fulfill the SAE criteria). Offspring should be followed for a minimum of eight 
weeks. Any congenital anomaly/birth defect in a child born to a subject exposed to the test 
article(s) should be recorded as a SAE with details documented in the pregnancy 
surveillance form. Abortion, whether accidental, therapeutic, or spontaneous should be 
reported as an SAE. 
15. 
BLINDING/UNBLINDING 
An Unblinded Evaluator will document AEs and LSRs. A Blinded Evaluator will perform 
clinical evaluations (IGA and lesion counts). The Blinded Evaluator will not be involved 
in randomization, test article application instructions, or documentation of test article 
compliance. 
16. 
CLINICAL SUPPLIES 
16.1 
Test Article Information 
Test articles will be packaged and labeled by the Sponsor or designee. Detailed information 
on the packaging/labeling, blinding/unblinding, storage and preparation, dispensing, 
accountability, etc. is included in Appendix 3. 
16.2 
Supplies Provided by Therapeutics, Inc. 
• CRFs 
• Source document draft templates 
• Site regulatory binder 
• UPT kits 
• Standard facial cleanser 
16.3 
Supplies Provided by Investigator 
• Personal computer to store and view study images 
• Urine collection containers for UPTs 
16.4 
Supplies Provided by Foamix Pharmaceuticals 
• Samples for demonstration to subjects of test article application 
17. 
STATISTICAL CONSIDERATIONS 
17.1 
Sample Size 
This is a pilot proof of principle study, as such no specific power calculations were used to 
establish the sizing of this study. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 41 of 57 
 
CONTROLLED & CONFIDENTIAL 
17.2 
Endpoints 
17.2.1 Efficacy Endpoints 
• IGA Assessment 
o 
IGA within subject, Treatment A versus Treatment B – at Week 6; 
Treatment A> Treatment B, Treatment A= Treatment B, Treatment A< 
Treatment B 
o 
IGA scores will be dichotomized to “success” or “failure” where 
“success” is defined as at least a two-point improvement in IGA score 
relative to Baseline, Treatment A versus Treatment B 
• Absolute and Percent Change from Baseline to Week 6 in the inflammatory 
(papules and pustules) lesion count, within subject Treatment A vs Treatment B 
• Absolute and Percent Change from Baseline to Week 6 in the non-inflammatory 
(open and closed comedones) lesion count, within subject Treatment A vs 
Treatment B 
• Sebum and TEWL assessments relative to Baseline versus Weeks 2, 4, 6, and 7, 
within subject Treatment A versus Treatment B 
• VISIA Digital Photographs may undergo an independent separate analysis for 
clinical changes relative to Baseline. 
17.2.2 Safety Endpoints 
Safety endpoints will include: 
• Incidence (severity and causality) of any reported or observed TEAEs, whether or 
not they are considered to be related to the test article. Note: all application site AEs 
will be analyzed for Test Article A vs Test Article B involvement.  
• Number of subjects with improved/same versus worsened severities compared to 
Baseline 
of 
the 
following 
LSRs: 
erythema, 
edema, 
scaling/dryness, 
burning/stinging, pruritus, erosion, and pain at each time point, Test Article A vs 
Test Article B. 
17.3 
Statistical Methods 
All statistical processing will be performed using SAS® Version 9.4 unless otherwise stated.  
 
The Safety population will include all randomized subjects who received test article and 
applied at least one application.  
 
The modified intent-to-treat (mITT) population will include all randomized subjects who met 
all I/E criteria, applied at least one dose of test article, and returned for at least one post-
Baseline evaluation visit.  
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 42 of 57 
 
CONTROLLED & CONFIDENTIAL 
The per-protocol (PP) population will include all randomized subjects who met all mITT 
population criteria, were compliant with the assigned test articles based on the subject diaries 
(applied at least 
 and no more than 
 of the expected test article applications for the 
specified duration of the study), did not miss the scheduled test article applications for more 
than three consecutive days (i.e., three consecutive days with no test article application), have 
no other evidence of material dosing noncompliance, and completed the primary endpoint 
evaluation at Week 6 within the designated visit window (±3 days) with no protocol 
violations and prohibited medications that would affect the treatment evaluation.  
17.3.1 Dosing Compliance  
As appropriate, outcomes relative to Test Article A vs Test Article B shall be tabulated. 
Descriptive statistics will be used to summarize test article compliance for each analysis 
population. Compliant subjects are defined as those who apply at least 
 and no more 
than 
 of the expected test article applications (Right and Left face), and did not miss 
scheduled applications for more than three consecutive days. The percentage of compliant 
subjects will also be presented. 
17.3.2 Efficacy Analyses 
As appropriate, outcomes relative to Test Article A vs Test Article B will be tabulated for 
all visits. The efficacy analyses will be conducted on the mITT and PP populations and 
will be compiled using descriptive statistics only for all efficacy variables. 
17.3.3 Safety Analyses 
As appropriate, outcomes relative to Test Article A vs Test Article B will be tabulated. All 
safety analyses will be performed in the Safety population unless otherwise stated. 
17.3.3.1 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. The number and percent of unique subjects reporting each TEAE will 
be summarized by MedDRA system organ class (SOC), MedDRA preferred term (PT), 
and treatment group. AEs will also be similarly summarized by SOC, PT, maximum 
severity, and treatment group as well as by SOC, PT, and closest relationship to test article. 
Application site AEs will be summarized separately by treatment group. All AEs reported 
during the study will be listed.  
17.3.3.2 
Local Skin Reactions 
The 
frequency 
of 
the 
individual 
LSRs 
(erythema, 
edema, 
scaling/dryness, 
burning/stinging, pruritus, erosion, and pain) will be tabulated by severity and treatment 
group at each onsite clinic visit. Subject counts for improved/same versus worsened 
compared to Baseline value will be also presented for the post-baseline visits. 
Type text here
CCI
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CCI


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 43 of 57 
 
CONTROLLED & CONFIDENTIAL 
17.4 
Subgroup Analyses 
There are no subgroup analyses planned for this study. 
17.5 
Interim Analyses 
There are no interim analyses planned for this study. 
18. 
ETHICAL AND REGULATORY CONSIDERATIONS 
18.1 
Compliance with Good Clinical Practice 
This study will be conducted in compliance with the principles of the Declaration of 
Helsinki, with the current Good Clinical Practice guidelines and with other applicable 
regulations. The investigator and all study staff will conduct the study in compliance with 
this protocol. The protocol, informed consent/assent (if applicable) documents, recruitment 
advertisements, and any amendments to these items will have IRB approval prior to study 
initiation. Voluntary informed consent/assent (if applicable) will be given by every subject 
prior to the initiation of any study-related procedures. The rights, safety and well-being of 
the study subjects are the most important considerations and prevail over the interests of 
science and society. All personnel involved in the conduct of this study must be qualified 
by education, training, and experience to perform their assigned responsibilities. Contact 
information for each site and any clinical laboratories used in the study will be maintained 
up to date in a separate reference document. 
18.2 
Institutional Review Board and Informed Consent 
Before study initiation, the investigator must have written and dated approval from the IRB 
for the protocol, consent/assent (if applicable) form, subject recruitment materials/process 
(e.g., advertisements), and any other written information to be provided to the subject/and 
parent/guardian or care giver (if applicable). The investigator should also provide the IRB 
with a copy of the product labeling, information to be provided to the subject and 
parent/guardian or care giver (if applicable) and any updates. The investigator will submit 
documentation of the IRB approval to TI.  
 
The IRB approved consent/assent (if applicable) form must include all elements required 
by FDA, state, and local regulations, and may include appropriate additional elements. 
 
The investigator/designee will explain the study to each potential subject and 
parent/guardian (if applicable) and the subject must indicate voluntary consent/assent by 
signing and dating the approved informed consent/assent (if applicable) form. The parent 
or legal guardian must provide written informed consent for the subject. The investigator 
must provide the subject and parent/guardian (if applicable) with a copy of the 
consent/assent (if applicable) form, in a language the subject understands.  
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 44 of 57 
 
CONTROLLED & CONFIDENTIAL 
The investigator will maintain documentation that informed consent was obtained prior to 
the initiation of any study-specific procedures. 
18.3 
Protocol Compliance 
The IRB approved protocol must be followed except in the case of a change that is intended 
to eliminate an immediate risk to subjects. All protocol deviations must be documented.  
18.4 
Protocol Revisions 
TI must prepare all protocol revisions. All protocol amendments must receive IRB approval 
prior to implementation. All administrative letters must be submitted to the IRB for their 
information. Copies of all correspondence with the IRB regarding this study must be sent 
to TI. 
 
New or altered consent/assent (if applicable) forms required by the IRB due to a protocol 
change must be signed by all subjects/care givers (if applicable) currently enrolled in the 
study and must be used for any subsequent subject enrollment. 
18.5 
Study Monitoring 
Representatives of TI and/or the Sponsor must be allowed to visit all study sites, to review 
study records, and to directly compare them with source documents (including, but not 
limited to patient and hospital records), to discuss the study conduct with the investigator 
and study staff, and to verify that the investigator, study staff, and facilities remain 
acceptable for the conduct of the study. 
 
Representatives of government regulatory authorities may also evaluate the study records, 
source documents, investigator, study staff, and facilities. 
 
The investigator should immediately notify TI of any audits of this study by any regulatory 
agency and must promptly provide copies of any audit reports. 
18.6 
Case Report Form Requirements 
This study utilizes paper CRFs; all forms must be completed legibly in black ink. All 
requested information must be entered on the CRFs in the areas provided. All corrections 
should be made by striking through the incorrect entry with a single line then entering the 
correct information adjacent to the incorrect entry. Every correction must be initialed and 
dated by the individual making the correction on the date the correction was made. Only 
individuals listed on the Delegation of Responsibilities Log with responsibility for CRF 
completion may make entries on the CRFs. 
 
The investigator or physician sub-investigator must review, sign, and date the subject’s 
CRFs as specified in the case books. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 45 of 57 
 
CONTROLLED & CONFIDENTIAL 
18.7 
Reports to Institutional Review Board 
The investigator should provide the IRB with reports, updates, and other information (e.g., 
safety updates, protocol amendments, and administrative letters) according to regulatory 
requirements or Institution procedures. 
18.8 
Quality Assurance Audits 
Representatives from TI and/or the Sponsor or a third party selected by the Sponsor may 
conduct a quality assurance audit of this study. During the audit, the investigator must 
provide the auditor with direct access to all relevant documents and discuss any findings 
with the auditor. 
 
In the event of an inspection by the FDA or other regulatory authorities, the investigator 
must give the inspector direct access to relevant documents and to discuss any findings 
with the inspector. The investigator must notify TI in the event of a FDA site audit. 
18.9 
Records Retention 
The investigator must maintain all study records (including test article disposition, 
informed consents/assents, CRFs, source documents, correspondence, regulatory 
documents, contracts, etc.) for the maximum period required by TI or the institution where 
the study is conducted, whichever is longer. Test Article Accountability Logs and original 
Label Pages (if applicable) must be kept with study records at the site. 
 
The investigator must contact TI or the Sponsor prior to destroying any records associated 
with this study. 
 
If the investigator withdraws from the study, the records shall be transferred to a mutually 
agreed upon designee. Written notification of such a transfer must be given to TI. 
18.10 Record Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the 
written permission of the subject or the subject’s parent/guardian (if appropriate), except 
as necessary for monitoring by TI or the Sponsor, the FDA or other regulatory authority, 
or the IRB. 
 
The investigator and all employees and coworkers involved with this study shall not 
disclose or use for any purpose other than performance of the study, any data, records, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from TI or the Sponsor must be obtained for the 
disclosure of any said confidential information to other parties. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
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CONTROLLED & CONFIDENTIAL 
19. 
REFERENCES 
1. Brown SK, Shalita AR. Acne vulgaris, folliculitis, and acne rosacea. Lancet. 
1998;351:1871-1876. 
 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 47 of 57 
 
CONTROLLED & CONFIDENTIAL 
APPENDIX 1 
SAMPLE SUBJECT INSTRUCTION SHEET 
Copies of the following sample subject instructions will be provided to the study site. The 
investigator must give each subject/parent/guardian/care giver (if applicable) a copy of this 
instruction sheet at Visit 1/Baseline. 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
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Page 48 of 57 
 
CONTROLLED & CONFIDENTIAL 
SAMPLE SUBJECT INSTRUCTION SHEET 
Please read and follow these instructions carefully. Contact the study staff at the telephone number 
noted below if you have any questions about the study: 
 
Contact: 
 
 
 
 
 
 
At: 
 
 
 
 
 
 
Please apply the study products to the correct sides of your face ONCE DAILY in the evening 
every day for 6 weeks. 
 
 
STUDY PRODUCT APPLICATION INSTRUCTIONS: 
 
One study product is provided in a canister and one study product is provided in a squeeze bottle. 
The study products are color-coded and labeled according to which side you should dose; you must 
not mix up the containers and apply the wrong study product to the wrong side of your face. 
 
 
 
Before applying the study product please confirm you are using the correct color coded 
study product for the side of the face you are treating. 
 
Wash your entire face with the provided facial cleanser and water and gently pat dry. 
Wash and dry your hands before and after both study product applications. 
 
 
WHEN USING THE STUDY PRODUCT CANISTER: Shake the study 
product canister well before use. To dispense the study product, hold the canister 
in the upright position and press down on the actuator (see diagram to the right). 
a) Dispense about ¼ gram (or a half of a cherry size) of the study product onto 
the fingertip of the hand.  
b) Gently dab small amounts of the study product over the correct side of your face, then 
spread the product evenly with your fingertip to COVER ALL FACIAL SKIN ON THE 
CORRECT SIDE OF YOUR FACE FROM THE HAIRLINE TO THE JAWLINE AND 
AVOID CROSSING THE MIDLINE with a thin, uniform layer until the study product is 
absorbed.  
c) Record the date and time of study product application in your Subject Diary. 
d) Wash your hands. 
 
WHEN USING THE STUDY PRODUCT SQUEEZE BOTTLE: Flip open the cap and 
uniformly wet an application pad with the study product. If necessary re-wet the pad one more 
time if additional product is needed to cover the entire half of the face. Close the flip cap when 
done. 
a) Using the moistened pad, gently apply a uniform coat of the solution on the correct side of 
the face. BEGIN ON THE FOREHEAD USING GENTLE STROKES STARTING AT 
THE MIDLINE MOVING TOWARDS THE CORRECT SIDE OF THE FACE 
WORKING DOWNWARD TO THE CHIN. COVER ALL FACIAL SKIN ON THAT 
SIDE OF THE FACE FROM THE HAIRLINE TO THE JAWLINE AND AVOID 
CROSSING THE MIDLINE.  
b) Record the date and time of study product application in your Subject Diary. 
c) Wash your hands. 
CCI


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 49 of 57 
 
CONTROLLED & CONFIDENTIAL 
 
 
REMINDERS: 
• 
The study products should be applied at approximately the same time each day, 
preferably about 1 hour before bedtime. 
• 
Do not wash face or apply the study products and allowed skin care products within 
4 hours before any study visit. 
• 
After study product applications, allow a 1 hour dry-down period before applying 
any other approved facial product. 
• 
Do not wash the treated area for at least 4 hours after study product applications. 
• 
Store the study products according to the instructions on the label. 
• 
If you miss a dose, apply the next dose at the regular time.  
• 
Bring all containers of the study products (used and unused) and the completed Subject 
Diary to each visit. 
• 
Do not allow anyone else to use the study products.  
• 
Keep containers of study products away from children/pets. 
• 
Only apply the study products as directed by the study doctor. 
• 
Do not apply the study products to any area other than your face. 
• 
If skin irritation develops, discontinue use and contact the study site immediately. 
• 
Avoid contact with eyes and all mucous membranes. If contact with eyes occurs, rinse 
thoroughly with cool tap water. 
 
STUDY VISIT SCHEDULE: 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Date: 
Date: 
Date: 
Date: 
Time: 
Time: 
Time: 
Time: 


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CONTROLLED & CONFIDENTIAL 
APPENDIX 2 
SAMPLE SUBJECT DIARY 
A copy of the following sample Subject Diary will be provided to the study site. The 
investigator must give each subject/parent/guardian/care giver (if applicable) a copy of this 
Subject Diary at Visit 1/Baseline and all follow-up visits, as necessary. 


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CONTROLLED & CONFIDENTIAL 
PROTOCOL: 
SITE: 
SUBJECT NO.: 
INITIALS: 
FX2018-23 
_____  _____ _____  _____  _____ _____  _____  _____ 
 
SAMPLE SUBJECT DIARY 
Apply the study products as prescribed. Contact the study staff at the telephone number 
below if you have any questions about the study. 
 
Contact:_______________________________ 
At:___________________________ 
 
After dosing, record the date and time of the study product applications. 
If you miss a dose, write MISSED in the space for time. 
DATE 
(dd/Mmm/yyyy) 
DOSE (Time) 
DATE 
(dd/Mmm/yyyy) 
DOSE (Time) 
DATE 
(dd/Mmm/yyyy) 
DOSE (Time) 
Left 
Right 
Left 
Right 
Left 
Right 
      /      / 
: 
: 
      /      / 
: 
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Next Appointment: __________________/_______/_______at___________AM/PM 
 
 
 
   Weekday       dd      MMM    yyyy 
Site Use Only: 
Diary Dispensed at: 
 Visit 1 (Day 1) 
 Visit 2 (Week 1) 
 Visit 3 (Week 2) 
 Visit 4 (Week 4) 
Date Dispensed: 
Date Returned:  


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 52 of 57 
 
CONTROLLED & CONFIDENTIAL 
APPENDIX 3 
TEST ARTICLE INFORMATION 
A 3.1 Test Article Packaging and Labeling 
The test articles will be packaged and labeled by the Sponsor or designee. FMX101 vehicle 
will be packaged in a canister and the hydro-alcohol solution based vehicle will be 
packaged in a squeeze bottle. Each subject will be assigned a subject number and provided 
with sufficient test article in standard packaging for the designated treatment period during 
the study. 
 
Each container of the test article will contain, at a minimum, the following information: 
the protocol number, subject identifiers (e.g., subject number and initials), the contents, the 
container number, an investigational test article disclaimer (e.g., Caution: New Drug 
Limited by United States law to investigational use), and the appropriate storage conditions 
for the test article. 
 
The randomization will be blocked by investigational site. When test article containers are 
dispensed to the subjects, the Subject label must be completed entirely with the necessary 
information and recorded in the Test Article Accountability Log at the investigational site. 
A 3.2 Test Article Storage and Preparation 
FMX101 vehicle canisters must be stored at 2°C – 8°C until being dispensed to the subject. 
Subsequently, they must be stored at 20°C – 25°C (refer to USP Controlled Room 
Temperature).  
Hydro-alcohol solution based vehicle squeeze bottles must be stored at 20°C – 25°C both 
at the study site and after being dispensed to the subject.  
 
The investigator will be responsible for the suitable storage of the investigational products 
in compliance with the storage instructions and must restrict access to the study personnel 
only. 
A 3.3 Dispensing Test Article 
Sites will receive shipments of one or more blocks of test articles. Subjects who are eligible 
for enrollment into the study will be assigned a three-digit subject number by the study 
staff in ascending order beginning with the lowest available number. 
 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 by authorized personnel as required by applicable regulations and 
guidelines. 
 
On dispensing the test article for the first time at Visit 1/Baseline, the weight of the 
containers will be measured prior to dispensing. Sufficient test article for the designated 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 53 of 57 
 
CONTROLLED & CONFIDENTIAL 
treatment period will be dispensed to the subject and the information recorded on the Test 
Article Accountability Log. The subjects will be instructed to bring all containers of the 
test article (used and unused) to each clinic visit. 
 
At each post-Baseline visit, site staff will collect all containers (used and unused) of the 
test article, weigh the returned test articles, and record the necessary information in the 
Test Article Accountability Log. Site staff will review the test article application procedure 
and subjects will be counseled on test article compliance, as necessary. Any discrepancies 
or concerns with the subject regarding the use of the Subject Diary to record test article 
applications should be addressed. Additional containers of the test article will be dispensed 
to the subject, as needed, to ensure that each subject has sufficient test article for the 
designated treatment period. 
A 3.4 Test Article Supply Records at Study Sites 
It is the responsibility of the investigator to ensure that a current record of test article 
disposition is maintained. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• Amount received placed in storage area. 
• Amount currently in storage area. 
• Label ID number or batch number. 
• Dates and initials of the person responsible for each product inventory 
entry/movement. 
• Amount (number and units and weights) dispensed to and returned by each subject, 
including unique subject identifiers. 
• Amount transferred to another area for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount returned to Sponsor. 
• Amount destroyed at study site, if applicable. 
 
TI will provide forms to facilitate inventory control if the staff at the study site does not 
have an established system that meets these requirements. 
A 3.5 Dose Modifications 
The subject should not modify the treatment regimen without consultation with the 
investigator. Subjects should be instructed to discontinue use if significant skin irritation 
or rash develops and to contact the study site. In the event that the investigator believes 
that dose modification is necessary (e.g., problems with tolerance), the subject’s care 
should be discussed with the Medical Monitor prior to making any dose modifications. All 
dose modifications must be reported on the appropriate CRF. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 54 of 57 
 
CONTROLLED & CONFIDENTIAL 
A 3.6 Documentation of Application and Compliance 
The date of the first and last application of the test article will be recorded on the 
appropriate CRF. A CRF will also be used to record any changes from the application 
specified in the protocol (e.g., missed applications, investigator directed reduction in 
application frequency, etc.). 
 
A Subject Diary will be dispensed to subjects to record the dates and times of all 
applications and to record any missed doses of the test article (Appendix 2). Subjects will 
be instructed to bring the Subject Diary with them to each study visit. 
A 3.7 Return and Destruction of Test Article Supplies 
Upon completion or termination of the study, all remaining test article containers must be 
a) returned to TI, Sponsor, or designee by a traceable method for final accountability and 
destruction or b) appropriately destroyed in accordance with applicable regulations with 
the provision of a certificate of destruction. All missing containers of test article must be 
explained on the completed Test Article Accountability Log. A copy of the Test Article 
Accountability Log and original Label Pages (if applicable) will be returned to TI or 
designee. 
 
 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 55 of 57 
 
CONTROLLED & CONFIDENTIAL 
APPENDIX 4 
PROTOCOL AMENDMENTS 
PROTOCOL AMENDMENT #1 
Date of Amendment: November 13, 2018 
 
This protocol was amended as follows: 
• The efficacy endpoint for the VISIA assessment was fixed to be optional, 
which aligns with the language used in other parts of the protocol that 
describe the VISIA assessment. 
• The ingredients in Test Article B were updated. 
• Text was updated to reflect that the test articles will not be dispensed in kits. 
• Subject numbers were updated to be three digit numbers. 
• The age range was changed from 12-40 years of age (inclusive) to 9 years 
of age or older. 
• The assessment of LSRs was changed from being done by a Blinded 
Evaluator to being done by an Unblinded Evaluator (i.e., the investigator). 
 
Specific changes to the protocol are listed below; new or revised sections are included 
(Added text has been bolded and deleted text has been redlined). Minor typographical 
errors, grammatical, and wording changes are not included in this section. 
 
Study Endpoints 
(Synopsis, Section 
17.2.1) 
• VISIA Digital Photographs will may undergo an independent 
separate be analysiszed for Absolute and Percent Change from 
Baseline to Week 6 for lesion counts, erythema, hyper-
pigmentation, and skin texture, within subject Test Article A vs 
Test Article Bclinical changes relative to Baseline. 
Study Population 
(Synopsis) 
Healthy male or female subjects 12 to 40 years of age (inclusive)9 
years of age or older with a clinical diagnosis of symmetric 
moderate facial acne vulgaris (Grade 3 on the Investigator’s Global 
Assessment [IGA]), ≥16 inflammatory lesions (i.e., papules and 
pustules) on the face, and no more than two active nodules on the 
face. 
Inclusion Criteria 
(Synopsis, Section 
5.1.1) 
Subject is a healthy male or non-pregnant, non-breastfeeding 
female 12 to 40 9 years of age or older (inclusive) at the time of 
consent/assent. 
Study Procedures 
(Synopsis) 
NOTE: Clinical evaluations (Right and Left Facial IGA and lesion 
counts) and local skin reaction (LSR) assessments will be 
performed by a Blinded Evaluator who is not involved in 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 56 of 57 
 
CONTROLLED & CONFIDENTIAL 
randomization, 
test 
article 
application 
instructions, 
or 
documentation of test article compliance. 
 
LSRs will be assessed by a Blinded Evaluator 15 minutes following 
test article application. 
 
LSRs will be assessed by a Blinded Evaluator for the Right and Left 
side of the face. 
 
The subject will return to the clinic for review of concomitant 
medications and procedures/therapies, LSRs (by a Blinded 
Evaluator), and AEs. 
Study 
Measurements 
(Synopsis) 
At each visit, LSRs (erythema, edema, scaling/dryness, 
burning/stinging, pruritus, erosion, and pain) will be assessed by a 
Blinded Evaluator. 
Section 4 
This is a randomized, evaluator-blinded, bilateral comparison study 
of FMX101 hydrophobic oil based vehicle (Test Article A) and 
hydro-alcohol solution based vehicle (Test Article B) in healthy 
male or female subjects 12 to 40 years of age9 years of age or older 
with facial acne vulgaris. 
Section 6.1 
water, alcohol denatured, butylene glycol, poloxamer 124, lactic 
acid, PEG-40 hydrogenated castor oil, sodium hydroxide, 
poloxamer 124, lactic acid,glyceryl caprylate, phenoxyethanol, 
methylparaben,and fragrance. 
Section 9 
Must be performed by a Blinded Evaluator: Assess LSRs on the 
Right and Left sides of the face separately prior to first test article 
applications. 
Section 10 
Clinical evaluations (Right and Left Facial IGA and lesion counts) 
and LSR assessments will be performed by a Blinded Evaluator 
who is not involved in randomization, test article application 
instructions, or documentation of test article compliance. The same 
Blinded Evaluator should evaluate a subject over the course of the 
study. The study staff, the Unblinded Evaluator, and subjects will 
also be instructed not to discuss the treatment, AEs, SAEs, or any 
study experiences with the Blinded Evaluator. 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
 
Protocol Date: November 13, 2018, v2.0 
 
Page 57 of 57 
 
CONTROLLED & CONFIDENTIAL 
 
The Blinded Evaluator will only have access to the page in the CRF 
required to document the Right and Left Facial IGA and lesion 
counts and LSR assessments; all other CRF content will be 
inaccessible. 
Section 10.5.2 
At each visit, LSRs (erythema, edema, scaling/dryness, 
burning/stinging, pruritus, erosion, and pain) will be assessed by a 
Blinded Evaluator. Erythema, edema, scaling/dryness, and erosion 
will be assessed by the Blinded Evaluatorinvestigator and 
burning/stinging, pain, and pruritus will be assessed by the subject. 
Section 15 
An Unblinded Evaluator will document AEs and LSRs. A Blinded 
Evaluator will assess LSRs and perform clinical evaluations (IGA 
and lesion counts). 
Appendix 3 
Section 3.1 
Containers of the test article will be contained in subject kits. The 
randomization will be blocked by investigational site. When 
kitstest article containers are dispensed to the subjects, the Subject 
Kit label must be completed entirely with the necessary information 
and recorded in the Test Article Accountability Log at the 
investigational site. In the event of an emergency, the contents of 
the kit test article containers can be unblinded using the proper 
procedures as outlined in the protocol and by instructions provided 
to the site.  
Appendix 3 
Section 3.3 
Subjects who are eligible for enrollment into the study will be 
assigned a twothree-digit subject number by the study staff in 
ascending order beginning with the lowest available number. 
 

SAP_001.pdf: 
A Randomized, Evaluator-Blinded, Bilateral Comparison Study of Two 
Topicals in the Treatment of Subjects with Acne Vulgaris 
ClinicalTrials.gov Identifier: NCT03743038 
Date of Statistical Analysis Plan: 07 February 2019 


Product Name: FMX101 Hydrophobic Oil Based Vehicle 
Report for Protocol: FX2018-23 
Sponsor Name: Foamix Pharmaceuticals 
Report Date: June 4, 2019, v1.0 
 
 
 
 
 
CONTROLLED & CONFIDENTIAL 
Appendix 16.1.9 Documentation of Statistical Methods 
 
 


 
 
 
 
 
 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
VERSION:1.0 
 
DATE: 07-Feb-2019 
 
 
SPONSOR: 
Foamix Pharmaceuticals 
PROTOCOL NUMBER: 
FX2018-23 
TI PROJECT NUMBER: 
152-11051-401 
PROTOCOL TITLE: 
A Randomized, Evaluator-Blinded, Bilateral Comparison 
Study of Two Topicals in the Treatment of Subjects with Acne 
Vulgaris 
PROTOCOL DATE: 
Version 2.0, 13-Nov-2018 
 
 
PREPARED BY: 
Therapeutics, Inc. 
 
PPD


Statistical Analysis Plan, v0.1 
 
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TI Project: 152-11051-401 
 
Protocol Number: FX2018-23 
152-11051-401_sap_07Feb2019_v1.0.docx 
 
Page 2 of 13 
 
CONFIDENTIAL 
 
ABBREVIATIONS 
AE 
Adverse Event 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
EOT 
End of Treatment 
IGA 
Investigator’s Global Assessment 
LSR 
Local Skin Reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
PP 
Per-Protocol 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TEWL 
Transepidermal Water Loss 
TI 
Therapeutics, Inc. 
UPT 
Urine Pregnancy Test 
 
 
 


Statistical Analysis Plan, v0.1 
 
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TI Project: 152-11051-401 
 
Protocol Number: FX2018-23 
152-11051-401_sap_07Feb2019_v1.0.docx 
 
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CONFIDENTIAL 
 
TABLE OF CONTENTS 
Statistical Analysis Plan .................................................................................................................. 1 
Abbreviations .................................................................................................................................. 2 
Table of Contents ............................................................................................................................ 3 
1. 
Introduction ............................................................................................................................. 5 
2. 
Purpose of the Analyses .......................................................................................................... 5 
3. 
Study Objectives and Endpoints ............................................................................................. 5 
3.1 
Objectives ....................................................................................................................... 5 
3.2 
Efficacy Endpoints .......................................................................................................... 5 
3.3 
Safety Endpoints ............................................................................................................. 5 
4. 
Study Design ........................................................................................................................... 5 
5. 
Definitions ............................................................................................................................... 7 
6. 
Clinical evaluations ................................................................................................................. 7 
6.1 
Investigator’s Global Assessment ................................................................................... 7 
6.2 
Acne Lesion Counts ........................................................................................................ 8 
6.3 
VISIA Photography ........................................................................................................ 8 
6.4 
Bioinstrumentation Assessments .................................................................................... 8 
7. 
Safety evaluations ................................................................................................................... 8 
7.1 
Adverse Events ............................................................................................................... 8 
7.2 
Local Skin Reactions ...................................................................................................... 9 
8. 
Statistical Methods .................................................................................................................. 9 
8.1 
General Considerations ................................................................................................... 9 
8.2 
Analysis Populations ....................................................................................................... 9 
8.2.1 Safety Population ........................................................................................................ 9 
8.2.2 Modified Intent-to-Treat Population ........................................................................... 9 
8.2.3 Per-Protocol Population .............................................................................................. 9 
8.3 
Final Analyses and Reporting ....................................................................................... 10 
8.4 
Sample Size ................................................................................................................... 10 
8.5 
Subject Disposition ....................................................................................................... 10 
8.6 
Screening and Baseline Assessments ........................................................................... 10 
8.6.1 Demographics ............................................................................................................ 10 
8.6.2 Dermatologic Examination ....................................................................................... 10 
8.6.3 Baseline Clinical Evaluations .................................................................................... 10 
8.6.4 Baseline Local Skin Reactions .................................................................................. 10 
8.7 
Dosing Compliance ....................................................................................................... 11 
8.8 
Efficacy Evaluation ....................................................................................................... 11 
8.8.1 Analysis of Efficacy .................................................................................................. 11 
8.8.1.1 Investigator’s Global Assessment ...................................................................... 11 
8.8.1.2 Acne Lesion Counts ........................................................................................... 11 
8.8.1.3 TEWL and Sebum Assessments ........................................................................ 11 
8.8.2 Statistical / Analytical Issues ..................................................................................... 12 
8.8.2.1 Handling of Dropouts or Missing Data .............................................................. 12 
8.8.2.2 Interim Analyses ................................................................................................ 12 
8.8.2.3 Multicenter Studies ............................................................................................ 12 


Statistical Analysis Plan, v0.1 
 
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CONFIDENTIAL 
 
8.8.2.4 Multiple Comparisons / Multiplicity .................................................................. 12 
8.8.2.5 Examination of Subgroups ................................................................................. 12 
8.9 
Safety Evaluation .......................................................................................................... 12 
8.9.1 Extent of Exposure .................................................................................................... 12 
8.9.2 Adverse Events .......................................................................................................... 12 
8.9.3 Local Skin Reactions ................................................................................................. 13 
8.9.4 Urine Pregnancy Tests .............................................................................................. 13 
8.9.5 Concomitant Medications and Concurrent Therapies/Procedures ............................ 13 
9. 
Changes to Protocol .............................................................................................................. 13 
 
 


Statistical Analysis Plan, v0.1 
 
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CONFIDENTIAL 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be performed 
for data from Protocol FX2018-23, “A Randomized, Evaluator-Blinded, Bilateral Comparison 
Study of Two Topicals in the Treatment of Subjects with Acne Vulgaris”. 
 
This SAP was created using Clinical Protocol FX2018, Version 2.0 dated 13-Nov-2018, and the 
Case Report Forms (CRF) Version 1.0, dated 12-Nov-2018. 
2. PURPOSE OF THE ANALYSES 
The purpose of this SAP is to outline the planned analyses to be completed to support the Clinical 
Study Report (CSR) for Protocol FX2018-23.  Any post-hoc or unplanned analyses not identified 
in this SAP will be clearly identified in the CSR. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
The objective of this study is to evaluate the safety and efficacy of the two topical formulations in 
acne vulgaris subjects. More specifically, the above formulations will be compared for their effect 
on facial sebum. 
3.2 
Efficacy Endpoints  
 Investigator’s Global Assessment (IGA) at Week 6 
 IGA “success” at Week 6 
 Absolute and Percent Change from Baseline to Week 6 in inflammatory lesion count 
 Absolute and Percent Change from Baseline to Week 6 in non-inflammatory lesion count 
 Sebum and Transepidermal Water Loss (TEWL) assessments relative to Baseline at Weeks 
2, 4, 6 and 7 
 VISIA Digital Photographs for analysis of clinical changes relative to Baseline may 
undergo an independent separate analysis 
3.3 
Safety Endpoints 
 Incidence (severity and causality) of any reported or observed treatment emergent adverse 
events (TEAEs) 
 LSR severity status [improved/same versus worsened] compared to Baseline at each time 
point 
4. STUDY DESIGN 
This is a randomized, evaluator-blinded, bilateral comparison study of FMX101 hydrophobic oil 
based vehicle (Test Article A) and hydro-alcohol solution based vehicle (Test Article B) in healthy 
male or female subjects 9 years of age or older with facial acne vulgaris. Eligible subjects must 


Statistical Analysis Plan, v0.1 
 
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TI Project: 152-11051-401 
 
Protocol Number: FX2018-23 
152-11051-401_sap_07Feb2019_v1.0.docx 
 
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CONFIDENTIAL 
 
have a clinical diagnosis of symmetric moderate facial acne vulgaris (IGA of Grade 3) and ≥16 
inflammatory lesions (i.e., papules and pustules) on the face. Approximately 12 subjects will be 
enrolled to obtain about 10 evaluable subjects at one to two study sites. Subjects will be 
randomized (1:1) to treatment with Test Article A to one side of the face versus Test Article B on 
the contralateral side. 
 
Test Articles: 
1. FMX101 hydrophobic oil based vehicle (Test Article A) 
2. Hydro-alcohol solution based vehicle (Test Article B) 
 
Test articles will be applied once daily in the evenings for six weeks to the appropriate side of the 
face. 
 
The study schedule of visits and assessments is provided in Table 1. Further details regarding the 
study may be found in the study protocol. 
 
Table 1: Schedule of Events 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Unscheduled 
Visit 
 
Screening/
Baseline 
Week 1 / 
Follow –
up 1 
Week 2 / 
Follow –
up 2 
Week 4 / 
Follow –
up 3 
Week 6 / 
EOT1 
Week 7 / 
EOS 
Days 
1 
8 ± 2 
15  3 
29  3 
43  3 
50  3 
Informed Consent/Assent2 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medications 
and Procedures/Therapies 
X 
X 
X 
X 
X 
X 
X 
Dermatological Exam 
X 
 
 
 
 
 
 
UPT3 for WOCBP4 
X 
 
 
 
X 
 
 
Clinical Evaluations (IGA 
and lesion counts, R vs L) 5 
X 
X 
X 
X 
X 
X 
 
LSR Assessment, R vs L 
X6 
X 
X 
X 
X 
X 
X 
VISIA Photography 
X 
 
X 
X 
X 
 
 
TEWL/Sebum, R vs L 
X 
 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
 
 
Test Article 
Accountability, R vs L 
X 
X 
X 
X 
X 
 
X 
Demonstrate how to apply 
test articles7 
X 
X 
X 
X 
 
 
 
Apply test articles 
X 
 
 
 
 
 
 
Subject Diary and 
Compliance Review8: 
Dispense (D), Review (R), 
and/or Collect (C) 
D 
C+R+D C+R+D C+R+D 
C+R 
 
C+R+D, as 
necessary 
Adverse Events 
X9 
X 
X 
X 
X 
X 
X 
 
 


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CONFIDENTIAL 
 
1Or early termination from the study. 
2 Consent/assent may be performed up to 45 days prior to Baseline. Subjects who require “washout” for longer than 
45 days will be re-consented. 
3 UPTs must have a minimum sensitivity of 25 mIU ß-hCG/mL. 
4 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, or bilateral oophorectomy). 
5 Clinical grading to be done by the same Blinded Evaluator. 
6 LSRs will be assessed both before and 15 minutes following test article application. 
7 Study staff will provide a Subject Instruction Sheet to the subject and parent/guardian (if applicable) and test article 
application will be demonstrated using the test article samples provided to the site.  
8 Review Subject Diary and amount of test article used since last visit to determine subject compliance. Re-educate 
subject on use of the test article with particular attention to inappropriate prior use of test article – be it amount of 
product applied and/or frequency of use. 
9 Recorded under Medical History. 
5. DEFINITIONS 
Study Day: The Study Day is the day of the study relative to the first dose of test article, 
therefore, the Baseline Visit is Study Day 1.   
Study Day = Follow-up Visit Date – Baseline Date + 1. 
6. CLINICAL EVALUATIONS 
6.1 
Investigator’s Global Assessment 
The IGA score is a static evaluation of the overall severity or “average” degree of severity of a 
subject’s disease by the Blinded Evaluator, taking into account all of the subject’s facial acne 
lesions as the subject appears on the day of the evaluation. Overall severity of acne will be assessed 
using a five-point scale from 0-Clear to 4-Severe. Subjects must have an identical IGA score of 
moderate severity (IGA Grade 3) on both the right and left side of the face at Baseline. 
 
Table 2: IGA Severity Grades 
 
Grade 
Description 
0 
Clear; Normal, clear skin with no evidence of acne vulgaris 
1 
Almost clear; Rare non-inflammatory lesions may be present, with rare 
non-inflamed papules (papules must be resolving and may be 
hyperpigmented, though not pink- red) 
2 
Mild; Some non-inflammatory lesions are present, with few inflammatory 
lesions (papules/pustules only; no nodulocystic lesions) 
3 
Moderate; Many non-inflammatory lesions. Multiple inflammatory 
lesions evident with several to many papules/pustules, and there may be 
one small nodulocystic lesion 
4 
Severe; Inflammatory lesions are more apparent, many comedones and 
papules/pustules, there may be a few nodulocystic lesions 
 


Statistical Analysis Plan, v0.1 
 
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CONFIDENTIAL 
 
6.2 
Acne Lesion Counts 
The number of non-inflammatory lesions (open and closed comedones), inflammatory lesions 
(papules and pustules), and nodulocystic lesions (nodules and cysts) on the face (including those 
present on the nose) will be counted by the Blinded Evaluator. Subjects must have a minimum of 
16 inflammatory lesions AND ≤ 2 nodulocystic lesions on the face in total (with no more than one 
nodule/cyst per the right or left side of the face) at Visit 1/Baseline. The inflammatory lesion count 
on the right and left side of the face should be similar (defined as within ~ 50% of each other) at 
the Baseline visit. 
 
Lesions will be counted separately for the right and left side of the subject’s face. Lesions are 
defined as follows: 
 
Non-inflammatory lesions: 
 Comedones: open (blackheads) and closed (whiteheads). 
 
Inflammatory lesions: 
 Papules: raised inflammatory lesions with no visible purulent material. 
 Pustules: raised inflammatory lesions with visible purulent material. 
 
Nodulocystic lesions: 
 Nodules and cysts: any circumscribed, inflammatory masses greater or equal to 5 mm in 
diameter with or without cystic changes. 
6.3 
VISIA Photography 
Digital photographs will be taken of the face with the VISIA (Canfield Scientific) to document the 
progress of the subject (right vs left sides) in the study at Visit 1/Baseline, Visit 3, Visit 4, and 
Visit 5. 
6.4 
Bioinstrumentation Assessments 
TEWL (g/m2/h) and sebum (%) measurements will be conducted on the right and left side of the 
face.  The sebum measurement represents the sebum score of saturation of the film and has a range 
of 0 to 99, where 99 equates to very oily skin. 
7. SAFETY EVALUATIONS 
7.1 
Adverse Events 
All reported or observed AEs will be recorded. At each visit, subjects will also be questioned 
specifically about the status of any ongoing AEs. Untoward events that occur prior to the first dose 
of test article will be captured in the Medical History section of the CRF unless they are related to 
a study-specific procedure. AEs in the face will be segmented to the right and/or left sides of the 
face. 


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CONFIDENTIAL 
 
7.2 
Local Skin Reactions 
At each visit, local skin reactions (LSRs) (erythema, edema, scaling/dryness, burning/stinging, 
pruritus, erosion, and pain) will be assessed. Erythema, edema, scaling/dryness, and erosion will 
be assessed by the investigator and burning/stinging, pain, and pruritus will be assessed by the 
subject. Assessments will be made using a 4-point ordinal scale where 0-absent, 1-mild (slight, 
barely perceptible), 2-moderate (distinct presence), and 3-severe (marked, intense). Only LSRs 
that require medical intervention (e.g., prescription medication), require withholding or 
discontinuation of the application of the test article, or extend 2 cm beyond the Treatment Area 
will be documented as AEs. LSRs will be segmented to the right and/or left sides of the face. 
8. STATISTICAL METHODS 
8.1 
General Considerations 
SAS® 9.4 will be used to provide all tables, figures, and listings. This section presents the statistical 
approaches that are anticipated for the analysis of the study data.  These approaches may at time 
require modifications due to unanticipated features of the data. Deviations from the analyses 
summarized below will be noted in the CSR. 
 
In general, continuous variables will be summarized by descriptive statistics including the number 
of subjects with non-missing data (n), mean, standard deviation, median, minimum, and maximum 
values.  Categorical variables will be summarized by frequency and percentage of subjects within 
each category.  Subject data listings sorted by study site and subject number will be presented.  
8.2 
Analysis Populations 
8.2.1 
Safety Population 
The Safety population will include all randomized subjects who received test article and applied 
at least one application. 
8.2.2 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population will include all randomized subjects who met all 
I/E criteria, applied at least one dose of test article, and returned for at least one post-Baseline 
evaluation visit. 
8.2.3 
Per-Protocol Population 
The per-protocol (PP) population will be a subset of the mITT population and will include subjects 
who meet the following criteria: 
 
 Applied at least 
 and no more than 
 of the expected test article applications 
 Did not miss the schedule test article applications for more than three consecutive days 
 No other evidence of material dosing noncompliance 
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 Completed the primary endpoint evaluation at Week 6 within the visit window (± 3 days) 
 No protocol deviations or prohibited medications that would affect the treatment 
evaluation. 
8.3 
Final Analyses and Reporting 
Final database lock will occur after all subjects have completed the study assessment period (or 
discontinued early) and all subject data has been monitored. Analysis may not occur until after 
database lock, this SAP is approved, and analysis populations have been identified. 
8.4 
Sample Size 
This is a pilot proof of principle study, as such no specific power calculations were used to establish 
the sizing of this study. 
8.5 
Subject Disposition 
The number and percentage of subjects who enrolled in the study, who completed the study, who 
withdrew from the study and their reasons for discontinuation will be tabulated.   
 
Subject data listings of protocol deviations, if any, and analysis population identification will be 
provided. 
8.6 
Screening and Baseline Assessments 
8.6.1 
Demographics 
Sex, age (computed from date of birth and Baseline visit date), ethnicity and race will be 
summarized. If a subject has more than one self-reported race, then he/she will be summarized in 
the “multiple” category.  
8.6.2 
Dermatologic Examination 
Any abnormalities noted during the dermatologic examination at the Baseline Visit will be 
captured in the Medical History. 
8.6.3 
Baseline Clinical Evaluations 
The frequency distribution of IGA scores will be tabulated as Test Article A versus Test Article B 
to reflect the paired data.  Descriptive statistics for the acne lesion counts, TEWL and sebum 
measurements will be presented for each test article. 
8.6.4 
Baseline Local Skin Reactions 
The frequency distribution of each of the pre-application LSR severity scores will be tabulated as 
Test Article A versus Test Article B to reflect the paired data. 


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8.7 
Dosing Compliance 
Descriptive statistics will be used to summarize dosing duration and test article compliance for 
each analysis population. Dosing duration (days) will be calculated as [date of last dose] – [date 
of first dose] + 1. Subjects will be instructed to apply each test article once daily for six weeks, 
therefore, the expected number of applications is 42.  Dosing compliance will be calculated as 
[reported number of applications] divided by [expected number of applications] multiplied by 100. 
Compliant subjects are defined as those who apply at least 
 and no more than 
 of the 
expected test article applications (Right and Left face), and did not miss scheduled applications 
for more than three consecutive days. The percentage of compliant subjects will also be presented. 
8.8 
Efficacy Evaluation 
As appropriate, outcomes relative to Test Article A versus Test Article B will be tabulated for all 
visits. The efficacy analyses will be conducted on the mITT and PP populations and will be 
compiled using descriptive statistics only for all efficacy variables. 
8.8.1 
Analysis of Efficacy 
8.8.1.1 
Investigator’s Global Assessment 
IGA scores will be recorded for each side of the face at every visit with Visit 5 / Week 6 being 
the primary time point of interest. IGA scores will be dichotomized to “success” or “failure” 
where “success” is defined as at least a two-point improvement in IGA score relative to Baseline. 
 
The following tabulations of IGA scores will be provided at each post-Baseline visit: 
 Frequency distribution of IGA scores for Test Article A versus Test Article B. 
 Proportions of subjects where Test Article A score > Test Article B score, Test Article A 
score = Test Article B score, and Test Article A score < Test Article B score. 
 Proportions of subjects with IGA “success” for Test Article A versus Test Article B. 
8.8.1.2 
Acne Lesion Counts 
Inflammatory and non-inflammatory lesion counts will be assessed at each visit with Visit 5 / 
Week 6 being the primary time point of interest.  Descriptive statistics will be provided for the 
observed and absolute and percent change from Baseline for each post-Baseline visit for each 
test article. In addition, descriptive statistics for the within subject differences (Test Article A – 
Test Article B) of the absolute and percent change values will be presented. 
8.8.1.3 
TEWL and Sebum Assessments 
Descriptive statistics will be provided for the observed and absolute and percent change from 
Baseline at Weeks 2, 4, 6 and 7 for the sebum (sebumetric value) and TEWL values. 
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8.8.2 
Statistical / Analytical Issues 
8.8.2.1 
Handling of Dropouts or Missing Data 
There will be no imputation of missing data. 
8.8.2.2 
Interim Analyses 
There are no interim analyses planned for this study. 
8.8.2.3 
Multicenter Studies 
Not applicable to this study. 
8.8.2.4 
Multiple Comparisons / Multiplicity 
Not applicable to this study. 
8.8.2.5 
Examination of Subgroups 
There are no subgroup analyses planned for this study. 
8.9 
Safety Evaluation 
As appropriate, outcomes relative to Test Article A vs Test Article B will be tabulated. All safety 
analyses will be performed in the Safety population unless otherwise stated. 
8.9.1 
Extent of Exposure 
The total amount of test article used (grams of test article applied) will be determined from the 
weights of the returned test articles. The average daily amount of test article used will be 
determined as [total amount used (grams)] divided by [dosing duration (days)]. Descriptive 
statistics will be provided by test article for the total amount of test article used by each subject 
and the average daily amount of test article used. 
8.9.2 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. The number and percent of unique subjects reporting each TEAE will be summarized 
by MedDRA system organ class (SOC), MedDRA preferred term (PT). AEs will also be 
similarly summarized by SOC, PT, maximum severity, as well as, by SOC, PT, and closest 
relationship to test article. Application site AEs will be summarized separately by test article. All 
AEs reported during the study will be listed. 


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8.9.3 
Local Skin Reactions  
The frequency distributions of the severity scores of the LSRs (erythema, edema, 
scaling/dryness, burning/stinging, pruritus, erosion, and pain) will be tabulated as Test Article A 
versus Test Article B at each visit. The frequency distribution of change from Baseline, 
categorized as improved/same versus worsened will also be presented. 
8.9.4 
Urine Pregnancy Tests 
Results from the UPT at Baseline and EOT will be presented in a listing. 
8.9.5 
Concomitant Medications and Concurrent Therapies/Procedures 
Concomitant medications and concurrent therapies/procedures will be provided in a subject 
listing. 
9. CHANGES TO PROTOCOL 
The statistical analyses presented here are consistent with the protocol with more details 
provided.