Clinical trial NCT02945657
Conditions: Atopic Dermatitis
Sponsor: Medimetriks Pharmaceuticals, Inc
Start date: 2016-10-01; Completion date: 2017-06-08
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the pharmacokinetic parameters and safety of topical MM36 (OPA-15406) ointment in pediatric subjects with atopic dermatitis under maximal use conditions.

Detailed description:
This is a multi-center, open-label study to assess the degree of systemic exposure and safety of MM36 1% ointment following 4 weeks of twice daily dosing under maximal-use conditions in pediatric subjects with atopic dermatitis.

Arms: arm 1: MM36 topical ointment, 1%, applied twice daily for 28 days
Interventions: intervention 1: MM36 topical ointment, 1%
Intervention descriptions: intervention 1: Twice daily application for 28 consecutive days

Protocol documents:
Prot_001.pdf: 
PROTOCOL MEDI-MM36-206: A PHASE 2 MULTI-CENTER, OPEN-LABEL STUDY 
TO ASSESS PHARMACOKINETIC PARAMETERS AND SAFETY OF TOPICAL 
MM36 (1%) IN PEDIATRIC SUBJECTS 2 TO < 18 YEARS OF AGE WITH ATOPIC 
DERMATITIS UNDER MAXIMAL USE CONDITIONS
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Compound:
MM36
US IND Number:
112973
Clinical Protocol Number:
MEDI-MM36-206
Phase:
2
Original Protocol Date:
19August 2016
Sponsor:
Medimetriks Pharmaceuticals, Inc.
383 Route 46 West
Fairfield, NJ 07004-2402
Medical Monitor:
Clinical Monitoring and Study 
Management: 
Serious Adverse Event Reporting:
Summary of Incorporated Protocol 
Amendments:
Amendment No. 
Version Date
1
30 January 2017
GCP Statement
This study will be conducted in accordance with the Food and Drug Administration (FDA) 
and International Conference on Harmonization (ICH) guidelines on current Good Clinical 
Practice (GCP), in accordance with the Declaration of Helsinki, and Good Laboratory 
Practice (GLP) guidelines. 




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AGREEMENT OF INVESTIGATOR COMPLIANCE
I have read the protocol entitled “MEDI-MM36-206: A Phase 2 Multi-center, Open-label Study to 
Assess Pharmacokinetic Parameters and Safety of Topical MM36 (1%) in Pediatric Subjects 2 to < 
18 Years of Age with Atopic Dermatitis Under Maximal Use Conditions” and
Agree that Protocol MEDI-MM36-206 contains all of the information necessary to conduct the 
study;
Agree to conduct the study in accordance with the protocol and as subsequently amended by the 
Sponsor (or designee), except when to protect the safety, rights or welfare of study subjects;
Agree to conduct the study in accordance with applicable federal, state and local laws and 
regulations, and in accordance with Good Clinical Practice (GCP) and the World Medical
Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human 
Subjects, updated October 2013; and 
Agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments.
Investigator
Site ID
Print Name
Signature
Date


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ABBREVIATIONS
Abbreviations
Definitions
AD
Atopic Dermatitis
AE 
Adverse Event 
Ag
Antigen
ALT
Alanine Amino Transferase
AST
Aspartate Transaminase
AUC0-last
Area under the plasma concentration-time curve from 
time zero to time last (time of last quantifiable plasma 
concentration) [AUC0-t]
BLQ
Below the limit of quantitation
BMI
Body mass index
BSA
Body surface area
BUN
Blood urea nitrogen
cAMP
cyclic adenosine 3’,5’-monophosphate
CBC
Complete blood count
CBP
Childbearing potential
CDC
Center for Disease Control
CK
Creatinine kinase
CLIA
Clinical Laboratory Improvement Act
Cmax
Maximum plasma concentration
CRF
Case report form
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
FDA
US Food & Drug Administration
GCP 
Good Clinical Practice
GGT
Gamma glutamyl transferase
HCT
Hematocrit
Hgb
Hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
High performance liquid chromatographic method with 
tandem mass spectrometric detection
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Institutional Ethics Committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
ITT
Intent to treat
LDH
Lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities


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ABBREVIATIONS
Abbreviations
Definitions
N
Number of observations
NCA
Non-Compartmental Analysis
PDE
Phosphodiesterase
PI
Principal investigator
PK
Pharmacokinetic
POC
Proof of concept
RBC
Red blood cells
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMP
Safety Management Plan
TCI
Topical calcineurin inhibitors
TEAE
Treatment emergent adverse event
Tmax
Time of maximum plasma concentration
ULN
Upper limit of normal
UV
Ultraviolet
US
United States
WBC
White blood cells
WHO
World Health Organization
WHODD
World Health Organization Drug Dictionary


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PROTOCOL SYNOPSIS
Study Title
Protocol MEDI-MM36-206: A Phase 2 Multi-center, Open-label Study to Assess Pharmacokinetic 
Parameters and Safety of Topical MM36 (1%) in Pediatric Subjects 2 to < 18 Years of Age with Atopic 
Dermatitis Under Maximal Use Conditions
Study Number
MEDI-MM36-206
Study 
Objectives
Primary Objective:
The primary objective of this study is to assess the degree of systemic exposure (active parent compound 
and metabolites) following 4 weeks of twice daily dosing with MM36 1%, applied topically under 
maximal-
n subjects 2 to less than 12 
years of age (excluding scalp and venous access areas)
< 18 years of age with atopic dermatitis (excluding scalp and venous access areas). 
Secondary Objective:
The secondary objective of this study is to assess the safety profile of MM36 1% applied topically twice 
daily for up to 4 weeks in pediatric subjects 2 to < 18 years of age, with atopic dermatitis.
Exploratory Objective:
Study 
Endpoints
Primary Endpoint
Determination of plasma concentrations of the parent compound MM36 and its metabolites after the first 
topical application of MM36 and after two weeks of twice daily application (steady state).
Secondary Endpoints
Incidence and severity of application site adverse events (AEs); 
Incidence and severity of all AEs and their relationship to study drug; 
Incidence of clinically meaningful change from baseline in safety laboratory parameters, ECG, 
and vital signs;
Proportion of subjects who discontinue treatment due to an adverse event.
Exploratory Endpoints


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Study 
Population
Subjects enrolled in this study will be males and females, 2 to < 18 years of age, with a diagnosis of 
atopic dermatitis, based upon the American Academy of Dermatology atopic dermatitis diagnostic 
recommendations (2014). Subjects that are 2 to less than 12 years of age will have atopic dermatitis that 
A (excluding scalp and venous access areas). Subjects that are at least 12 years but 
less than 18 years of age will have 
25% BSA involvement (excluding scalp and venous access areas).  
Study Design
This multicenter, open-label study, will evaluate the pharmacokinetics, safety, tolerability, and the 
exploratory efficacy of MM36 1% ointment when applied twice daily for up to 4 weeks in subjects 2 to < 
18 years of age with atopic dermatitis, at the upper range of disease severity. This study will also 
evaluate the systemic availability of MM36 1% when applied topically under maximal use conditions.  
Following screening (within 30 days prior to the first application of study drug) and confirmation of 
study qualification, subjects will be registered and assigned (V2) to one of three treatment groups based 
on the subject’s age at Screening (V1). The first dose of study drug will be applied in the study clinic 
(V2/Day 1) and blood samples will be collected for pharmacokinetic (PK) evaluation (plasma 
concentration of MM36) prior to the first application (0 hours) and at 1 hour (± 15 minutes), 4 hours (± 
30 minutes) and at 8 hours (± 1 hour) post application. On Day 15, the study drug will again be applied 
in the study clinic, and blood samples will be collected for PK prior to dosing and at 1 hour (± 15 
minutes), 4 hours (± 30 minutes) and at 8 hours (± 1 hour) post application.
At Screening (V1) and Baseline (V2), subjects with atopic dermatitis that are 2 to less than 12 years of 
(excluding scalp and venous access 
areas), and subjects 12 year
(excluding scalp and 
venous access areas) (i.e., maximal use conditions). The same (or greater, BSA if area involved expands) 
amount of study drug topically applied at baseline will continue to be applied twice daily, to the same 


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area where study drug was applied on Day 1, even if the % BSA improves over the course of the first 2 
weeks (14 days) of treatment. Between Day 15 (after the maximal use application and collection of PK 
samples) and Day 28, the study drug will only be applied to the involved areas. The last application of 
study drug will be given the evening before the final visit (V6). 
An independent Data Safety Monitoring Board (DSMB) will facilitate the management and identification 
of potential safety concerns, on a regular basis, that could affect the safety of trial subjects, and will 
examine whether the information collected during these periodic intervals is consistent with knowledge 
about the product’s safety (e.g., unanticipated adverse events). The DSMB will also assess whether 
revisions to the study protocol and/or consent are required, and will evaluate the overall progress of the 
study. Details regarding the policies and procedures of the DSMB and intervals and data to be evaluated 
will be described in the DSMB Charter. 
Description of 
Test Article,
Dosage, and 
Administration
MM36 1% Ointment for topical administration is a white petrolatum based ointment containing MM36
1% weight/weight (w/w), 
. 
Each gram of MM361 % w/w ointment contains 10 mg of active MM36.
All subjects will receive active study drug and the dosage will be based on % BSA involvement 
(intended area to be treated). The study drug will be applied twice daily (approximately 12 hours apart) 
for up to 4 weeks (28 days).
Study Centers
Up to 12 investigational sites in the United States (U.S.) , Honduras, and Panama will participate. 
Main Inclusion 
Criteria
For a study subject to be evaluated for study participation: 
1.
Written Informed Consent (including HIPAA) will be obtained prior to the conduct of any study 
related procedures from the Parent(s)/Legal Guardian(s) to permit participation of a minor in a 
clinical research study in accordance with federal and local laws. Additionally, assent from a 
minor child will be obtained in accordance with federal and local laws as well as in compliance 
with the recommendations of the approving Institutional Review Board (IRB)/Ethics Committee 
(EC) (Refer to Section 6.1).
Study subjects will be eligible for inclusion in the study if they meet all of the following criteria at 
screening and up to the time of enrollment as applicable:
2.
Have a diagnosis of atopic dermatitis, based upon the American Academy of Dermatology 
atopic dermatitis diagnostic recommendations (2014) (refer to Section 6.5.2). 
3.
(excluding scalp and venous access areas) if 2 
(excluding scalp and venous access areas) if subject is at 
least 12 years of age as assessed the by the hand method (one back-of-hand of the subject 
[palms and fingers] equivalent to 1% of a subject’s BSA; refer to Section 6.10) and as 
confirmed by the Investigator at the Screening visit (V1) and prior to the first dose of study drug 
(V2). 
4.
Are male or female between 2 and <18 years of age at the time of Screening visit (V1; when 
consent for study participation is given).
5.
Be in generally good health based on Investigator's assessment (other than AD), with no 
clinically significant laboratory abnormalities, co-morbidities or psychiatric conditions which, 
in the opinion of the Investigator, would place the subject at increased risk or would confound 
the objectives of the study.
6.
The Parent(s)/Legal guardian(s) and study subject are willing and able to follow all study-
related procedures, including but not limited to application of study drug and pharmacokinetic 


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(PK) sampling, and be willing and able to return to the study clinic for study visits.
7.
If female of childbearing potential (CBP), must be willing to take a take a pregnancy test at 
screening and prior to the first dose and the results must be negative. For purposes of this study, 
che, 
whichever occurred first. Females must either practice abstinence from heterosexual contact or 
use one of the approved contraceptive options described in the protocol (refer to Section 6.25)
from the time of the Screening visit (V1) and for 7 days after the last study visit (V6). 
Or
If male, of reproductive potential, must be willing to practice effective contraception during the 
study (while receiving study drug from V2 and for 7 days after the last study visit (V6). 
The Investigator will educate the subject regarding abstinence or contraception options and the 
correct and consistent use of effective contraceptive methods in order to successfully prevent 
pregnancy.
8.
Willingness to refrain from the use of tanning beds, sunlamps and artificial tanning products, 
and be willing to avoid excessive unprotected exposure to natural sunlight from Screening (V1) 
through the end of the study period (V6). Use of topical sunscreen will be permitted providing it 
has been used consistently (i.e., > 28 days) by the subject and does not contain any prohibited 
medications/ingredients.  
9.
Have a baseline Investigator Global Assessment (IGA) score of 
2 (mild) prior to the first dose 
of study drug (V2).
Main Exclusion 
Criteria
A study subject will be excluded from the study if they meet any of the following criteria at Screening or 
Baseline (V2):
1.
Have a known allergy or intolerance (hypersensitivity) to the study drug (MM36 or OPA-15406) or 
any of its components.
2.
Pregnant or planning to become pregnant during the study or breastfeeding.
3.
Subjects with known difficulty undergoing venipuncture or poor venous access.
4.
Subjects with active or acute viral skin infection (e.g., herpes simplex, herpes zoster, chicken pox), 
and/or clinically infected AD.
5.
Subjects with a suspected and/or diagnosed malignancy (including skin) or who have a history of 
malignancy.
6.
Subjects with a history of recurrent bacterial infection, defined as at least 3 major infections 
resulting in hospitalization and/or requiring intravenous antibiotic treatment within 12 months prior 
to Screening (V1).
7.
Investigator assessed, clinically significant history or physical findings of:  cardiac (e.g., rheumatic 
fever or heart valve replacement), dermatologic (e.g., skin conditions with a skin barrier defect such 
as  but not limited to, Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma or 
cutaneous Graft Versus Host Disease), endocrinologic (e.g., severe or uncontrolled diabetes), 
pulmonary, neurologic, psychiatric, hepatic (e.g., HBsAg, anti HCV), renal, hematologic, 
immunologic/immunocompromised (e.g., lymphoma, acquired immune deficiency syndrome, 
Wiskott-Aldrich Syndrome, current or prior hepatitis or acquired immunodeficiency syndrome or 
known carriers of HIV antibodies), or other major disease (e.g., systemic fungal infection) or other 
severe uncontrolled conditions (e.g., drug or alcohol abuse), that are significant and/or that may pose 
a health risk to the subject in the study or may have an impact on the study assessments.
8.
Clinically significant findings on 12-lead electrocardiogram (ECG) such as, but not limited to, AV 


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block, or evidence of prolongation of the QRS complex based on gender and age in subjects where 
an adequate quality ECG could be obtained.
9.
Any abnormal laboratory parameter which in the opinion of the Investigator would place the 
subject's health at risk for participation. An abnormal test may be repeated once to confirm study 
eligibility if there is a satisfactory reason to suggest that the initial elevation was either spurious or 
due to an acute intermittent, now resolved illness (e.g. elevated WBC due to an acute infection).
10. Clinically significant liver dysfunction defined as one or both of the following at Screening (V1). An 
abnormal test may be repeated once to confirm study eligibility.  
a.
Aspartate aminotransferase (AST) > 1.5 x ULN
b.
Alanine aminotransferase (ALT) > 1.5 x ULN
11. Use of the following restricted medications or therapies prior to (as specified) and throughout the 
study period (V6/Day 29): 
a.
Within 60 days Prior to Baseline (V2/Day): 
i.
Use of a topical or oral PDE4 Inhibitor (i.e. crisaborole) or scheduled use during the study 
period; or
ii.
Use of any investigational systemic or topical medication or scheduled use during the 
study period.
b.
Within 28 days Prior to Baseline (V2/Day 1): 
i.
Use of systemic immunosuppressive/immunomodulator medication, corticosteroids, 
antimetabolite medication, or retinoid medication, or scheduled use during the study 
period.  Intra-ocular, intra-nasal, and inhaled corticosteroids may be considered if, in the 
opinion of the investigator, their use will not impact the assessment of the selected 
treatment area;
ii.
Phototherapy (ultraviolet light A, narrowband ultraviolet B, and ultraviolet light B); or
iii.
Use of new sunscreen or sunscreen with excluded ingredients, or use during the study 
period.
c.
Within 14 days Prior to Baseline (V2/Day 1): Use of topical immunomodulators, topical 
corticosteroids (with exception of 1% hydrocortisone as described in Exclusion 11e) or 
scheduled use during the study period.  
d.
Within 7 days Prior to Baseline (V2/Day 1):
i.
Topical antihistamines;
ii.
Sedating antihistamines, or scheduled use during the study period;
iii.
Non-sedating antihistamines. If stable use within 2 weeks of the study, continued use will 
be allowed as a concomitant medication and should be continued during the study; or
iv.
Use of topical retinoids, or scheduled use during the study period.
e.
Within 3 days Prior to Baseline (V2/Day 1): Use of topical 1% hydrocortisone, or scheduled 
use during the study period.  
f.
Within 24 Hours Prior to Baseline (V2/Day 1): Use of other prescription or non-prescription 
non-study topical emollients, occlusive agents, humectants, wet-wraps, coal tar, or bleach baths 
or scheduled use during the study period.
12. Participation in any other interventional clinical study or trial within 60 days of the Baseline 
(V2/Day 1) visit, or scheduled participation in another interventional clinical study during the study 
period.


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13. Children or relatives of the Sponsor, CRO, or the Study Site personnel are excluded from 
participating in the study.
Statistical 
Analysis
Sample Size
The sample size is not driven by inferential statistics. A sample size of 32 subjects is set for qualitative 
investigation of the pharmacokinetic profile as well as the safety and tolerability and responsiveness 
(efficacy) of MM36 1% when applied topically twice daily for 4 weeks to pediatric subjects 2 to < 18 
years of age.
Analysis Population
Two populations will be used for analysis: safety and intent-to-treat. The definition of these populations 
follows:
Safety Population:  All enrolled subjects who received at least one dose of study medication and 
have at least one post-baseline safety assessment constitute the Safety Population.
Intent-to-Treat (ITT) Population:  All enrolled subjects who took at least one dose of study 
medication constitute the Intent-to-Treat Population.
PK and safety data will be analyzed based on the safety population. Efficacy data will be analyzed based 
on the ITT population.
Primary and Secondary Analysis
Pharmacokinetics
Individual plasma concentrations of MM36 and its metabolites (MAP-15484, MAP15497 and MAP-
15485) will be summarized descriptively using the arithmetic mean, standard deviation (SD), CV (%), 
median, minimum and maximum. Individual plasma concentration-time profiles of MM36 will be 
plotted on both a linear and a semi-logarithmic scale. Mean values will also be presented graphically.  
The following pharmacokinetic parameters will be analyzed for each subject and for each PK time point 
at which a sufficient (detectable) concentration of MM36 or its metabolites will be measured to permit 
their derivation. If there are sufficient concentration data above the level of quantification the following 
pharmacokinetic parameters will be calculated:
Cmax = Maximum plasma concentration;
Tmax = Time of maximum plasma concentration;
AUC0-last = Area under the plasma concentration-time curve from time zero to time last (time 
of last quantifiable plasma concentration) [AUC0-t].
Safety
Safety evaluations will consist of adverse events (AEs), application site reactions, physical examinations, 
vital signs, ECGs, weight, and laboratory measurements (hematology, chemistry, and urinalysis). Full 
details will be specified in the SAP. 
Exploratory
Study Duration
The maximum individual study participation is approximately 60 days (screening (Day -30) through final 
Day 29 (± 1 day) Visit).


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1
SCHEDULE OF ACTIVITIES
Week/Description
Screening
Week 0
Week 1
Week 2
Week 3
Week 4
Visit
V1
V2
V3
V4
V5
V6/ET
Study Day
-30 to -2 
Day 1
Day 8
(±1)
Day 15 
(±1)  
Day 22
(±1)
Day 29
(±1)
Consent/Assent
Refer to Section 6.1
X 
Inclusion/Exclusion Criteria
Refer to Sections 5.1and 5.2
X 
Xa
Demographics
Refer to Section 6.2
X 
Height/Weight/BMI and Body Surface Area (BSA) Calculation
Refer to Sections 6.6 and 6.7
X 
Xa,j
Xa,j
Xj
Medical History (General, Surgical, Social and Medications)
Refer to Sections 6.3.1and 6.3.3
X 
Targeted Medical History – Atopic Dermatitis
Refer to Section 6.3.2
X 
Physical Examination
Refer to Section 6.4
X 
Xa
Xc
Xc
Xc
X 
Fitzpatrick Skin Type Assessment 
Refer to Section 6.5
X 
BSA% Involvement 
Refer to Section 6.8
X 
Xa
Xa
Xa
Xa
X 
Photography (as applicable)
Refer to Section 6.19
Xa
Xa
Xa
Xa
X 
Vital Signs
Refer to Section 6.21
X 
Xa
Xa
Xa
Xa
X 


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Week/Description
Screening
Week 0
Week 1
Week 2
Week 3
Week 4
Visit
V1
V2
V3
V4
V5
V6/ET
Study Day
-30 to -2
Day 1
Day 8
(±1)
Day 15
(±1)
Day 22
(±1)
Day 29
(±1)
12 Lead Electrocardiogram
Refer to Section 6.22
X 
X 
X 
X 
Safety Laboratory Testing (Hematology, Chemistry and UA)
Refer to Section 6.23.4.2
X 
Xk
Xk
Pregnancy Testing – Females of Childbearing Potential only
Refer to Section 6.23.4.1
Xf
Xa,b
Xb
Pharmacokinetic Sampling
Refer to Section 6.23.5
Xg
Xg
Registration
Refer to Section 4.3
Xa
Dispensing Study Drug
Refer to Section 8.3
Xa
X 
X 
X 
Training Subject/Parent/guardian (caregiver) (instructions) and 
Observation of Dose Application 
Refer to Section 8.4
Xa
X 
X 
X 
Dosing and Diary Completion
Refer to Section 8.4
X-------------------------------------------------------------X e
Compliance 
Refer to Section 8.5
Xa
Xa
Xa
X 
Concomitant Medications
Refer to Section 6.24
Xa
Xa
Xa
Xa
X 
Adverse Events and Serious Adverse Events
Refer to Section 0
X 
X 
X 
X 
X 
X 
Application Site Assessments
Refer to Section 6.18
Xa
Xa
Xa
X 


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a
Prior to dosing 
b
For females of childbearing potential, urine pregnancy test will be done locally
c
Abbreviated examination of the skin and other areas with previous abnormal findings
d
Ongoing adverse events will be followed at 1 to 2 week intervals (unscheduled visit) until resolution or until the event has resolved or improved/stabilized and in the opinion of the Investigator, no longer 
needs to be followed. 
e
The last dose of study drug will be applied the evening before this visit
f
Serum pregnancy test for females of childbearing potential
g
Assessed at 0 hour (pre-dose), 1 hour (± 15 minutes), 4 hours (± 30 minutes), and 8 hours (± 1 hour) after application of the study drug in the study clinic.
h
i
Assessment prior to each application of study drug (approximately every 12 hours) during the first week of dosing
j
Weight only
k
CBC and chemistry panel only
l


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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ..............................................................................................2
AGREEMENT OF INVESTIGATOR COMPLIANCE ...........................................................3
ABBREVIATIONS ...................................................................................................................4
PROTOCOL SYNOPSIS ..........................................................................................................6
1
SCHEDULE OF ACTIVITIES .....................................................................................13
2
INTRODUCTION ........................................................................................................21
2.1
Background Information ..........................................................................................21
2.2
Rationale ...................................................................................................................21
2.3 
 ........................................................................................22
3
STUDY OBJECTIVES AND ENDPOINTS ................................................................24
3.1 
Objectives .................................................................................................................24
3.1.1 
Primary Objective ................................................................................................24
3.1.2 
Secondary Objectives ..........................................................................................24
3.2 
Exploratory Objectives .............................................................................................24
3.3 
Criteria for Evaluation ..............................................................................................24
3.3.1 
Primary Endpoints ...............................................................................................24
3.3.2 
Secondary Endpoints ...........................................................................................24
3.3.3 
Exploratory Endpoints .........................................................................................24
4
STUDY DESIGN ..........................................................................................................27
4.1 
General Description ..................................................................................................27
4.2 
Enrollment ................................................................................................................28
4.3 
Registration ..............................................................................................................28
4.4 
Screen Failure ...........................................................................................................28
4.5 
Completion ...............................................................................................................28
4.6 
Early Termination (ET) ............................................................................................28
4.6.1 
Criteria for Premature Discontinuation ...............................................................29
4.6.1.1 
Discontinuation from Treatment .......................................................................29
4.6.1.2 
Discontinuation from Study ..............................................................................29
4.6.1.3 
Lost to Follow-up ..............................................................................................29
4.6.1.4 
Subject Replacement .........................................................................................29
4.7 
Safety Oversight .......................................................................................................30
4.7.1 
Data Safety Monitoring Board (DSMB) .............................................................30
4.7.2 
Investigator ..........................................................................................................30
5
STUDY SUBJECT SELECTION .................................................................................31
5.1 
Inclusion Criteria ......................................................................................................31
5.2 
Exclusion Criteria .....................................................................................................32


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6
DESCRIPTION OF STUDY PROCEDURES .............................................................35
6.1 
Informed Consent .....................................................................................................35
6.1.1
Written Parental/Legal Guardian Consent ...........................................................35
6.1.2
Minimum Federal Requirements for Consent .....................................................35
6.1.3 
When Parents/Legal guardians Disagree .............................................................36
6.1.4 
Assent ..................................................................................................................36
6.1.5 
Documenting the Consent/Assent Process ..........................................................36
6.2
Demographics ...........................................................................................................37
6.3
Histories ...................................................................................................................37
6.3.1 
General Medical/Surgical and Social History .....................................................37
6.3.2 
History - Atopic Dermatitis .................................................................................37
6.3.3 
Medication History ..............................................................................................38
6.4 
Physical Examination ...............................................................................................38
6.5 
Fitzpatrick Skin Type Assessment ...........................................................................38
6.6 
Height/Weight and Body Mass Index (BMI) Calculation .......................................39
6.7 
Body Surface Area (BSA) Calculation ....................................................................39
6.8 
Body Surface Area (BSA)% Involvement ...............................................................40
6.9 
Selected Treatment Area and BSA% to be Treated .................................................40
6.9.1 
Maximal Use Treatment Area .............................................................................40
6.9.2 
Treatment Area for Improvement in Selected Treatment Area ...........................41
6.9.3 
Treatment for Worsening Selected Treatment Area ............................................41
6.10 
Dosing Diary ............................................................................................................41
6.11 
 
 
 
 
 
 
 
 
 
 
 
6.18 
Application Site Assessment ....................................................................................45
6.19 
 
6.20 
Photography .............................................................................................................45
6.21 
Vital Signs ................................................................................................................46
6.21.1 
Temperature and Respiratory Rate ......................................................................46
6.21.2 
Seated Blood Pressure and Heart Rate ................................................................46
6.22 
Electrocardiogram (ECG).........................................................................................46
6.23 
Laboratory Testing ...................................................................................................46
6.23.1 
Testing Facilities .................................................................................................46
6.23.2 
Blood Volumes ....................................................................................................47


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6.23.3 
Sample Identification...........................................................................................47
6.23.4 
Screening and Safety Laboratory Testing ...........................................................47
6.23.4.1
Pregnancy Testing.............................................................................................47
6.23.4.2
Routine Safety Laboratory Testing...................................................................47
6.23.5 
Pharmacokinetics.................................................................................................48
6.24 
Concomitant Medications ........................................................................................49
6.24.1 
General ................................................................................................................49
6.24.2
Concomitant Medication Restrictions .................................................................49
6.25
Prevention of Pregnancy during the Study...............................................................51
6.25.1 
Instructions for Female Subjects of Childbearing Potential................................51
6.25.2 
Instructions to Males of Reproductive Potential .................................................51
6.26 
Lifestyle Guidelines .................................................................................................51
6.26.1 
Restricted/Limited Exposure to Artificial/Natural Sunlight or Artificial 
Tanning Agents ...................................................................................................51
6.26.2 
Use of Sunscreen .................................................................................................51
6.26.3 
Bathing and Swimming.......................................................................................52
7
STUDY VISITS............................................................................................................52
7.1 
Screening (Visit 1) ...................................................................................................52
7.2 
Baseline (Visit 2/Day 1)...........................................................................................53
7.3 
Visit 3/Day 8 (±1).....................................................................................................54
7.4 
Visit 4/Day 15 (±1)...................................................................................................55
7.5 
Visit 5/Day 22 (±1)...................................................................................................56
7.6 
Visit 6/Day 29 (±1) or Early Termination (ET) .......................................................56
7.7 
Unscheduled Visit(s)................................................................................................57
7.8 
Unscheduled Procedures ..........................................................................................57
8
STUDY DOSING .........................................................................................................58
8.1
Formulation, Packaging and Labelling ....................................................................58
8.1.1 
Formulation .........................................................................................................58
8.1.2 
Packaging ............................................................................................................58
8.2 
Storage......................................................................................................................58
8.3 
Dispensing................................................................................................................58
8.4 
Dosing ......................................................................................................................60
8.5 
Compliance...............................................................................................................60
8.6 
Study Drug Accountability.......................................................................................61
8.7 
Blinding....................................................................................................................61
8.8 
Breaking the Study Blind .........................................................................................61
9
PROTOCOL VIOLATIONS ........................................................................................62
10 
ADVERSE EVENTS....................................................................................................63


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10.1 
Definition of an Adverse Event................................................................................63
10.2 
General Guidelines...................................................................................................63
10.3
Reporting Period ......................................................................................................63
10.4
Assessment of Severity ............................................................................................64
10.5 
Relationship of an Adverse Event to Study Drug ....................................................64
10.6 
Suspected Adverse Reaction ....................................................................................65
10.7 
Unexpected Adverse Events.....................................................................................65
10.8
Serious Adverse Event Definition............................................................................65
10.9
Reporting..................................................................................................................66
10.9.1 
Serious Adverse Event Reporting Requirements ................................................66
10.9.2 
Non-Serious Adverse Event Reporting Requirements and Ongoing Safety 
Review.................................................................................................................67
10.10 
Pregnancy Reporting................................................................................................67
11
DATA ANALYSIS AND STATISTICAL METHODS ..............................................68
11.1 
Sample Size Determination......................................................................................68
11.2 
Analysis Populations................................................................................................68
11.3 
Statistical Analysis ...................................................................................................68
11.3.1 
General Statistical Methodology.........................................................................68
11.3.2 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications .........................................................................................................68
11.3.3 
Treatment Compliance ........................................................................................68
11.3.4 
Drug Exposure.....................................................................................................69
11.4 
Primary Analysis......................................................................................................69
11.4.1 
Pharmacokinetics.................................................................................................69
11.5 
Secondary Analysis..................................................................................................69
11.5.1 
Safety...................................................................................................................69
11.6
Exploratory Analysis................................................................................................70
11.7 
Interim ......................................................................................................................70
12 
DATA COLLECTION, RETENTION AND MONITORING.....................................71
12.1 
Data Collection Instruments.....................................................................................71
12.2 
Data Management Procedures..................................................................................71
12.2.1 
Data Quality Control and Reporting....................................................................71
12.2.2 
Data Entry............................................................................................................71
12.2.3 
Medical Information Coding ...............................................................................72
12.2.4 
Data Validation....................................................................................................72
12.3 
Archival of Data.......................................................................................................72
12.4 
Availability and Retention of Investigational Records ............................................72
12.5 
Monitoring................................................................................................................73


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12.6 
Subject Confidentiality .............................................................................................73
12.7 
Retained Blood Samples ..........................................................................................73
13
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................74
13.1
Protocol Amendments ..............................................................................................74
13.2 
Institutional Review Boards and Independent Ethics Committees ..........................74
13.3 
Informed Consent Form – General Provisions .........................................................75
13.4 
Publications ..............................................................................................................75
14
SPONSOR DISCONTINUATION CRITERIA ...........................................................75
15
REFERENCES ..............................................................................................................76
APPENDIX A – DOSING INSTRUCTIONS .........................................................................79


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2
INTRODUCTION
2.1 Background Information 
MM36 (also known as OPC-271 and OPA-15406) is a novel nonsteroidal phosphodiesterase 
type 4 (PDE4) inhibitor which selectively inhibits the synthesis of the intracellular second 
messengers that activate inflammation
2.2 Rationale  
Currently, the pathogenesis of AD is unknown; however, Hanifin et al reported increased 
PDE activity and decreased intracellular cAMP levels in peripheral blood leukocytes of 
subjects with AD, which has been associated with higher production of proinflammatory 
mediators (Hanifin et al., 1985). Cooper et al reported the inhibition of immunoglobulin E 
synthesis with the PDE inhibitor, Ro 20-1724, in a study using the peripheral blood 
mononuclear cells of subjects with AD (Cooper et al., 1985).  These studies have shown that 
PDE inhibitors exert an anti-inflammatory action by increasing the intracellular cAMP 
concentration, inhibiting the production of cytokines and chemical mediators, and inhibiting 
cellular activity. Due to these effects, PDE inhibitors, particularly Type-4, are thought to be 
useful for the treatment of allergic inflammatory diseases.


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Phosphodiesterases (PDEs) are cyclic nucleotide-degrading enzymes associated with the 
conversion of cyclic adenosine 3’,5’-monophosphate (cAMP) to 5'-adenylic acid.  Type-4
phosphodiesterase (PDE4) is widely expressed in a variety of inflammatory cells.  PDE4 
activity promotes a pro-inflammatory response and increased PDE activity has been 
associated with increased cytokine production and an abnormally elevated immune response.


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3
STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
3.1.1 Primary Objective
The primary objective of this study is to assess the degree of systemic exposure (active 
parent compound and metabolites) following 4 weeks of twice daily dosing with MM36 1%, 
applied topically under maximal-use conditions; 
35% Body Surface Area [BSA]
involvement (excluding scalp and venous access areas) in subjects 2 to less than 12 years of 
age,
(excluding scalp and venous access areas) in subjects at least 12 years of age
to < 18 years of age with atopic dermatitis.
3.1.2 Secondary Objectives
The secondary objective of this study is to assess the safety profile of MM36 1% applied 
topically twice daily for up to 4 weeks in pediatric subjects 2 to < 18 years of age, with atopic 
dermatitis.
3.2 Exploratory Objectives 
3.3 Criteria for Evaluation 
3.3.1 Primary Endpoints
Determination of plasma concentrations, of the parent compound MM36 and its metabolites, 
after the first topical application of MM36 and after two weeks of twice daily application 
(steady state).
3.3.2 Secondary Endpoints
Incidence and severity of application site adverse events (AEs); 
Incidence and severity of all AEs and their relationship to study drug;  
Incidence of clinically meaningful change from baseline in safety laboratory 
parameters, ECG, and vital signs; 
Proportion of subjects who discontinue treatment due to an adverse event. 
3.3.3 Exploratory Endpoints


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4
STUDY DESIGN
4.1 General Description
This multicenter, open-label study, will evaluate the pharmacokinetics, safety, tolerability, 
and the exploratory efficacy of MM36 1% ointment when applied twice daily for up to 4 
weeks in subjects 2 to < 18 years of age with atopic dermatitis, at the upper range of disease 
severity. This study will also evaluate the systemic availability of MM36 1% when applied 
topically under maximal use conditions.   
Following screening (within 30 days prior to the first dose of study drug) and confirmation of 
study qualification, subjects will be registered and assigned (V2) to one of three treatment 
groups based on the subject’s age at Screening (V1). The first dose of study drug will be 
applied in the study clinic (V2/Day 1) and blood samples will be collected for evaluation of 
PK prior to the first application (0 hours) and at 1 hour (± 15 minutes), 4 hours (± 30 
minutes) and at 8 hours (± 1 hour) after application of study drug. On Day 15, the study drug 
will again be applied in the study clinic, and blood samples will be collected for PK prior to 
dosing and at 1 hour (± 15 minutes), 4 hours (± 30 minutes) and at 8 hours (± 1 hour) after 
application of study drug.  
At Screening (V1) and Baseline (V2), subjects with atopic dermatitis that are 2 to less than 
12 years of age (Group 2 and 3) must have a treatable area comprising
BSA
involvement (excluding scalp and venous access areas), and subjects 12 years of age and 
older (Group 1) must 
vement (excluding scalp and venous access 
areas) (i.e., maximal use conditions). The same (or greater, BSA if area involved expands) 
amount of study drug topically applied at baseline will continue to be applied twice daily, to 
the same area where study drug was applied on Day 1, even if the % BSA improves over the 
course of the first 2 weeks (14 days) of treatment. Between Day 15 (after the maximal use 
application and collection of PK samples) and Day 28, the study drug will only be applied to 
the involved areas. The last application of study drug will be given the evening before the 
final visit (V6). Refer to Figure 1.
An independent Data Safety Monitoring Board (DSMB) will facilitate the management and 
identification of potential safety concerns, on a regular basis, that could affect the safety of 
trial subjects, and will examine whether the information collected during these periodic 
intervals is consistent with knowledge about the product’s safety (e.g., unanticipated adverse 
events). The DSMB will also assess whether revisions to the study protocol and/or consent 
are required, and will evaluate the overall progress of the study. Details regarding the policies 
and procedures of the DSMB and intervals and data to be evaluated will be described in the 
DSMB Charter. 


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Figure 1  Study Schematic
4.2 Enrollment  
A subject is considered enrolled in the study when the subject’s parent(s)/legal guardian(s)
has provided written informed consent and the child/adolescent has provided assent (as 
applicable). 
4.3 Registration 
Following verification that the subject meets all inclusion criteria and none of the exclusion 
criteria (V1), the subject will be scheduled for Visit 2 (Day 1). A subject who continues to 
meet all inclusion and no exclusion criteria will be registered, and study drug will be 
dispensed.  
4.4 Screen Failure
A subject who has been enrolled but subsequently fails to meet enrollment criteria prior to 
receipt of study drug will be deemed a screen failure. 
4.5 Completion
Each subject will participate in the study up to a maximum of 8 weeks, from the time the 
informed consent form (ICF) is signed/assent provided (V1) through the final visit (V6/Week 
4). A subject is considered to have completed the study after he/she has completed V6/Day 
29.
4.6 Early Termination (ET) 
A subject or the subject’s parent/legal guardian may withdraw the subject from treatment or 
from the study at any time at their request or may be withdrawn at any time at the discretion 
of the Investigator or Sponsor for safety, behavioral, or administrative reasons.   


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4.6.1 Criteria for Premature Discontinuation
4.6.1.1
Discontinuation from Treatment
A subject must be permanently discontinued from the study drug for any of the following 
reasons:
The subject becomes pregnant;
Allergic or adverse reaction to the study drug;
Clinically significant adverse event, which in the opinion of the Investigator, or 
DSMB, would put the subject at unnecessary risk if dosing was continued; or
The subject’s atopic dermatitis worsens and requires alternative or supplemental 
medication during the study.
If a subject is discontinued from treatment, they should continue to be followed in the study.
If subject refuses to stay in the study, then they will be encouraged to complete the V6 (Week 
4/ET visit).
4.6.1.2
Discontinuation from Study
A subject must be discontinued from the study drug and from the study for the following 
reason:
The subject withdraws consent. From the time consent is withdrawn, no additional 
data should be collected. However, the Sponsor may retain and continue to use data 
collected before such withdrawal of consent. 
A subject may be discontinued from the study drug or from the study for the following 
reason:
The subject requests withdrawal from the study. For the safety of the subject, if 
withdrawal is requested, the subject should be encouraged to complete the Week 
4/ET study procedures.
4.6.1.3
Lost to Follow-up
A subject is considered to have been lost to follow-up if he/she [subject or parent/legal 
guardian] cannot be contacted by the Investigator (or designee). The Investigator (or 
designee) will document efforts to attempt to reach the subject twice by telephone and will 
send a certified letter before considering the subject lost to follow-up.  The end of 
participation for a subject lost to follow-up is documented as the delivery date of the certified 
letter.
4.6.1.4
Subject Replacement
Subjects who prematurely discontinue and do not have at least three samples collected on 
either Day 1 or Day 15 post study drug application, may be replaced. The Sponsor may also 


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replace subjects who prematurely discontinue at their discretion or at the recommendation of 
the Data Safety Monitoring Board (DSMB). 
4.7 Safety Oversight
4.7.1 Data Safety Monitoring Board (DSMB)
An independent DSMB will be assembled and will facilitate the management and 
identification of potential safety concerns. The DSMB will also assess whether revisions to 
the study protocol and/or consent are required, and will evaluate the overall progress of the 
study.  Details regarding the DSMB will be further described in the study specific DSMB
Charter.
4.7.2 Investigator
The Principal Investigator must have access and be available to promptly review the results 
of all safety assessments (i.e., clinical laboratory testing), electrocardiogram (ECG) results, 
vital signs and adverse events (AEs) including application site assessment information 
throughout the study. Safety assessments must be promptly (should be within 48 hours of 
notification of event) entered into the Electronic Data Capture (EDC) system. Clinical 
laboratory data will be evaluated by the Principal Investigator and clinical relevance will be 
assessed for abnormal values and the assessment will be documented on the laboratory 
report. A copy of the reports will be maintained as part of the source documentation.


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5
STUDY SUBJECT SELECTION
5.1 Inclusion Criteria
For a study subject to be evaluated for study participation: 
1. Written Informed Consent (including HIPAA) will be obtained (prior to the conduct 
of any study related procedures) from the Parent(s)/Legal Guardian(s) to permit 
participation of a minor in a clinical research study in accordance with federal and 
local laws.  Additionally, assent from a minor child will be obtained in accordance 
with federal and local laws as well as in compliance with the recommendations of the 
approving Institutional Review Board (IRB/Ethics Committee (EC) (Refer to Section
6.1).
Study subjects will be eligible for inclusion in the study if they meet all of the following 
criteria at screening and up to the time of enrollment as applicable:
2. Have a diagnosis of atopic dermatitis, based upon the American Academy of 
Dermatology atopic dermatitis diagnostic recommendations (2014) (refer to Section
6.3.2). 
3.
(excluding scalp and venous access 
areas) if 2 to less than 12 years of age or 
(excluding scalp and venous access 
areas) if subject is at least 12 years of age as assessed the by the hand method (one 
back-of-hand of the subject [palms and fingers] equivalent to 1% of a subject’s BSA;
refer to Section 6.8) and as confirmed by the Investigator at the Screening visit (V1) 
and prior to the first dose of study drug (V2). 
4. Are male or female between 2 and <18 years of age at the time of Screening visit 
(V1; when consent for study participation is given).
5. Be in generally good health based on Investigator’s assessment (other than AD), with 
no clinically significant laboratory abnormalities, co-morbidities or psychiatric 
conditions which, in the opinion of the Investigator, would place the subject at 
increased risk or would confound the objectives of the study.
6. The Parent(s)/Legal guardian(s) and study subject are willing and able to follow all 
study-related procedures, including but not limited to application of study drug and 
pharmacokinetic (PK) sampling, and be willing and able to return to the study clinic 
for study visits.
7. If female of childbearing potential (CBP), must be willing to take a take a pregnancy 
test at screening and prior to the first dose and the results must be negative.  For 
or has reached menarche, whichever occurred first.  Females must either practice 
abstinence from heterosexual contact or use one of the approved contraceptive 
options described in the protocol (refer to Section 6.25) from the time of the 
Screening visit (V1) and for 7 days after the last study visit (V6).


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Or
If male, of reproductive potential, must be willing to practice effective contraception 
during the study (while receiving study drug from V2 and for 7 days after the last 
study visit (V6). 
The Investigator will educate the subject regarding abstinence or contraception 
options and the correct and consistent use of effective contraceptive methods in order 
to successfully prevent pregnancy.
8. Willingness to refrain from the use of tanning beds, sunlamps and artificial tanning 
products and willing to avoid excessive unprotected exposure to natural sunlight from 
Screening (V1) through the end of the study period (V6). Use of topical sunscreen 
will be permitted providing it has been used consistently (i.e., > 28 days) by the 
subject and does not contain any prohibited medications/ingredients.  
9. Have a baseline Investigator Global Assessment (IGA) score of 
2 (mild) prior to the 
first dose of study drug (V2).
5.2 Exclusion Criteria
Study subjects will be excluded from the study if they meet any of the following criteria at 
screening and up to the time of enrollment as applicable:
1. Have a known allergy or intolerance (hypersensitivity) to the study drug (MM36 or 
OPA-15406) or any of its components.
2. Pregnant or planning to become pregnant during the study or breastfeeding.
3. Subjects with known difficulty undergoing venipuncture or poor venous access.
4. Subjects with active or acute viral skin infection (e.g., herpes simplex, herpes zoster, 
chicken pox), and/or clinically infected AD.
5. Subjects with a suspected and/or diagnosed malignancy (including skin) or who have 
a history of malignancy.
6. Subjects with a history of recurrent bacterial infection, defined as at least 3 major 
infections resulting in hospitalization and/or requiring intravenous antibiotic
treatment within 12 months prior to Screening (V1).
7. Investigator assessed, clinically significant history or physical findings of:  cardiac 
(e.g., rheumatic fever or heart valve replacement), dermatologic (e.g., skin conditions 
with a skin barrier defect such as  but not limited to, Netherton’s syndrome, lamellar 
ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease), 
endocrinologic (e.g., severe or uncontrolled diabetes), pulmonary, neurologic, 
psychiatric, hepatic (e.g., HBsAg, anti HCV), renal, hematologic, immunologic/
immunocompromised (e.g., lymphoma, acquired immune deficiency syndrome, 


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Wiskott-Aldrich Syndrome, current or prior hepatitis or acquired immunodeficiency 
syndrome or known carriers of HIV antibodies), or other major disease (e.g., systemic 
fungal infection) or other severe uncontrolled conditions (e.g., drug or alcohol abuse), 
that are significant and/or that may pose a health risk to the subject in the study or 
may have an impact on the study assessments.
8. Clinically significant findings on 12-lead electrocardiogram (ECG) such as, but not 
limited to, AV block, or evidence of prolongation of the QRS complex based on 
gender and age in subjects where an adequate quality ECG could be obtained
years of age).
9. Any abnormal laboratory parameter which in the opinion of the Investigator would 
place the subject's health at risk for participation. An abnormal test may be repeated 
once to confirm study eligibility.
10. Clinically significant liver dysfunction defined as one or both of the following at 
Screening (V1). An abnormal test may be repeated once to confirm study eligibility.
a.
Aspartate aminotransferase (AST) > 1.5 x ULN
b. Alanine aminotransferase (ALT) > 1.5 x ULN
11. Use of the following restricted medications or therapies prior to (as specified) and 
throughout the study period (V6/Day 29):
a.
Within 60 days Prior to Baseline (V2/Day 1):
i. Use of a topical or oral PDE4 Inhibitor (i.e. crisaborole) or scheduled 
use during the study period.
ii. Use of any investigational systemic or topical medication or scheduled 
use during the study period.
b. Within 28 days Prior to Baseline (V2/Day 1):
i. Use of systemic immunosuppressive/immunomodulator medication, 
corticosteroids, antimetabolite medication, or retinoid medication, or 
scheduled use during the study period.  Intra-ocular, intra-nasal, and 
inhaled corticosteroids may be considered if, in the opinion of the 
investigator, their use will not impact the assessment of the selected 
treatment area;
ii. Phototherapy (ultraviolet light A, narrowband ultraviolet B, and 
ultraviolet light B);
iii. Use of new sunscreen or sunscreen with excluded ingredients or use 
during the study period;


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c.
Within
14 days Prior to Baseline (V2/Day 1):
Use of topical 
immunomodulators, 
topical 
corticosteroids 
(with 
exception 
of 
1% 
hydrocortisone as described in Exclusion 10e) or scheduled use during the 
study period.  
d. Within 7 days Prior to Baseline (V2/Day 1):
i. Topical antihistamines;
ii. Sedating antihistamines, or scheduled use during the study period;
iii. Non-sedating antihistamines with stable use within 2 weeks of the 
study are allowed as a concomitant medication;
iv. Use of topical retinoids, or scheduled use during the study period.  
e.
Within 3 days Prior to Baseline (V2/Day 1):
Use of topical 1% 
hydrocortisone, or scheduled use during the study period.  
f.
Within 24 Hours Prior to Baseline (V2/Day 1): Use of other prescription or 
non-prescription non-study topical emollients, occlusive agents, humectants, 
wet-wraps, coal tar, or bleach baths or scheduled use during the study period.
12. Participation in any other interventional clinical study or trial within 60 days of the 
Baseline (V2/Day 1) visit, or scheduled participation in another interventional clinical 
study during the study period.
13. Children or relatives of the Sponsor, CRO, or the Study Site personnel are excluded 
from participating in the study.


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6
DESCRIPTION OF STUDY PROCEDURES 
A description of study procedures listed in the Schedule of Activities is provided within the 
content of this protocol. Refer to the Schedule of Activities 1 for additional information on 
the frequency of each procedure. 
6.1 Informed Consent
6.1.1 Written Parental/Legal Guardian Consent
Adequate provisions must be made for soliciting the permission of the child/adolescent’s 
(less than 18 years of age) parent(s) or legally authorized representative/guardian. The 
process for obtaining oral and/or written consent for children and adolescents is similar to 
that of obtaining consent for adults.  An effective informed consent process involves at 
minimum these elements:   
Conducting the process in a manner and location that ensures privacy;
Giving adequate information about the study in a language understandable to the 
parent/legal guardian and child/adolescent;
Providing adequate opportunity for the parent/legal guardian and child/adolescent to 
consider all options;
Responding to the parent(s)/legal guardian(s) and child/adolescent’s questions;
Ensuring the parent/legal guardian and child/adolescent has understood the 
information provided;
Obtaining the parent/legal guardian and child/adolescent voluntary agreement to 
participate, and 
Continuing 
to 
provide 
information 
as 
the 
parent(s)/legal 
guardian(s),
child/adolescent, or research requires.
6.1.2 Minimum Federal Requirements for Consent
The minimum United States (U.S.) federal requirements for consent indicated below should
be met. However, the Investigator or the Institutional Review Board (IRB)/Ethics Committee 
(EC) may determine that more stringent requirements are appropriate.   
Regulatory Category of Permitted Research with 
Children
Permissions Required
Minimal Risk (45 CFR 46.404, 21 CFR 50.51)
One parent/legal guardian may be sufficient
Greater than Minimal Risk, Direct Benefit to Subject 
(45 CFR 46.405, 21 CFR 50.52)
One parent/legal guardian may be sufficient but IRB 
must determine whether one or two is required
Greater than Minimal Risk, No Direct Benefit to 
Subject, but Likely to Yield Generalizable 
Knowledge about Subject’s Condition (45 CFR 
46.406 21, CFR 50.53)
Both parents/legal guardians, unless one parent is 
deceased, unknown, incompetent, not reasonably 
available, or does not have legal responsibility for 
the custody of the child.
Greater than Minimal Risk, No Direct Benefit to 
Subject, but Results May Alleviate Serious Problems 
of Children’s Health or Welfare (45 CFR 46.407 21 
Both parents/legal guardians, unless one parent is 
deceased, unknown, incompetent, not reasonably 
available, or does not have legal responsibility for 


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Regulatory Category of Permitted Research with 
Children
Permissions Required
CFR 50.54)
the custody of the child.
6.1.3 When Parents/Legal guardians Disagree   
If there are two parents/legal guardians available to give permission but they disagree about 
allowing their child to participate in the study, the child may not be enrolled unless that 
disagreement can be resolved. This applies to all permissible categories, even if only one 
parent’s signature is required, when both parents are involved in the decision, they must 
agree for the child to be enrolled. If a parent who was not involved or available for the 
original consent later becomes involved or available, the two parents must then agree.
6.1.4 Assent
The Investigator should carefully consider and propose adequate provisions for obtaining 
assent of children and adolescents prior to their participating in research. The approving 
IRB/EC application should address whether the intended subject population of children 
would be capable of understanding the nature of their participation in the research, and if so, 
whether or how assent will be obtained.  In determining whether a child is capable of 
assenting, their age, maturity, and psychological state should be taken into account. In 
may be made for all children and adolescents to be involved in research under a particular 
protocol, or for each child, as appropriate. An assent process that takes into account the 
child’s experience and level of understanding, assures an element of cooperation and a 
feeling of inclusion on the part of the child, and also illustrates the Investigator’s respect for 
the rights and dignity of the child in the context of research.   The child should be provided 
with essential information and asked whether or not they wish to participate in the research 
study. 
6.1.5 Documenting the Consent/Assent Process
Consent/Assent MUST be obtained and documented PRIOR to initiation of any study 
procedures. Additionally, the consent form approved for use by the IRB/EC will either 
contain language regarding subject confidentiality, the Health Insurance Portability and 
Accountability Act (HIPAA) or a separate form will also be signed as required by local law
(as applicable).  The PI or his/her approved designee must explain the nature of the study and 
associated risks to the parent(s)/legal guardian and study subject. The date/time that the 
informed consent is signed, a brief description of the consent/assent process (e.g., questions 
asked by the subject), and the name of the individual who obtained consent will be recorded 
in the source record. A copy of the signed informed consent should be provided to the 
parent(s)/legal guardian. Depending on the approving IRB and local requirements, an assent 
form may be included as part of the consent and may or may not be required to be signed by
the child. Investigators must adhere to their local requirements for proper documentation of 
consent/assent. A summary of assent procedures for execution of this study must be 
maintained in the Investigator Essential Regulatory File. It is the responsibility of the PI to 
ensure that any individual delegated the responsibility for obtaining consent/assent are 


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familiar and adhere to the applicable consent/assent requirements. Refer to protocol section 
13.3 for other general provisions.
6.2 Demographics 
Study subject demographic information will be recorded at Screening (V1). Demographic 
information will include date of birth, gender (at the time of birth), race, and ethnicity. 
Findings will be documented in the source documentation and the eCRF. 
6.3 Histories
6.3.1 General Medical/Surgical and Social History
Relevant medical and surgical history will be recorded at Screening (V1) and will include 
medical diagnoses, major surgical procedures within the last 3 years. Social history (tobacco, 
drug, and alcohol use) as well as dietary habits (e.g., unrestricted, vegetarian, gluten-free, 
vegan, other) and allergies (food, medications and environmental) will also be recorded at 
screening. Findings will be documented in the source documentation and the eCRF.
6.3.2 History - Atopic Dermatitis
Diagnostic criteria adopted by the American Academy of Allergy, Asthma, and Immunology 
(Eichenfield, et al, 2014) are defined below will be assessed at Screening (V1) for 
confirmation of study eligibility and will be documented in the source documents and 
recorded in the eCRF.
Essential features — must be present:
•
Pruritus 
•
Eczema (acute, subacute, chronic)
-
Typical morphology and age specific patterns*
-
Chronic or relapsing history
*Patterns include:
1. Facial, neck, and extensor involvement in infants and children
2. Current or previous flexural lesions in any age group
3. Sparing of the groin and axillary regions
Important features — seen in most cases, adding support to the diagnosis:
•
Early age of onset
•
Atopy
-
Personal and/or family history
-
Immunoglobulin E reactivity
•
Xerosis
Associated features — These clinical associations help to suggest the diagnosis of atopic 
dermatitis but are too nonspecific to be used for defining or detecting atopic dermatitis 
for research and epidemiologic studies:


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•
Atypical vascular responses (eg facial pallor, white dermographism, delayed 
blanch response)
•
Keratosis pilaris/ pityriasis alba/ hyperlinear palms/ ichthyosis
•
Ocular/periorbital changes
•
Perifollicular accentuation/ lichenification/ prurigo lesions
Exclusionary conditions — It should be noted that a diagnosis of atopic dermatitis 
depends on excluding conditions, such as:
•
Scabies
•
Seborrheic dermatitis
•
Contact dermatitis (irritant or allergic)
•
Ichthyoses
•
Cutaneous T-cell lymphoma
•
Psoriasis 
•
Photosensitivity dermatoses
•
Immune deficiency diseases
•
Erythroderma of other causes
6.3.3 Medication History 
Medications taken within the last 2 months (60 days) prior to screening will be recorded in 
the source document and on the eCRF. Also refer to Section 6.23.5 concomitant medications 
for additional information.
6.4 Physical Examination
The physical examination will also include an examination of general appearance, skin, eyes, 
ears, nose, throat, neck/thyroid, lungs, heart, upper/lower extremities, lymph nodes, 
abdomen, musculoskeletal system and basic neurological assessment. Additional systems 
will be evaluated as needed. Physical exam findings must be recorded in the source 
documentation and include the date and name of the individual conducting the examination. 
Physical examinations must be performed by an individual licensed to conduct standard 
physical examinations.
Significant findings that are present prior to dosing with the study drug will be recorded in 
the eCRF as adverse events. Clinically significant findings present after dosing will be 
recorded as an adverse event in the eCRF.
6.5 Fitzpatrick Skin Type Assessment
The Fitzpatrick Skin assessment (Fitzpatrick, 1988) will be conducted at Screening (V1) and 
the information will be recorded in the source document and in the eCRF. 


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6.6 Height/Weight and Body Mass Index (BMI) Calculation
Height (cm) and weight (kg) should be obtained with shoes off and only light clothing.
Scales should be calibrated and the same scale should be used for each weight assessment. 
Body Mass Index (BMI) will be calculated by dividing the weight (kg) by the height squared 
(cm) and will be obtained at Screening (V1). 
6.7 Body Surface Area (BSA) Calculation 
The Mosteller Formula (Mosteller, 1987) will be utilized to assess the overall BSA of each 
subject in this study utilizing height and weight collected at Screening (V1).


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The average BSA of individual subjects in this study will vary based on each subject’s height 
and weight; however, the following general estimates, can be made regarding the average 
CDC (50th percentile) (Kuczmarski et al., 2000) expected overall BSA.
Age
Estimated (based on 50th percentile) 
Overall BSA m2
2
0.5
3
0.6
4-5
0.7
6
0.8
7-8
1.0
9-10
1.1
11
1.2
12-13
1.3
14-17
1.6
6.8 Body Surface Area (BSA)% Involvement
The BSA% involvement is the numerical area of active atopic dermatitis disease assessed by 
the Investigator at Screening (V1) and confirmed at Baseline (V2). One back-of-hand of the 
subject (palms and fingers) is equivalent to approximately 1% of a subject’s BSA. All 
eligible subjects 2 to less than 12 years of age must have a BSA% involvement (affected 
area/treatable area) of
35% (excluding scalp and venous access areas) and subjects 
years of age must 
(excluding scalp and venous access 
areas). The BSA% affected score may increase or decrease in area (i.e., size/shape) during 
the duration of the study and should be recorded in the source document and the eCRF. The 
BSA% involvement should be calculated by a qualified physician. 
6.9 Selected Treatment Area and BSA% to be Treated
6.9.1 Maximal Use Treatment Area  
The selected treatment area is defined as the collective areas selected for treatment in the 
study and it must be identified by the Investigator. At Baseline (V2) subjects 2 to less than 
12 years of age must have BSA% involvement (affected area
(excluding scalp and 
venous access areas)
25% BSA% (excluding scalp and venous access areas). Once the selected treatment area is 
set at Baseline, it may increase in area during the duration of the study (for expanded 
disease), but will not decrease in area during the first 2 weeks (14 days) of treatment (through 
collection of the Day 15 PK samples).


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6.9.2 Treatment for Improvement in Selected Treatment Area 
In order to assess the pharmacokinetic profile of MM36 1% (w/w) under maximal use 
conditions, all originally involved BSA treated with study drug at Baseline will continue to 
be treated with MM36 1% ointment even if the area has cleared until after the PK samples 
have been collected on Day 15.  On Day 15, the proportion of the treatment area will be 
defined as either involved or normal (cleared) skin and will be recorded in the source and 
eCRF.
6.9.3 Treatment for Worsening Selected Treatment Area
If the selected treatment area worsens, the Investigator will evaluate whether this worsening 
warrants withdrawal of the subject from study treatment.  Worsening is defined as a post-
baseline selected treatment area which requires additional study medication application due 
to an enlarged area of the BSA% involvement. If the worsening does not warrant 
discontinuation, the investigator will re-evaluate the selected treatment area and assess the
new BSA% treated and increase the ointment dispensing, as appropriate, to cover the 
increased BSA% affected.
The source document body diagram will require updating and a new copy will be provided to 
the subject/parent/guardian (caregiver) along with updated dosing/application instructions
(refer to Appendix A). 
6.10 Dosing Diary  
The subject/parent/guardian (caregiver) will be provided with an electronic dosing diary to 
record the time and amount of each study drug application. The importance of adherence to 
the study schedule will be reinforced at each study visit.   
6.11


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6.18 Application Site Assessment
The study drug application sites will be evaluated at each visit, preferably by the same 
assessor. The study drug should not be applied prior to the study visit to ensure accurate 
visualization of the areas of involvement. Skin irritation will be recorded as an adverse event 
and followed until resolution (or stabilization, as applicable).  Should a skin irritation event 
occur, patch testing is recommended to be performed, if feasible, to rule out an 
allergic/hypersensitivity event.
6.20 Photography  
Photographs of the lesions will be taken at the times presented in the schedule of
Assessments.  Selected sites will take standardized color photographs of the subject’s lesions.  
Photographic equipment and photography standards and procedures will be outlined in the 
photographic manual. All selected sites will be properly trained and instructions will be 
detailed in the Photographic Manual that will be provided. 


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6.21 Vital Signs
6.21.1 Temperature and Respiratory Rate
Temperature (oral or oral equivalent) and respiratory rate will be recorded once at each 
scheduled time point. Findings will be recorded in the source documentation and in the 
eCRF.
6.21.2 Seated Blood Pressure and Heart Rate
Blood pressure should be measured on the SAME arm (location should be documented) and 
with an appropriately sized (e.g., pediatric cuff) blood pressure cuff (that should be the same 
sized cuff throughout the study) for accurate comparison of readings over time.  Position is 
critical for accurate BP measurements. Therefore, when the BP is measured, the arm (cuff)
should be at the level of the heart. When seated, feet should be flat on the floor (if possible) 
with back supported and arm supported at the level of the heart (e.g., resting on a table). 
Blood pressure (systolic/diastolic) and heart rate will be assessed after the study subject has 
rested in a seated position for at least five (5) minutes. Blood pressure readings and heart rate 
readings will be measured in triplicate (approximately 1 minute apart) and the results will be 
recorded in the source document and eCRF along with the time they were taken.
It is important that vital signs be taken either before a meal, or at least 30 minutes after a 
meal or consuming caffeine. If the subject is a smoker, the subject must not be permitted to 
smoke within 30 minutes prior to scheduled study activities.
6.22 Electrocardiogram (ECG)
All investigative sites will be provided with an identical make/model calibrated portable 
ECG machine. Site personnel must assess the quality of the ECG while the subject is still at 
the investigative site in the event that additional ECGs need to be performed (i.e., if artifact is 
present). QT intervals will be reported uncorrected as well as corrected for heart rate 
according to the Fridericia Formula (QTcF).
For young children, the parent/parent/guardian (caregiver) should practice, prior to the study 
visit, lying still (starting with 5 seconds and work up to lying still for 1 minute [time to 
capture the ECG reading]). Suggest use of a timer to help the child understand how long to 
hold still. If possible, have the subject rest quietly for at least 10 minutes. Collection of the 
ECG should be considered for all subjects and this data will be read by a central core lab.
Refer to ECG manual for additional details regarding data collection and transmission.  
6.23
Laboratory Testing
6.23.1 Testing Facilities
Blood samples for screening and routine safety laboratory testing will be analyzed by a 
centralized laboratory that is certified under the Clinical Laboratory Improvement Act 
(CLIA).  


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6.23.2 Blood Volumes
Total blood volume (TBV) is related to body weight. The TBV of a child is about 75-80
mL/kg. Existing guidelines for blood sample volume limits (ranging from 1–5% of total 
blood volume within 24 hours and up to 10% of total blood volume over 8 weeks) are 
consistent with the limited evidence available on “minimal risk” to children (Howie, 2010). 
In this study, the smallest volume of blood will be collected for analysis of safety and PK. A
total of approximately 29.5 mL will be collected over the study period.
Blood samples are scheduled to be collected ten (10) times over the course of the study. 
Additional blood samples may be collected for evaluation of safety as clinically indicated. 
6.23.3 Sample Identification 
Blood samples will be labeled with the subject ID and initials and sample collection 
date/time and sample type.  The Sponsor will not have any information that would identify 
the study subject.
6.23.4 Screening and Safety Laboratory Testing
6.23.4.1 Pregnancy Testing
A pregnancy test is required for all female subj
or has reached 
menarche, whichever occurs first. A serum pregnancy test will be collected at Screening (V1) 
and must be negative. A urine pregnancy test will also be repeated at V2/Day 1. Additionally, 
a urine pregnancy test (local) will be done on the last study visit (V6/Day 29).
6.23.4.2 Routine Safety Laboratory Testing 
The following safety laboratory panel will be analyzed by a central reference laboratory.


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Test Group
Parameter
Serum Chemistry (approximately 2.5
mL sample required for testing)
Alanine Amino Transferase (ALT)
Aspartate Transaminase (AST)
Albumin
Alkaline phosphatase
Amylase
Anion gap
Bilirubin (total, direct and indirect)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide
Chloride
Creatinine, serum 
Creatinine kinase (CK) 
Gamma glutamyltransferase (GGT)
glucose
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphorous 
Potassium
Sodium
Total protein 
Hematology (approximately 2 mL 
sample required for testing)
Complete blood count [red blood cells (RBC), hematocrit (HCT), 
hemoglobin (Hgb), white blood cells (WBC), platelets] (reported 
as % and absolute values)
Differential (Automated)
Urinalysis/Microscopy  
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Microscopic examination [bacteria, casts, red blood cells (RBC), 
white blood cells (WBC), crystals] pH Protein Protein/creatinine 
ratio and Urobilinogen]
6.23.5 Pharmacokinetics
At each collection time point, 2 mL of blood will be collected in a sodium heparin collection 
tube.
Samples are stable at room temperature for up to 2 hours after sample collection. 
Transfer an equal amount of plasma into each of two (2) pre-labeled polypropylene tubes 
(label one as Set A and one as Set B) and immediately store in a freezer at -
(± 10) until 
shipment is initiated. If a -
if not available, samples may be stored up to 2 months at -
2
(± 10). Refer to the Laboratory Procedure Manual for instructions regarding sample 
processing and other additional information.
Samples will be analyzed for MM36 and its metabolites (MAP-15484, MAP15497 and 
MAP-15485) using a high performance liquid chromatographic method with tandem mass 


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The detection range
for MM36 and its 
metabolites is 0.2 to 40 ng/mL. 
6.24 Concomitant Medications
6.24.1 General
Use of chronic medications or as-needed medications (e.g., acetaminophen) will be permitted 
during the screening and active study period (unless otherwise restricted, refer to Section
6.24.2) and should be recorded in the source document and on the eCRF. Any changes in 
concomitant medication usage will be recorded in the source documents and on the eCRF. If 
the reason for change is related to an adverse event, the event should be recorded in the 
source documents and as an adverse event in the eCRF. 
Study medication and procedures which are not detailed in Table 2 will be allowed while the 
subject is in Screening (V1) and for the 4-week duration of the study (through V6), at the 
discretion of the Investigator, as long as they will not confound assessments of the treatment 
area.
The following concomitant medications, although not an exhaustive list of allowable 
medications, can be considered for use during the study treatment period, as long as 
reviewed/cleared by the investigator and have been at stable doses at the time of Screening 
and will be maintained at stable doses throughout the study period:
Intra-ocular or intra-nasal corticosteroids 
Intra-ocular or intra-nasal antihistamines
Inhaled corticosteroids/bronchodilators
Additional post-treatment (i.e., end-of-study) therapy, including medication to treat adverse 
events or atopic dermatitis, can be prescribed to the subject as needed, at the discretion of the 
investigator.
6.24.2 Concomitant Medication Restrictions
The following medications will not be permitted during the study period:
Medications (prescription and non-prescription) that are prohibited prior to Baseline (Visit 2)
and during study treatment are detailed in Table 2. The study treatment period is defined as 
Baseline (V2/Day 1) through to Week 4 (V6/Day 29) even though the last study medication 
dosing will be the evening (Day 28) prior to V6/Day 29.


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Table 2
Table of Restricted Medications
List of Prohibited Medications/Products
For 60 days prior to Baseline (V2) through the Week 4 visit (V6)
Approved PDE4 Inhibitor, or Investigational systemic or topical medication within 60 days of Baseline (V2).
Examples include, but are not limited to:  MM36 (1%) (OPA-15406) and other topical PDE4 inhibitors such as 
crisaborole (also known as AN-2728 or AN2728).   
For 28 days prior to Baseline (V2/Day 1) through the Week 4 visit (V6)
1.
Systemic immunosuppressive/immunomodulatory medications or oral corticosteroids.  Examples include, 
but are not limited to:  glucocorticoids, cytostatics, antibodies, and drugs acting on immunophilins.
Glucocorticoids, such as: hydrocortisone, cortisol, prednisone, prednisolone, methylprednisolone, 
dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, and 
deoxycorticosterone acetate 
Cytotoxic antibiotics, such as: actinomycin, bleomycin, plicamycin and mitomycin
Antimetabolites, such as: methotrexate, azathioprine, mercaptopurine, fluorouracil
Alkylating agents, such as:  mechlorethamine, cyclophosphamide, melphalan, chlorambucil,
ifosfamide,busulfan
Mycophenolate:  mycophenolate mofetil
Drugs acting on immunophilins, such as: calcineurin inhibitors, cyclosporine, tacrolimus, sirolimus
2.
Systemic antimetabolite medication.  Examples include, but are not limited to:  methotrexate, 
hydroxyurea, and thioguanine.
3.
Systemic oral retinoid medication.  Examples include, but are not limited to:  acitretin, isotretinoin,
tazarotene, bexarotene.
4.
Phototherapy (ultraviolet light A, narrowband ultraviolet B, and ultraviolet light B).
5.
New sunscreen or sunscreen with excluded ingredients.
For 14 days prior to Baseline (V2/Day 1) through the Week 4 visit (V6)
1.
Topical immunomodulators.  Examples include, but are not limited to:  pimecrolimus and tacrolimus.
2.
Use of topical corticosteroids, with exception of 1% hydrocortisone, as described below. Examples 
include, but are not limited to:  betamethasone, clobetasol, desoximetasone, flurandrenolide, fluticasone,
triamcinolone, and hydrocortisone of > 1% potency.
For 7 days prior to Baseline (V2/Day 1) through the Week 4 visit (V6) 
1.
Topical antihistamines. Examples include, but are not limited to:  hydroxyzine, desloratadine, 
cyproheptadine, carbinoxamine, levocetirizine, fexofenadine, diphenhydramine, brompheniramine, 
loratadine, clemastine, chlorpheniramine, and cetirizine.
2.
Sedating systemic antihistamines.  Examples include, but are not limited to:  chlorpheniramine, 
diphenhydramine, and promethazine.
3.
Non-sedating antihistamines. Examples include acrivastine, bilastine, cetirizine, desloratadine, 
fexofenadine, levocetirizine, loratadine, and mizolastine. NOTE: Will be allowed if taking at stables 
doses for at least 14 days prior to V2/Day 1 and remain at stable doses throughout the study.
4.
Topical retinoids.  Examples include, but are not limited to:  tretinoin, tazarotene, adapalene.
For 3 days prior to Baseline (V2/Day 1) through the Week 4 visit (V6)
1.
Use of topical 1% hydrocortisone. 
For 24 hours prior to Baseline (V2/Day 1) through the Week 4 visit (V6)
1.
Other prescription or non-prescription topical emollients, occlusive agents or humectants.  Examples 
include, but are not limited to:  non-medicated prescription topicals (Neosalus®, EpiCream®), 
nonprescription emollients (eg, Eucerin®, CeraVe®, Cetaphil®).
2.
Bleach baths, wet wraps or other similar treatments.


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6.25 Prevention of Pregnancy during the Study
6.25.1 Instructions for Female Subjects of Childbearing Potential
Women who are pregnant or breastfeeding will not be allowed to participate in this study.
Females must either practice abstinence from heterosexual sexual contact or use one of the 
approved highly effective methods to prevent contraception that are described below. These 
methods should be followed from the time of consent/assent through the last dose of study 
drug. The Investigator will educate the subject regarding abstinence or contraception options 
and the correct and consistent use of effective contraceptive methods in order to successfully 
prevent pregnancy. 
Acceptable Method Option 1: Any one of the following methods may be used: hormonal 
contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device 
(IUD), tubal ligation: or partner’s vasectomy.
Acceptable Method Option 2: Male or female condom (latex condom or nonlatex condom 
NOT made out of natural [animal] membrane (e.g., polyurethane: PLUS, one additional 
barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) 
contraceptive sponge with spermicide.
Unacceptable Methods: Periodic abstinence (e.g., calendar, ovulation) or withdrawal.
6.25.2 Instructions to Males of Reproductive Potential
Due to unknown risks and potential harm to the unborn fetus, male subjects of reproductive 
potential (capable of impregnating their partner) who are sexually active with women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Refer to the acceptable methods listed above.
6.26 Lifestyle Guidelines
6.26.1
Restricted/Limited Exposure to Artificial/Natural Sunlight or Artificial 
Tanning Agents
Subjects must not use tanning beds, sunlamps, or artificial topical tanning materials, while 
participating in the study. Subjects should also avoid excessive unprotected exposure to 
sunlight from Screening (V1) through the final visit (V6), in order to reduce the risk of 
sunburn during the treatment period as this may confound the treatment area assessment, 
from Screening and for the 4-week duration of the study.
6.26.2 Use of Sunscreen
Use of sunscreens is permitted providing that the sunscreen has been used consistently (> 28
days) by the subject and does not have any prohibited medications/ingredients and is 
reviewed by the investigator at Screening V1).  Sunscreen should be applied at least 20 
minutes following study ointment application. 


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6.26.3 Bathing and Swimming
Subjects should be advised to avoid bathing or swimming, for at least 20 minutes after 
application of study ointment. Additionally, if subject sweats excessively, they should not
wipe ointment off of skin for at least 20 minutes following study ointment application.
7
STUDY VISITS
The procedures and assessments to be performed at each visit are indicated in the Schedule 
of Activities. The timing of each visit (while on treatment) is relative to V2 when study 
registration occurs. An estimated time for the conduct of each visit is provided as a guide 
only to the study site personnel and study subject (parent/guardian/caregiver) for planning 
purposes. Note: it will not be considered a departure from the protocol if the visit length is
shorter or longer than anticipated.  
7.1 Screening (Visit 1)
The screening visit can occur up to 30 days prior to the first dose.  It is estimated that this 
visit will take approximately 2 hours to complete.  
Informed Consent Process
o
The parent(s)/legal guardian (s) must provide written informed consent prior 
to any study procedure being done; and
o
If able, the subject must provide assent to participate in the study. 
Interview
o
Evaluate Inclusion/Exclusion Criteria; 
o
Review and record demographic information;  
o
Review and record prior medications (those taken within the last 60 days and 
current medications); 
o
Review prior medical and surgical histories; 
o
Review atopic dermatitis history; and  
o
Assessments
o
Measure and record height, weight and calculate BMI and BSA; 
o
Obtain and record vital signs; 
o
Perform a 12-Lead ECG; 
o
Perform a complete physical examination and Fitzpatrick Skin Type
Assessment; 
o
Assess BSA for affected AD and record on body grid; and  
o


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Sample Collection
o
Collect blood samples for safety laboratory testing and pregnancy testing (as 
applicable), and 
o
Collect urine sample for UA.
Instructions
o
Inform Parent/guardian (caregiver)/subject that they will be contacted within 
approximately 1 week regarding study qualification and will be scheduled for 
Visit 2 (as applicable). 
7.2 Baseline (Visit 2/Day 1) 
It is estimated that this visit will take approximately 8 hours to complete. Following 
verification of study eligibility (meets all inclusion and none of the exclusion criteria), the 
subject will be registered in the study.  
Interview
o
Review and record prior medications (those taken since the last visit); 
o
Evaluate Inclusion/Exclusion Criteria (update);
o
Update AEs since last visit; 
o
Assessments Prior to First Application
o
Measure and record weight;  
o
Obtain and record vital signs; 
o
Perform a 12-Lead ECG; 
o
Perform a complete physical examination;  
o
Assess BSA for affected AD and record on body grid; 
o
o
Photograph AD sites as applicable. 
Sample Collection
o
Prior to first application:
Collect blood samples for safety laboratory testing and PK; and  
Collect urine sample for urine pregnancy testing (as applicable).  
o
Post application: 


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Collect a blood sample for PK at 1 hour (± 15 minutes), 4 hours (± 30 
minutes) and 8 hours (± 1 hour) post application. 
Instructions
o
Dosing and Application Training 
Based on the BSA involved, the appropriate number of tubes of study 
drug will be dispensed along with a scale and dosing cups.  
The parent/guardian (caregiver) and/or subject will be trained by the 
study site personnel on measuring and applying the study drug and 
recording the information in the electronic dosing diary. 
The parent/guardian (caregiver) or subject will apply the study drug to 
the affected areas twice daily (approximately 12 hours apart).
7.3 Visit 3/Day 8 (±1)
It is estimated that this visit will take approximately 1.5 hours to complete.
Interview
o
Update medications (those taken since the last visit); 
o
Assess for AEs; and  
o
Assessments 
o
Assess application sites; 
o
Perform abbreviated physical exam (only as applicable for evaluation of AEs);
o
Obtain and record vital signs; 
o
Assess BSA for affected AD and record on body grid; 
o
o
Photograph AD sites as applicable; and  
o
Compliance check (weight check of study drug and review diary completion).


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Instructions
o
Dispense study drug; 
o
Review dosing procedure and have the parent/guardian (caregiver)/subject 
apply the study drug to the affected areas; and 
o
Schedule Return visit for 1 week (Day 15) and remind parent/guardian 
(caregiver) not to apply study drug in the morning before the visit and to bring 
all used and unused study dug to next visit. 
7.4 Visit 4/Day 15 (±1)
It is estimated that this visit will take approximately 8 hours to complete. 
Interview
o
Update medications (those taken since the last visit); 
o
Assess for AEs; and  
o
Assessments 
o
Assess application sites; 
o
Perform abbreviated physical exam (only as applicable for evaluation of AEs); 
o
Obtain weight; 
o
Obtain and record vital signs; 
o
Assess BSA for affected AD and record on body grid; 
o
Photograph AD sites as applicable; 
o
o
Compliance check (weight check of study drug and review diary completion). 
Sample Collection 
o
Collect a blood sample for PK prior to application at the study clinic and again 
at 1 hour (± 15 minutes), 4 hours (± 30 minutes) and 8 hours (± 1 hour) post 
application.  
Instructions
o
Dispense study drug; 
o
Review dosing procedure and have the parent/guardian (caregiver)/subject 
apply the study drug to the affected areas; and 


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o
Schedule Return visit for 1 week (Day 22) and remind parent/guardian 
(caregiver) and subject not to apply study drug in the morning before the visit 
and to bring all used and unused study dug to next visit. 
7.5 Visit 5/Day 22 (±1)
It is estimated that this visit will take approximately 1.5 hours to complete. 
Interview
o
Update medications (those taken since the last visit); 
o
Assess for AEs; 
o
Assessments 
o
Assess application sites; 
o
Perform abbreviated physical exam (only as applicable for evaluation of AEs); 
o
Obtain and record vital signs; 
o
Assess BSA for affected AD and record on body grid; 
o
Photograph AD sites as applicable; 
o
o
Compliance check (weight check of study drug and review diary completion). 
Instructions
o
Dispense study drug; and 
o
Review dosing procedure and have the parent/guardian (caregiver)/subject 
apply the study drug to the affected areas. 
Schedule Return visit for 1 week (Day 29) and remind parent/guardian (caregiver) that the 
last dose of study drug should be applied the night before the final visit (Day 28). They 
should also be reminded to bring all used and unused study drug and the scale, to final visit.
7.6 Visit 6/Day 29 (±1) or Early Termination (ET) 
It is estimated that this visit will take approximately 1.5 hours to complete. 
Interview
o
Update medications (those taken since the last visit); 
o


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o
Assess for AEs. 
Assessments 
o
Assess application sites; 
o
Perform physical examination; 
o
Obtain weight; 
o
Obtain and record vital signs; 
o
Perform a 12-Lead ECG; 
o
Assess BSA for affected AD and record on body grid; 
o
Photograph AD sites as applicable; 
o
o
Compliance check (weight check of study drug and review diary completion).
Collect all used and unused study drug and scale.  
Sample Collection 
o
Collect blood samples for safety laboratory testing.  
o
Collect urine sample for urine pregnancy testing (as applicable).  
7.7 Unscheduled Visit(s) 
An unscheduled visit will be scheduled every 7 to 14 days in order to follow-up on 
unresolved adverse events that were still present at the final visit (V6). Additionally, the 
Study subject may be asked to return for additional visits to follow clinically significant 
abnormal laboratory results.  
7.8 Unscheduled Procedures
It may be necessary to collect unscheduled procedures as clinically indicated for evaluation 
of subject safety. Procedures completed at an unscheduled visit will be driven by the reason 
for the unscheduled visit. Should a skin irritation event occur, a patch testing can be 
performed, if feasible, to rule out an allergic/hypersensitivity event.


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8
STUDY DOSING
8.1 Formulation, Packaging and Labelling  
8.1.1 Formulation 
MM36 1% is a white petrolatum based ointment. A list of all components in MM36 1%, is 
presented in Table 3.  Each gram of MM361 % w/w ointment contains 10 mg of active 
MM36. 
Table 3
Components of MM36 1%  
Components Ointment
MM36 1% w/w
8.1.2 Packaging 
Five labeled tubes will be assembled into a subject box. Each box will be labeled with a 
single panel label and tamper sealed. Five labeled subject boxes will be assembled into block 
kits. Each kit will be labeled with a 2-part tear away label and tamper sealed. 
8.2 Storage   
Study drug will be stored at the clinical site in a secured (limited access to authorized site 
personnel only) storage area. The investigational drug product will be stored at controlled 
room temperature (15°C to 25°C).   
8.3 Dispensing    
As reported in Nelson et al, 2006, “an average of 9.9 g/m2 (equivalent of 1.0 mg/cm2) of a 
topical agent (by weight) are required by a disciplined operator to achieve a thin, even layer 
of ointment on a patient” (pp. 224). Therefore, to determine the number of grams (by weight) 
per day, the Investigator/designee will use the following formula: 
Step 1 Formula to Calculate Grams (by weight) of MM36 1% to Use Per Dose: 
Overall BSA (m2)
X
Total (BSA %) of All
areas of involvement that 
will be treated
X
10
grams/m2
=
Grams of 
ointment per 
application
Example:  A six-year-old boy with 32% BSA involved areas of AD 
0.7 m2
X 
32% (or 0.32) 
X 
10 grams/m2
=
2.24 grams/ 
application


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Step 2 Formula to Calculate Grams Needed to Dose BID for 1 Week (7 Days):
Grams of 
ointment needed 
per Application
X
Number of 
applications 
Per day 
=
Total grams of 
ointment 
needed per day
X
Number of 
Treatment 
Days
=
Total Grams 
Needed
Example continued:
2.24 grams
X
2
=
4.48 grams
X
7
=
31.36
grams
Step 3 Formula to Calculate Number of MM36 Tubes of Study Drug (27 grams per 
each) Needed for 1 Week (7 Days) of Treatment:
Total Grams 
Needed
÷
27 grams
(weight per 1 tube of study drug)
=
Number of Tubes to 
be dispensed
Example continued:
31.36 grams
÷
27 grams
(weight per 1 tube of study drug)
=
1.16 tubes
(dispense 2 tubes)
The table below (Table 4) is provided as general guide to determine the amount of study drug 
to be dispensed based on a subject’s BSA and their intended area of application. Exact 
calculation will be done on an individual basis. The Investigator or designee will enter the 
subject’s overall BSA, BSA% involvement and intended number of treatments (until the next 
visit) into the dosing module in the eCRF. The number of tubes to be dispensed will be 
calculated.
Table 4
Estimated Dispensing Table
Age 
Range
Estimateda BSA m2
Of the Average 50th
Percentile for Males 
and Females
Approxb Grams of 
Ointment Needed for 
Application to Every 
1% BSA
Involvement
Grams (weight) of 
Ointment Required 
Per Application to a
Minimum Involved 
Area of 25%
Grams of Ointment 
Required Per 
Application to a
Minimum Involved 
Area of 35%
2- 3
0.07
1.75
2.45
4 – 6
0.10
2.5
3.5
7 – 11
0.13
3.25
4.55
12 – 13
0.15
3.75
5.25
14 – 17
0.20
5.0
7
a Kuczmarski et al, 2000
b Nelson, 2006
The subject/subject’s parent/guardian (caregiver) will be provided a calibrated scale and 
measuring cups to dispense the calculated dose for each application.  Procedure will be 


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discussed with the subject or parent/guardian (caregiver) at the site and documented that 
proper training occurred prior to first application (refer to Appendix A).
8.4 Dosing
The subject (parent/guardian (caregiver) will be instructed on proper application of the study 
drug and will apply the initial application on Day 1 at the study site.  The proper dose 
dispensing procedure and use of the study drug will be demonstrated and observed by study 
staff to ensure subject (parent/guardian (caregiver) understand the instructions.   
For each dosing period, the subject, under the supervision of the parent/guardian 
(caregiver), or the parent/guardian (caregiver), will dispense the required amount of 
ointment (by weight) using the measuring cup(s) provided. 
The subject should wash his/her hands both before and after applying study ointment.  If 
applied by the parent/guardian (caregiver), they should also wash hands before and after 
applying study ointment, but will also wear non-latex gloves (provided by the Sponsor).  
The subject (parent/guardian (caregiver) will apply a thin layer of ointment to affected 
areas twice daily (approximately 12 hours apart) for 28 consecutive days.  
It is recommended that the ointment be applied after showering/bathing. The skin should 
be dry prior to application. Important: Subjects should not swim or bathe or wipe 
application area for a minimum of 20 minutes after application of ointment.
The ointment should be rubbed in gently and completely, avoiding contact with the eyes.  
Subject’s (parent/guardian (caregiver) will be instructed not to administer the study drug 
in the morning on the day of the study visit to avoid any effect of the study drug on the 
assessments.  
18 years of age) parent/guardian (caregiver) will verify if the study drug was 
weighed appropriately and applied as directed. Application details will be recorded in the 
electronic diary.
8.5 Compliance
The parent/guardian (caregiver)/subject will record the amount of drug used at each 
application and application location in the electronic diary. All used and unused study drug 
will be returned at all protocol-specified visits for study drug inventory and assessment of 
subject adherence.
The weight of the study drug will be measured before it is dispensed and after it is returned at 
Visit 3/Week 1, Visit 4/Week 2, Visit 5/Week 3 and Visit 6/Week 4.  Each dispensing and 
return of study drug as well as the weight of study drug will be documented in the eCRF.
The dispensing and return of all study drug will be recorded on the study drug dispensing 
log.  The subject number/initials and the initials and date of the person dispensing and 
receiving the returned medication will be documented on this form.  


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8.6 Study Drug Accountability
Inventory records must be readily available for inspection by the study monitor and/or 
auditor, and open to inspection by regulatory authorities at any time. Study drug will be 
received and dispensed by the designed study staff and returned to the Sponsor (unused study 
at completion of the study. All study drug will be accounted for on the study drug
inventory/accountability log and will include:
Subject ID and initials 
Date/time dispensed
Amount dispensed 
Amount remaining in inventory
Damaged or lost study drug will also be accounted for and recorded in the drug 
accountability records.
At completion of the study, the Investigator (or designee) is responsible for returning all 
unused study drug and used study drug containers to the Sponsor or representative, and must 
verify that no supplies remain in the investigator’s possession.
8.7 Blinding
Not applicable as this is an open-label study.
8.8 Breaking the Study Blind
Not applicable.


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9
PROTOCOL VIOLATIONS
A protocol violation occurs when the study subject, Investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, study subject safety and 
primary endpoint criteria. Protocol violations for this study include, but are not limited to, the 
following:
Failure to meet inclusion/exclusion criteria
Dosing error
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a 
study subject or if data analysis will be censored.
When a protocol violation occurs, it will be discussed with the Investigator, and the details
will be documented and reviewed by the Sponsor representative and the Investigator. A copy 
of such documentation will be filed in the site’s regulatory binder and in the Sponsor’s files.


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10
ADVERSE EVENTS
10.1 Definition of an Adverse Event
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans whether or not considered drug related.
An adverse event (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, and does not imply any judgment about causality. An 
adverse event can arise with any use of the drug (e.g., off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an 
overdose. 
10.2 General Guidelines
All observed or volunteered adverse events regardless of suspected causal relationship to the 
study drug are to be recorded on the appropriate eCRF from the time consent/assent is 
obtained through the end of the study as described in the following sections. 
For all adverse events, the Investigator (Principal Investigator or Sub-Investigator) must 
pursue and obtain information adequate both to determine the outcome of the adverse event 
and to assess whether it meets the criteria for classification as a serious adverse event 
requiring immediate notification to the Sponsor or designee. For all adverse events, sufficient 
information should be obtained by the Investigator to determine the causality of the adverse 
event. The Investigator (Principal or physician Sub-Investigator) is required to assess 
causality. For adverse events with a causal relationship to the study drug, follow-up by the 
Investigator (Principal or physician Sub-Investigator) is required until the event or its 
sequelae resolve or stabilize at a level acceptable to the Investigator (Principal or physician 
Sub-Investigator) and Medical Monitor concurs with that assessment.
10.3 Reporting Period
Serious adverse events require immediate notification to the Sponsor or designee, beginning 
from the time that the informed consent is signed, which is obtained prior to participation in 
the study, i.e., prior to undergoing any study-related procedure and/or receiving study drug,
through and including the day of the last dose of study drug or longer as applicable. Any 
serious adverse event occurring any time within the reporting period must be promptly 
reported if a causal relationship to investigational product is suspected. 
Adverse events (serious and non-serious) should be recorded on the eCRF from the time 
the study subject has signed informed consent (assent) through last study visit, unless 
otherwise specified.
Any changes in the subject’s status between enrollment (signing informed consent) up to 
the time of the first dose of study drug will be recorded as a pre-treatment adverse event 
and severity will be assessed. 


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Any adverse event occurring after the first dose of study drug will be considered a 
treatment emergent adverse event (TEAE). 
10.4 Assessment of Severity
Mild – An event that is usually transient in nature and generally not interfering with 
normal activities.
Moderate – An event that is sufficiently discomforting to interfere with normal activities.
Severe – An event that is incapacitating with inability to work or do usual activity or 
inability to work or perform normal daily activity.
10.5 Relationship of an Adverse Event to Study Drug
The investigator is to classify the relationship of an AE to the investigational product using 
good clinical judgment and the following definitions:
Relationship
Description
Not Related
The AE is clearly explained by another cause not related to the study product;
Probably Not Related
A potential relationship between study product and the AE could exist (i.e., the 
possibility cannot be excluded), but the AE is most likely explained by causes other 
than the study agent;
Possibly Related
The AE and administration of study product are temporally related, but the AE can be 
explained equally well by causes other than the study product;
Probably Related
The AE and use of study product are temporally related, and the AE is more likely 
explained by study product than by other causes;
Definitely Related
The AE and use of study product are related in time, and a direct association can be 
demonstrated.
The following factors should also be considered:
The temporal sequence from study medication administration: The event should occur 
after the study medication is given. The length of time from study medication exposure to 
event should be evaluated in the clinical context of the event.
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the study subject may have.
Concomitant medication: The other medications the study subject is taking or the 
treatment the study subject receives should be examined to determine whether any of 
them might be recognized to cause the event in question.
Known response pattern for this class of study medication: Clinical and/or preclinical 
data may indicate whether a particular response is likely to be a class effect.
Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.


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The pharmacology and pharmacokinetics of the study medication: The known 
pharmacologic properties (absorption, distribution, metabolism, and excretion) of the 
study medication should be considered.
In the case of skin irritation, the results of any patch testing should be considered.  
10.6 Suspected Adverse Reaction
An adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. For the purposes of Investigational New Drug safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug and the 
adverse event
10.7 Unexpected Adverse Events
An adverse event or suspected adverse reactions is considered “unexpected” if it is not listed 
in the investigator brochure (IB) or it is not listed at the specificity or severity that has been 
observed; or, if an IB is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere, as applicable. Unexpected, as used 
in this definition, also refers to adverse events or suspected adverse reactions that are 
mentioned in the IB or other applicable documentation as occurring with a class of drug or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
10.8 Serious Adverse Event Definition
An adverse event or suspected adverse event reaction is considered serious if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes:
Death;
A life-threatening adverse event;
NOTE: An adverse event or suspected adverse event is considered “life-
threatening” if, in view of either the Investigator or Sponsor, its occurrence places 
the study subject at immediate risk of death. It does not include an event that, had 
it occurred in a more severe form, might have caused death.
Requires hospitalization or prolongation of existing hospitalizations;
NOTE: Any hospital admission will be considered an inpatient hospitalization,
regardless of duration. An emergency room visit without hospital admission will 
not be recorded as an SAE under this criterion, nor will hospitalization for a 
procedure scheduled before signing of informed consent. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective 
surgery should be recorded as adverse events and assessed for seriousness.
Admission to the hospital for a pre-planned procedure or social or situational 


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reasons (i.e., no place to stay, lives too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
A congenital anomaly/birth defect; or
Other important medical event (event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above). 
NOTE: Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the study subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
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 hospitalizations, or the development of 
drug dependency. 
10.9 Reporting
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event. If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate. 
All adverse events occurring from the time consent/assent is obtained through the end of the 
study will be reported on the adverse event page(s) of the eCRF. It should be noted that the 
form for collection of serious adverse event information is not the same as the adverse event 
CRF. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms.  Adverse 
events should be reported using concise medical terminology on the eCRFs as well as on the 
form for collection of serious adverse event information. 
10.9.1 Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, the Sponsor or designee is to be notified (see below) within 
24 hours of awareness of the event by the Investigator. In particular, if the serious adverse 
event is fatal or life-threatening, notification to the Sponsor or designee, must be made 
immediately, irrespective of the extent of available adverse event information. This 
timeframe also applies to additional new information (follow-up) on previously forwarded 
serious adverse event reports as well as to the initial and follow-up reporting of Pregnancy 
cases. A site designee will complete the Serious Adverse Event (SAE) Reporting Form and 
send the report(s), within 24 hours of learning of an initial SAE to 
with supporting documentation, if 
applicable.  


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Medical Monitor
Serious Adverse Event (SAE) Reporting
In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (e.g., if an outpatient trial study subject initially seeks treatment 
elsewhere), the Investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the Investigator is obligated to pursue and provide information 
to the Sponsor or designee, in accordance with the timeframes for reporting specified above.  
In addition, an Investigator may be requested by the Sponsor or designee to obtain specific 
additional follow-up information in an expedited fashion. This information may be more 
detailed than that captured on the adverse event case report form. In general, this will include 
a description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a study subject death, a summary of available autopsy findings must 
be submitted as soon as possible to the Sponsor or its designated representative. The 
Investigator must continue to follow the study subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
study subject dies. Within 24 hours of receipt of follow-up information, the Investigator must
update the SAE form and submit it to the Sponsor or Designee Safety Coordinator. 
10.9.2 Non-Serious Adverse Event Reporting Requirements and Ongoing Safety Review
Non-serious adverse events are to be reported in the eCRF which will be reviewed by the 
Sponsor or designee Medical Monitor on an ongoing basis. 
10.10 Pregnancy Reporting
If a study subject becomes pregnant during the study, the Investigator should report the 
pregnancy to the Sponsor, or its representative, within 24 hours of being notified.  
The Pregnancy Report form must be completed by the site and sent within 24 hours of 
learning of a pregnancy to 
with supporting documentation, if applicable.   
The study subject should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should 
notify the Sponsor. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the Investigator should follow the procedures for 
reporting an SAE. Otherwise, a Pregnancy Outcome Report should be completed. 


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11
DATA ANALYSIS AND STATISTICAL METHODS
11.1 Sample Size Determination
The sample size is not driven by inferential statistics. A sample size of 32 subjects is set for 
qualitative investigation of the pharmacokinetic profile as well as the safety and tolerability 
and responsiveness (efficacy) of MM36 1% when applied topically twice daily for 4 weeks to 
pediatric subjects 2 to < 18 years of age.
11.2 Analysis Populations
Two populations will be used for analysis: safety and intent-to-treat. The definition of these 
populations follows:
Safety Population:  All enrolled subjects who received at least one dose of study 
medication and have at least one post-baseline safety assessment constitute the Safety 
Population.
Intent-to-Treat (ITT) Population:  All enrolled subjects who took at least one dose of 
study medication constitute the Intent-to-Treat Population.
Safety and PK data will be analyzed based on the safety population. Efficacy data will be 
analyzed based on the ITT population.
11.3 Statistical Analysis
11.3.1 General Statistical Methodology
All statistical processing will be performed using SAS® unless otherwise stated.
Continuous data will be summarized using descriptive statistics (number of values, mean, 
standard deviation, median, minimum and maximum). Categorical data will be 
summarized using frequency tables (frequencies and percent).
A statistical analysis plan (SAP), describing all statistical analyses will be provided as a 
separate document. The SAP will be finalized prior to locking the database. The SAP will 
contain any modifications to the analysis plan presented below.
11.3.2 Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications
Demographic data, medical history including history of acute dermatitis, and prior and 
concomitant medications will be summarized using descriptive statistics. 
11.3.3 Treatment Compliance
The Parent/guardian (caregiver)/Subject will record all applications made or missed in the 
electronic diary. Subject compliance during the overall treatment period and by visit will be 
summarized.


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11.3.4 Drug Exposure
Amount of study drug (weight) and the number of days with study drug application will be 
summarized.
11.4
Primary Analysis
11.4.1 Pharmacokinetics
Individual plasma concentrations of MM36 and its metabolites (MAP-15484, MAP15497 
and MAP-15485) will be summarized descriptively using the arithmetic mean, standard 
deviation (SD), CV (%), median, minimum and maximum. Individual plasma concentration-
time profiles of MM36 will be plotted on both a linear and a semi-logarithmic scale. Mean 
values will also be presented graphically.  The following pharmacokinetic parameters will be 
analyzed for each subject and for each PK time point at which a sufficient (detectable) 
concentration of MM36 or its metabolites will be measured to permit their derivation. If there 
are sufficient concentration data above the level of quantitation the following 
pharmacokinetic parameters will be calculated:
Cmax = Maximum plasma concentration
Tmax = Time of maximum plasma concentration
AUC0-last = Area under the plasma concentration-time curve from time zero to time last 
(time of last quantifiable plasma concentration) [AUC0-t]
The pharmacokinetic analysis will be implemented in SAS®, and conducted using Non-
Compartmental Analysis (NCA) on plasma concentrations of MM36 in the subjects who will 
receive MM36 1% ointment and had evaluable plasma concentration-time profiles. PK 
parameters will be listed for all individuals. Descriptive summary statistics (number of 
observations (N), arithmetic mean, standard deviation (SD), CV%, median, minimum, 
maximum and geometric mean) will be reported for PK parameters. Individual elapse 
sampling time will be used in the pharmacokinetic analysis. Cmax and tmax will be obtained 
directly from the experimental observations. AUC(0-t) will be calculated using the linear 
trapezoidal rule.
BLQ (< 0.2 ng/mL) samples will be set to zero for the summary of the statistics for 
concentration values. For the purpose of the NCA, BLQ set to zero before tmax and missing 
after tmax.  Any quantifiable concentrations at pre-dose at Day 1 will be set to zero.
11.5 Secondary Analysis
11.5.1 Safety
Safety evaluations will consist of adverse events (AEs), application site reactions, physical 
examinations, vital signs, ECGs, weight, and laboratory measurements (hematology, 
chemistry, and urinalysis). Full details will be specified in the SAP.  A general description of 
the planned analysis is as follows: 


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Descriptive statistics and frequency tables will be prepared as appropriate for physical 
examinations, vital signs, weight, ECG (HR, QTcF, PR, and QRS) and laboratory 
measurements (hematology, chemistry, and urinalysis).
Adverse Events
o
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA); the version will be identified in the clinical study report.
o
AEs that occurred during the screening period will be listed separately and 
will not be included in the AE tabulations. 
o
All other AEs that start on or after first dose will be considered TEAEs. 
Summaries will be presented by system organ class and preferred term, and 
further by severity and relationship to study drug.  Application site AEs and 
any 
5% of subjects will also be tabulated.
o
The proportion of subjects who discontinue treatment due to an adverse event 
will be presented.
Concomitant medications will be classified according to the World Health Organization 
(WHO) Drug Dictionary and will be presented in data listings.
11.6 Exploratory Analysis 
11.7 Interim 
A pre-specified interim analysis will not be conducted.


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12
DATA COLLECTION, RETENTION AND MONITORING
12.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents designed 
to record all observations and other pertinent data for each study subject treated with the test 
article. The Investigator is responsible for ensuring that data is properly entered into the 
electronic devices (diaries and site electronic devices) as this will serve as source 
documentation for certain scales, measures, dosing for the study.  Study personnel at each 
site will enter data from source documents corresponding to a study subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding 
to that visit is available.  
Study subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a site 
number, study subject number and initials.
If a correction is required for an eCRF, the time and date stamps will track the person 
entering or updating eCRF data and creates an electronic audit trail. 
The Investigator is responsible for all information collected on study subjects enrolled in this 
study. All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  Copies of final completed eCRFs will be 
provided on a compact disk (CD) or other similar media for archiving at the study site 
following database lock and at or prior to study closure.
12.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. All procedures for 
the handling and analysis of data will be conducted using good computing practices meeting 
FDA guidelines for the handling and analysis of data for clinical trials.
12.2.1 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. Queries 
are entered, tracked, and resolved through the electronic data capture (EDC) system directly.  
The study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented.
12.2.2 Data Entry
Data must be recorded using the EDC system as the study is in progress. All site personnel 
must log into the system using their secure user name and password in order to enter, review, 
or correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords 


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will be strictly confidential. Data should be entered onto the eCRF approximately no later 
than 72 hours after the visit has taken place.
12.2.3 Medical Information Coding
For medical information, the following thesauri will be used:
Latest version of the Medical Dictionary for Regulatory Activities (MedDRA) for 
medical history and adverse events; and
World Health Organization Drug Dictionary (WHODD) for prior and concomitant 
medications.
12.2.4 Data Validation
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the uploaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries.
The CRFs must be reviewed and electronically signed by the Investigator who signed the 
protocol.
12.3 Archival of Data
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained.
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database. At critical junctures of the protocol (e.g., production of interim 
reports and final reports), data for analysis is locked and cleaned per established procedures.
12.4 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each study subject must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that study subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived.
All study documents (patient and subject files, signed informed consent forms, copies of 
CRFs, Study File Notebook, etc.) must be kept secured for a period of two years following 
marketing of the investigational product or for two years after centers have been notified that 
the IND has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason.


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12.5 Monitoring
Monitoring visits will be conducted by representatives of the Sponsor (or designee) 
according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).  
By signing this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation.
12.6 Subject Confidentiality
In order to maintain study subject confidentiality, only a site number, study subject number 
and initials will identify all study subjects on CRFs, blood samples, and other documentation 
submitted to the Sponsor.  Additional study subject confidentiality issues (if applicable) are 
covered in the Clinical Study Agreement.
12.7 Retained Blood Samples
Blood samples collected during the study for pharmacokinetic analysis may be retained for 
future testing as necessary. Study subject’s confidentiality will be maintained and only the 
site and study subject number and initials will identify the sample. No other linked or 
identifying information is maintained by the Sponsor. 


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13
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Subjects (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312 Subpart D).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be kept 
in a locked file cabinet.  The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC).
13.1 Protocol Amendments
Any amendment to the protocol will be written by the Sponsor or Sponsor designee. Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except as 
necessary to eliminate immediate safety hazards to study subjects/patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to study subjects/patients 
may be implemented immediately, provided the IRBs are notified within five working days.
13.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed 
as to the progress of the study. The Investigator will obtain assurance of IRB/IEC compliance 
with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
subject/patient recruitment, payment or compensation procedures, or other pertinent 
information) will be submitted to the IRB/IEC. The IRB/IECs written unconditional approval 
of the study protocol and the informed consent form will be in the possession of the 
Investigator before the study is initiated.  The IRB/IECs unconditional approval statement 
will be transmitted by the Investigator to the Sponsor prior to the shipment of study supplies 
to the site.  This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the 
subjects/patients or when the change(s) involves only logistical or administrative aspects of 
the study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new information 


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that may affect adversely the safety of the subjects/patients of the conduct of the study; an 
annual update and/or request for re-approval; and when the study has been completed.
13.3 Informed Consent Form – General Provisions
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, 
US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 
50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act 
(HIPAA, if applicable), and local regulations. Also refer to Protocol Section 6.1.
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor 
and be approved by the IRB/IEC.  The written consent document will embody the elements 
of informed consent as described in the International Conference on Harmonization and will 
also comply with local regulations. The Investigator will send an IRB/IEC-approved copy of 
the Informed Consent Form to the Sponsor (or designee) for the study file.
A properly executed, written, informed consent will be obtained from each study subject or 
the subject’s legally authorized representative prior to entering the study subject into the trial 
and conducting any Screening visits.  Information should be given in both oral and written 
form and study subjects (or their legally authorized representatives) must be given ample 
opportunity to inquire about details of the study.  If appropriate and required by the local 
IRB/IEC, assent from the study subject will also be obtained.  If a study subject is unable to 
sign the informed consent form (ICF) and the HIPAA authorization, a legal representative 
may sign for the study subject.   A copy of the signed consent form (and assent) will be given 
to the study subject or legal representative of the study subject and the original will be 
maintained with the study subject’s records.
13.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating Investigators.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996. 
14
SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB, drug safety problems, or at the discretion of the Sponsor. In 
addition, the Sponsor retains the right to discontinue development of the referenced 
investigational drug at any time.
If the study is prematurely terminated or discontinued, the Sponsor, or designee, will 
promptly notify the Investigator. After notification, the Investigator must contact all 
participating study subjects within 5 business days. As directed by the Sponsor all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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15
REFERENCES
Cooper, K.D., Kang, K., Chan, S.C., & Hanifin, J.M. (1985). Phosphodiesterase inhibition 
by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro. 
Journal of Investigational Dermatology. 84; 477-482.  
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, . . ., 
Sidbury, R. (2014). Guidelines of care for the management of atopic dermatitis: 
section 1. Diagnosis and assessment of atopic dermatitis. Journal of American 
Academy of Dermatology.70(2):338-51.  
Fitzpatrick, T.B. (1988), "The validity and practicality of sun-reactive skin types i through 
vi", Archives of Dermatology 124 (6): 869–871, 
Doi:10.1001/archderm.1988.01670060015008 
Hanifin, J.M., Butler, J.M., & Chan, S.C. (1985). Immunopharmacology of the atopic 
diseases. Journal of Investigational Dermatology. 85(Suppl 1): S161-164.


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Howie, S.R. C. (2011). Blood sample volumes in child health research: review of safe 
limits. Bulletin of the World Health Organization.  World Health Organization.
Accessed on 28JUN2016 from: http://www.who.int/bulletin/volumes/89/1/10-
080010/en/
Kuczmarski, R.J., Ogden, C.L., Guo, S.S., Grummer-Straum, L.M., Flegal, K.M., Mei, Z.,  
Roche, A.F. (2000) 2000 growth charts for the United States: Methods and 
development. National Center for Health Statistics. Vital Health Stat. 11(246). 
Retrieved from: http://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf
Mosteller RD. (1987). Simplified calculation of body surface area. New England Journal 
of Medicine; 317:1098. 


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APPENDIX A – DOSING INSTRUCTIONS
Apply ____ grams on the affected areas noted below 
and on the diagram by your doctor:
(Site: Please circle areas affected below and on 
diagram)
Head/Neck
Trunk
Upper Limbs
Lower Limbs
 
Acceptable Range for Dosing:_______to_________ 
 
 


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At each study visit, you/your child will be given enough tubes of study drug until the next 
visit.
Be sure to wash your hands before and after applying study drug.
Using the measuring cups and scale, measure out the amount of ointment to be applied.
If you squeeze out too much of the ointment in the medicine cup, record the initial weight 
and scoop off the excess ointment and discard it (throw it away). Reweigh the ointment
again to make sure that the dose is within the acceptable range for dosing (bottom of page 
1).  Please record the details of the change in the chart on the next page.
Apply the study drug twice daily; once in the morning and once in the evening for 4
weeks.
If the study drug is applied by a parent/caregiver, they will need to wear the protective 
gloves provided.
It is recommended that the ointment be applied after showering/bathing. The skin should 
be dry. Important: Subjects should not swim or bath or wipe application area for a 
minimum of 20 minutes after application of ointment. 
The ointment should be rubbed in gently and completely, avoiding contact with the eyes.  
A parent/caregiver must confirm how much of the study drug was applied and note this 
on the dosing diary (provided). 
On the morning of a study visit:
o
Do not apply the study drug so that the application areas can be checked by the 
study doctor/nurse. 
o
You/your child will be asked to apply the study drug in the study clinic so that a 
study team member can see how you are using the study drug.
o
Bring the dosing diary and ALL used and unused tubes of study drug to the clinic. 
The Next Study Visit is Scheduled for: ________________ at ____________
 
 


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If you accidentally squeezed out too much medication into the cup, please fill out this section.
Please record the weights BEFORE and AFTER you scoop off the extra ointment in the chart below.
 
Date of Dose
AM/PM Dose
BEFORE
weight of study 
ointment
AFTER weight 
of study 
ointment
Discarded by:
 


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SAP_000.pdf: 
C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
S T A TI S TI C A L A N A L Y SI S  P L A N  
Pr ot oc ol  N u m ber : M E DI -M M 3 6 -2 0 6  
 
 
 
St u d y Title:  A P hase 2 M ulti -ce nter, O p e n -la bel St u d y t o Assess P har m ac o ki netic 
Para meters a n d Safet y of T o pical M M 3 6 ( 1 %) i n Pe diatric S u bjects 2 t o < 1 8 Years of A ge 
wit h At o pic Der matitis U n der Ma xi mal Use C o n diti o ns  
 
 
 
De vel o p me nt P hase of St u d y : 2  
 
 
 
S p o ns or:  Me di metri ks P har mace uticals, I nc.  
 
S p o ns or C o ntact:  
 
 
 
 
Statistical A nal ysis Pla n base d o n Pr ot oc ol Versi o n : A me n de d Pr ot oc ol 1 2 0  J a n uar y 2 0 1 7  
 
 
 
Statistical A nal ysis Pla n Date:  Ma y 1 8 , 2 0 1 7 
 
Statistical A nal ysis Pla n Versi o n : Draft v 1  
 
P er s o n al D at a
 
 


P er s o n al D at a
P er s o n al D at a
P er s o n al D at a


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 3 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
2. 
INTRODUCTION .................................................................................................................6 
3. 
STUDY OBJECTIVES .........................................................................................................6 
3.1 Primary Objective ...........................................................................................................6 
3.2 Secondary Objectives .....................................................................................................7 
3.3 Exploratory Objectives ...................................................................................................7 
4. 
STUDY DESIGN ...................................................................................................................7 
4.1 Overall Study Design ......................................................................................................7 
4.1.1 
Schedule of Visits and Assessments .................................................................8 
4.1.2 
Method of Assigning Subjects to Treatment Groups ........................................8 
4.1.3 
Blinding .............................................................................................................8 
4.2 Determination of Sample Size ........................................................................................8 
5. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .........9 
6. 
PHARMACOKINETIC, EFFICACY AND SAFETY ENDPOINTS ..............................9 
6.1 Pharmacokinetic Endpoints ............................................................................................9 
6.1.1 
Primary Pharmacokinetic Endpoint ...................................................................9 
6.2 Efficacy Endpoints ..........................................................................................................9 
6.2.1 
Primary Efficacy Endpoints ..............................................................................9 
6.2.2 
Secondary Efficacy Endpoints ..........................................................................9 
6.2.3 
Additional Efficacy Endpoints ..........................................................................9 
6.3 Safety Endpoints ...........................................................................................................11 
6.3.1 
Primary Safety Endpoint .................................................................................11 
6.3.2 
Secondary Safety Endpoints ............................................................................11 
7. 
STATISTICAL METHODS AND ANALYSIS ................................................................12 
7.1 General Methodology ...................................................................................................12 
7.2 Adjustments for Covariates ..........................................................................................12 
7.3 Handling of Dropouts or Missing Data .........................................................................12 
7.4 Interim Analyses and Data Monitoring ........................................................................12 
7.5 Multicenter Studies .......................................................................................................13 
7.6 Multiple Comparisons/Multiplicity ..............................................................................13 
7.7 Examination of Subgroups ............................................................................................13 
7.8 Analysis Populations .....................................................................................................13 
7.8.1 
Intent-to-Treat (ITT) Population .....................................................................13 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 4 
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
7. 8. 2  
Safet y P o p ulati o n ............................................................................................ 1 3  
7. 9  Statistical A nal ysis  ........................................................................................................ 1 3 
7. 9. 1  
Baseli ne Defi niti o n  .......................................................................................... 1 3 
7. 9. 2  
Visit Wi n d o wi n g  ............................................................................................. 1 4 
7. 9. 3  
S u bject Dis p ositi o n  .......................................................................................... 1 4 
7. 9. 4  
Pr ot oc ol De viati o ns ......................................................................................... 1 5  
7. 9. 5  
De m o gra p hic a n d Baseli ne C haracteristics  ..................................................... 1 5 
7. 9. 6  
Pri or a n d C o nc o mita nt Me dicati o ns ................................................................ 1 5  
7. 9. 7  
P har mac o ki netic A n al ys es ............................................................................... 1 5 
7. 9. 8  
Efficac y A nal yses  ............................................................................................ 1 6 
7. 9. 8. 1  
Pri mar y Efficac y A nal ysis  ........................................................... 1 6 
7. 9. 8. 2  
Sec o n dar y Efficac y A nal ysis  ....................................................... 1 6 
7. 9. 8. 3  
E x pl orat or y Effi cac y A n al yses  .................................................... 1 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 9. 9  
Sa fet y A nal yses ............................................................................................... 2 0 
7. 9. 9. 1  
E xte nt of E x p os ure ....................................................................... 2 0  
7. 9. 9. 2  
A d verse E v e nts  ............................................................................ 2 0 
7. 9. 9. 3  
Cli nical La b orat or y E val uti o ns .................................................... 2 1  
7. 9. 9. 4  
Ot her O bser vati o ns Relate d t o Safet y  .......................................... 2 1 
7. 9. 9. 4. 1  
E C G Meas ure m e nts  .............................................. 2 1 
7. 9. 9. 4. 2  
Vital Si g ns  ............................................................ 2 1 
7. 9. 9. 4. 3  
P h ysical E x a mi nati o n  ........................................... 2 2 
8.  
R E F E R E N C E S  .................................................................................................................... 2 2 
C or p or at e C o nfi d e nti al I nf or m ati o n
 
 


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 5 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AD 
Atopic dermatitis 
AE(s) 
Adverse event(s) 
ATC 
Anatomical therapeutic chemical 
AUC(0-last) 
Area under the plasma concentration-time curve from time zero to the time 
of last quantifiable plasma concentration 
BLQ 
Below the limit of quantitation 
BSA 
Body surface area 
Cmax 
Maximum plasma concentration 
CV 
Coefficient of variation 
DSMB 
Data Safety Monitoring Board 
 
 
ECG 
Electrocardiogram 
GM 
Geometric mean 
 
 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
Max 
Maximum 
Min 
Minimum 
n 
Number of observations 
nquant 
Number of quantifiable concentrations 
N 
Number of subjects (sample size) 
 
 
PDE 
Phosphodiesterase 
PK 
Pharmacokinetic 
 
 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE(s) 
Serious adverse event(s) 
SAS® 
Statistical Analysis System (SAS® Institute Inc., Cary, NC) 
 
 
SD 
Standard deviation 
TCIs 
Topical calcineurin inhibitors 
TEAE(s) 
Treatment-emergent adverse event(s) 
Tmax 
Time of  maximum plasma concentration 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 6 
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
 
 
 
 
W H O -D D E  
W orl d Healt h Or ga nizati o n  Dr u g D icti o nar y 
2.  I N T R O D U C TI O N 
M M 3 6 (als o k n o w n as O P C- 2 7 1 a n d O P A- 1 5 4 0 6) is a n o vel n o nster oi dal p h os p h o diesterase t y pe 
4 ( P D E 4) i n hi bit or w hic h selecti vel y i n hi bits t he s y nt hesis of t he i ntracell ul ar sec o n d m esse n gers 
t hat acti vate i nfla m mati o n. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  S T U D Y O B J E C TI V E S  
3. 1  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y is t o assess t he de gree of s yste mic e x p os ure (acti ve pare nt 
c o m p o u n d a n d meta b olites) f oll o wi n g 4 wee ks of t wice dail y d osi n g wit h M M 3 6 1 %, a p plie d 
t o picall y u n der ma xi mal- use c o n diti o ns; ≥ 3 5 % B o d y S urface Area [ B S A] i n v ol ve me nt 
(e x cl u di n g scal p a n d ve n o us access areas) i n s u bjects 2 t o less t ha n 1 2 years of a ge, a n d ≥ 2 5 % 
C or p or at e C o nfi d e nti al I nf or m ati o n


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 7 
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
(e x cl u di n g scal p a n d ve n o us access areas) i n s u bjects at least 1 2 years of a ge t o < 1 8 years of a ge 
wit h at o pic der matitis.  
3. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ve of t his st u d y is t o assess t he safet y pr ofile of M M 3 6 1 % a p plie d 
t o picall y t wice dail y f or u p t o 4 wee ks i n pe diatri c s u bjects 2 t o < 1 8 years of a ge, wit h at o pic 
der matitis.  
3. 3  
E x pl or at or y O bjecti ves  
T his st u d y will als o e x pl ore t he I n v esti gat or - a n d s u bject -assesse d effi cac y pr ofile of M M 3 6 1 %, 
a p plie d t o picall y t wice d ail y f or u p t o 4 wee ks i n pe diatric s u bjects 2 t o < 1 8 years of a ge, wit h 
at o pic der matitis,
 
 
 
 
. 
4.  S T U D Y D E SI G N  
4. 1  
O ver all St u d y Desi g n 
C or p or at e C o nfi d e nti al I nf or m ati o n
T his m ultice nter, o pe n- la bel st u d y, will e val uat e the p har mac o ki netics, safet y, t olera bilit y, a n d 
t he e x pl orat or y efficac y of M M 3 6 1 % oi nt me nt w he n a p plie d t wice d ail y f or u p t o 4 wee ks i n 
s u bjects 2 t o < 1 8 years of a ge wit h at o pic d er matitis, at t he u p per ra n ge of disease se verit y. T his 
st u d y will als o eval uat e t he s yste mic a vaila bilit y of M M 3 6 1 % w he n a p plie d t o picall y u n der 
ma xi mal use c o n diti o ns.  
A p pr o xi matel y 4 5 s u bj ects will be re gistere d f or a n esti mate d 3 2 c o m plete d s u bjects. F oll o wi n g 
scree ni n g ( wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g) a n d c o nfir mati o n of st u d y 
q ualificati o n, s u bjects will be re gistere d a n d assi g ne d ( Da y 1) t o o ne of t hree gr o u ps bas e d o n t he 
s u bject’s a ge at Scree ni n g. T he first d ose of st u d y dr u g will be a p plie d i n t he st u d y cli nic ( Da y 1) 
a n d bl o o d sa m ples will be c ollecte d f or e v al uati o n of p har mac o ki netics ( P K ) pri or t o t he first 
a p plicati o n ( 0 h o urs) a n d at 1 h o ur ( ± 1 5 mi n utes), 4 h o urs ( ± 3 0 mi n utes) a n d at 8 h o urs ( ± 1 
h o ur) after a p plicati o n of st u d y dr u g. O n D a y 1 5, t he st u d y dr u g will a gai n be a p plie d i n t h e 
st u d y cli nic, a n d bl o o d sa m ples will be c ollecte d f or P K pri or t o d osi n g a n d at 1 h o ur ( ± 1 5 
mi n utes), 4 h o urs ( ± 3 0 mi n utes) a n d at 8 h o urs ( ± 1 h o ur) after a p plicati o n of st u d y dr u g. 
 
  
At Scree ni n g a n d Bas eli ne ( Da y 1) , s u bjects wit h at o pic der matitis t hat are 2 t o less t ha n 1 2 years 
of a ge ( Gr o u p 2 a n d 3) m ust ha ve a treata ble area c o m prisi n g ≥ 3 5 % B S A i n v ol ve me n t 
C or p or at e C o nfi d e nti al I nf or m ati o n


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 8 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
(excluding scalp and venous access areas), and subjects 12 years of age and older (Group 1) must 
have ≥ 25% BSA involvement (excluding scalp and venous access areas) (i.e., maximal use 
conditions). The same (or greater, BSA if area involved expands) amount of study drug topically 
applied at baseline will continue to be applied twice daily, to the same area where study drug was 
applied on Day 1, even if the % BSA improves over the course of the first 2 weeks (14 days) of 
treatment. Between Day 15 (after the maximal use application and collection of PK samples) and 
Day 28, the study drug will only be applied to the involved areas. The last application of study 
drug will be given the evening before the final visit (Day 29).  
The maximum individual study participation is approximately 60 days (screening (Day -30) 
through final Day 29 (± 1 day) Visit). 
4.1.1 
Schedule of Visits and Assessments 
The schedule of assessments can be found in Section 1 of the protocol. 
4.1.2 
Method of Assigning Subjects to Treatment Groups 
This is a non-randomized one-arm study with subjects split into three groups based on the 
subject’s age at Screening. Group 1 will consist of approximately 16 subjects who are 12 to < 18 
years of age. Subjects in Group 1 must have ≥25% BSA involvement. Groups 2 and 3 will each 
contain approximately 8 subjects, and subjects must have ≥35% BSA involvement.  Group 2 will 
consist of subjects 6 to < 12 years of age and Group 3 will have subjects 2 to < 6 years of age. 
Following screening and confirmation of study qualification, subjects will be registered and 
assigned a kit of study drug. Five labeled tubes will be assembled into a subject box. Each box 
will be labeled with a single panel label and tamper sealed. Five labeled subject boxes will be 
assembled into block kits. Each kit will be labeled with a 2-part tear away label and tamper 
sealed. At Visit 2/Baseline, Visit 3/Week 1, Visit 4/Week 2 and Visit 5/Week 3, subjects will be 
dispensed tubes of study drug from the assigned kit. 
4.1.3 
Blinding 
Not applicable. 
4.2 
Determination of Sample Size 
The sample size is not driven by inferential statistics. A sample size of 32 subjects is set for 
qualitative investigation of the pharmacokinetic profile as well as the safety and tolerability and 
responsiveness (efficacy) of MM36 1% when applied topically twice daily for 4 weeks to 
pediatric subjects 2 to < 18 years of age. 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 9 
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
5.  C H A N G E S I N T H E C O N D U C T O F T H E S T U D Y O R P L A N N E D A N A L Y S E S  
T here are n o c ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ys es. 
6.  P H A R M A C O KI N E TI C, E F FI C A C Y  A N D S A F E T Y  E N D P OI N T S  
6. 1  
P h ar m a c o ki netic E n d p oi nts  
6. 1. 1  
Pri m ar y P h ar m a c o ki netic E n d p oi nt  
Deter mi nati o n of plas ma c o nce ntr ati o ns, of t he pare nt c o m p o u n d M M 3 6 a n d its meta b olites, 
after t he first t o pical a p pli cati o n of M M 3 6 a n d aft er t w o wee ks of t wice dail y a p plicati o n (stea d y 
state). 
6. 2  
Effic ac y E n d p oi nts  
6. 2. 1  
Pri m ar y Effic ac y E n d p oi nt s 
T here are n o pri mar y effi cac y e n d p oi nts.  
6. 2. 2  
Sec o n d ar y Effic ac y E n d p oi nt s 
T here are n o s ec o n dar y efficac y e n d p oi nts. 
6. 2. 3  
A d diti o n al Effic ac y E n d p oi nts  
T he e x pl orat or y effi cac y e n d p oi nts are as f oll o ws: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n
 
 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 0  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n
 
 
 
 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 1  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 3  
S af et y E n d p oi nts  
6. 3. 1  
Pri m ar y S af et y E n d p oi nt 
T here are n o pri mar y saf et y e n d p oi nts.  
6. 3. 2  
Sec o n d ar y S af et y E n d p oi nts 
T he sec o n d ar y saf et y  e n d p oi nts are as f oll o ws: 
•  I n ci de nce a n d se v erit y of a p plicati o n site a d vers e e ve nts ( A Es); 
•  I n ci de nce a n d se v erit y of all A Es a n d t heir relati o ns hi p t o st u d y dr u g; 
•  
C or p or at e C o nfi d e nti al I nf or m ati o n
I n ci de nce of cli nicall y m ea ni n gf ul c ha n ge fr o m b aseli ne i n safet y la b orat or y p ara m eters, 
1 2- lea d electr ocar di o gra ms ( E C G ), a n d vital si g ns; 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 2  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
•  Pr o p orti o n of s u bjects w h o disc o nti n ue treat me nt d ue t o a n a d verse e v e nt. 
7.  S T A TI S TI C A L M E T H O D S  A N D A N A L Y SI S  
7. 1  
Ge ner al Met h o d ol o g y 
All a nal ys es will be perf or me d b y 
 T he sta n d ar d o perati n g pr oced ures of 
 will be f oll o we d i n t he creati o n a n d q ualit y c o ntr ol of all data dis pla ys a n d 
a nal ys es.  
Efficac y a nal ys es will be perf or me d f or t he i nte nt -t o-treat (I T T) p o p ulati o n a n d safet y a n d P K 
a nal ys es will be perf or m e d usi n g t he s afet y p o p ul ati o n.  
All a nal ys es will be perf or me d usi n g S A S ® Versi o n 9. 3 or later. C o nti n u o us data will be 
s u m marize d usi n g descri pti ve statistics ( n u m ber of val ues [ n], mea n, sta n dar d de viati o n [ S D], 
me dia n, mi ni m u m [ mi n], a n d ma xi m u m [ ma x]) . A d diti o nal s u m mar y statistics, c oeffi cie nt of 
variati o n ( C V %) a n d ge o metric mea n ( G M), will be i ncl u de d f or P K d ata s u m maries. P K 
c o nce ntr ati o n s u m maries will i ncl u de C V %, a n d P K para met er s u m maries will i ncl u de b ot h 
C V % a n d G M. Cate g ori cal data will be s u m marize d usi n g fre q u e nc y ta bles  (fre q u e ncies a n d 
perce nt s). 
Re p orte d A Es, me dical hist or y ter ms , a n d pri or a n d c o nc o mita nt pr oce d ures a n d t hera pies will 
be classifie d o n t he b asis of Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) 
ter mi n ol o g y, Versi o n 1 9. 1. Pri or a n d c o nc o mita nt me dicati o ns a n d s ki n care pr o d ucts will be 
classifie d o n t he basis of W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y ( W H O- D D E) t er mi n ol o g y, 
F or mat B 2, Versi o n Mar c h 1, 2 0 1 6. 
Data c ollecte d at a ti me p oi nt  will be s u m marize d re gar dl ess of treat me nt wit h st u d y dr u g. P ost -
treat me nt assess me nts f or s u bjects w h o disc o nti n ue treat me nt b ut c o nti n ue d t o be f oll o we d i n t he 
st u d y will be i ncl u de d i n s u m maries. 
7. 2  
A dj ust me nts f or C o v ari ates  
N ot a p plica ble t o t his st u d y.  
7. 3  
H a n dli n g of Dr o p o uts or Missi n g D at a 
U nless ot her wise s pecifie d, m issi n g data will n ot be i m p ute d f or a n al yses.   
7. 4  
I nteri m A n al yses a n d D at a M o nit ori n g 
C o nfi d e nti al
A n i n de pe n de nt D ata Saf et y M o nit ori n g B o ar d ( D S M B) will facilitate t he ma na ge me nt a n d 
i de ntificati o n of p ote ntial safet y c o n cer ns, o n a re g ular basis, t hat c o ul d affect t he safet y of trial 
s u bjects, a n d will e x a mi ne w het her t h e i nf or mati o n c ollecte d d uri n g t hes e peri o dic i nter vals is 
c o nsiste nt wit h k n o wle d ge a b o ut t he pr o d uct’s safet y (e. g., u na ntici pat e d a d verse e v e nts). T he 
C o nfi d e nti al


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 3  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
D S M B will als o assess w het her r e visi o ns t o t he st u d y pr ot o c ol a n d/ or c o ns e nt are re q uire d, a n d 
will e val uate t he o verall pr o gress of t he st u d y.  
T he D S M B will c o nsist of 3 v oti n g me m bers , a n d t he first D S M B data re vi e w meeti n g will be 
sc he d ule d after at least 5 0 % or 1 6 e nr olle d s u bjects i n t he st u d y. A d h oc m eeti n gs ma y b e 
re q ueste d b y a n y me m ber of t he D S M B or a n y ot her i n v ol ve d part y, if d ee me d necess ar y. 
F oll o wi n g eac h D S M B meeti n g ( pl a n ne d or a d h oc), t he D S M B will ma ke rec o m me n d ati o ns 
re gar di n g st u d y c o nti n uati o n, m o dificati o n or ter mi nati o n base d o n t he o bser ve d a d verse effects 
of t he treat me nt u n d er st u d y. D etails re gar di n g t h e p olicies a n d pr o ce d ures of t he D S M B a n d 
i nter vals a n d data t o b e e val uate d will be descri be d i n t he D S M B C harter.  
A pre -s p ecifie d i nteri m a nal ysis will n ot be c o n d u cte d. 
7. 5  
M ultice nter St u dies  
T he cli nical st u d y will be c o n d ucte d u n der a c o m m o n pr ot oc ol f or eac h i n vesti gati o nal site wit h 
t he i nte nti o n of p o oli n g t he data f or a nal ysis. E ver y eff ort will be ma d e t o pr o m ote c o nsiste nc y 
i n st u d y e x ec uti o n at eac h st u d y site. 
7. 6  
M ulti ple C o m p aris o ns/ M ulti plicit y  
N o a dj ust me nts f or m ulti ple c o m paris o ns or m ulti plicit y will be ma de.  
7. 7  
E x a mi n ati o n of S u b gr o u ps 
 a d verse e ve nts will  be s u m marize d b y 
a ge gr o u p (s u bj ects 2- 5 years ol d a n d s u bjects 6- 1 7 years ol d). 
7. 8  
A n al ysis P o p ul ati o ns 
7. 8. 1  
I nte nt-t o-Tre at (I T T) P o p ul ati o n  
All e nr olle d s u bjects w h o t o o k at least o ne d ose of st u d y dr u g will be i ncl u de d i n t he I T T 
p o p ulati o n .  All efficac y a nal yses will be pres e nte d usi n g t he I T T p o p ul ati o n. 
7. 8. 2  
S af et y P o p ul ati o n 
All s u bjects i n t he I T T p o p ulati o n w h o ha ve at least o ne p ost- baseli ne safet y assess me nt will be 
i ncl u de d i n t he safet y p o p ulati o n. All safet y a nal yses will be perf or me d usi n g t he safet y 
p o p ulati o n. 
7. 9  
St atistic al A n al ysis  
7. 9. 1  
B aseli ne Defi niti o n  
C or p or at e C o nfi d e nti al I nf or m ati o n
Baseli ne is defi ne d as t he last n o n- missi n g assess me nt pri or t o first d ose of st u d y dr u g.   


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 14 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
7.9.2 
Visit Windowing 
Data will be summarized based on nominal visit indications with the exception of data captured 
at early termination and unscheduled visits. Data from early termination and unscheduled visits 
will be summarized based on mapped visit values.  The analysis windows for early termination 
and unscheduled visits are presented in the following table. 
Analysis Windows for Efficacy and Safety Assessments 
Scheduled Visit 
Target Study Day 
Window (Days) 
Day 8 
8 
5 to 11 
Day 15 
15 
12 to 18 
Day 22 
22 
19 to 25 
Day 29 
29 
26 to 32 
Data collected at early termination and unscheduled visits prior to study day 5 will not be 
analyzed, with the exception of those identified as baseline values. Data collected at early 
termination and unscheduled visits after study day 32 will not be included in analyses. 
The definition for the study day included in each study window is defined as below: 
 
Study Day Prior to Day 1 = Visit Date – Day 1 Date 
 
Study Day On or After Day 1 = Visit Date – Day 1 Date + 1 
If an assessment’s mapped visit is a visit at which the subject has data present, or if no analyses 
are planned for the assessment at the mapped visit, the data collected at the early termination or 
unscheduled visit will not be included in analyses.   
In the event of multiple values from unscheduled or early termination assessments within an 
analysis window, the value closest to the scheduled visit target study day will be used for 
analyses.  If two values tie as closest to the time point (for example, one value is before and the 
other value is after the time point), then the later value will be selected.  
Data collected at all visits will be included in the data listings. 
7.9.3 
Subject Disposition 
The number of subjects included in each analysis population (ITT and safety), as well as the 
number of subjects in the safety population with PK data will be summarized.  The number of 
subjects treated, completed, discontinued treatment (including the reason for treatment 
discontinuation), and discontinued study (including the primary reason for study discontinuation) 
will be presented. 
Subjects who are excluded from an analysis population will be summarized by the reasons for 
exclusion. 


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 15 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
7.9.4 
Protocol Deviations 
Protocol deviations will not be entered into the database and therefore will not be summarized.   
7.9.5 
Demographic and Baseline Characteristics 
All baseline summaries will be done on the ITT and safety populations. 
Sex, race, ethnicity, Fitzpatrick skin type, dietary habits, and alcohol, tobacco and drug use will 
be summarized by counts and percentages.  Age, height, and weight will be summarized with 
descriptive statistics (n, mean, SD, median, min, and max).   
Atopic dermatitis history, including family history of atopic dermatitis, location of disease, and 
diagnoses of allergic rhinitis and asthma, will be summarized by counts and percentages. 
Medical histories will be coded using the MedDRA dictionary and will be summarized by 
MedDRA system organ class and preferred term. 
7.9.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded to preferred term and anatomical therapeutic 
chemical (ATC) classification of ingredients using the WHO-DDE. 
Counts and percentages will be provided to summarize the use of medications other than the 
study drug reported throughout the study.  The number and percent of subjects reporting 
medications will be summarized by ATC level 2 term and preferred name.  Medications which 
start prior to first dose will be considered prior medications, and medications which start on or 
after first dose will be considered concomitant medications. Medications with incomplete start 
dates which could be prior to first dose or after first dose will be considered concomitant. 
Skin care products used during the study and prior and concomitant procedures and therapies 
will be included in by-subject listings. 
7.9.7 
Pharmacokinetic Analyses 
The pharmacokinetic analysis will be conducted using non-compartmental analysis on plasma 
concentrations of MM36 and its metabolites (MAP-15484, MAP15497 and MAP-15485) in the 
subjects in the safety population who have PK data. 
Individual plasma concentrations of MM36 and its metabolites will be summarized descriptively 
at Day 1 and Day 15 using the arithmetic mean, SD, CV%, median, min, and max. Individual 
plasma concentration-time profiles of MM36 and its metabolites will be plotted on both a linear 
and a semi-logarithmic scale at each visit. Mean values will also be presented graphically.  
Plasma concentrations below the lower limit of quantitation (BLQ) (< 0.2 ng/mL) will not be 
considered quantifiable concentrations. BLQ values and quantifiable concentrations will be 


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 16 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
summarized separately using summary statistics. Any quantifiable concentrations at pre-dose at 
Day 1 will be set to zero in both concentration summaries, as well as in PK parameter 
calculations. Plasma concentration-time profiles will display BLQ values as 0 ng/mL on the 
linear scale, and will omit BLQ values on the semi-logarithmic scale. 
The following pharmacokinetic parameters will be analyzed for each subject at Day 1 and Day 
15 if there are a sufficient number of quantifiable concentrations of MM36 or its metabolites to 
permit their derivation. 
Cmax 
Maximum plasma concentration 
Cmax = BLQ if concentrations are BLQ at all time points 
Tmax 
Time of maximum plasma concentration 
Tmax will be calculated if at least one quantifiable plasma concentration is 
detected in the time interval. Individual elapsed sampling times will be 
used. If the maximum concentration is observed pre-dose, Tmax will be 
considered 0 hours. 
AUC0-last 
Area under the plasma concentration-time curve from time zero to the 
time of last quantifiable plasma concentration 
AUC0-last will be calculated if at least two consecutive quantifiable 
plasma concentrations are detected in the time interval. Area will be 
computed using the linear trapezoidal rule with individual elapsed 
sampling times and observed concentratinos. BLQ values will be set to 
zero before Tmax and missing after Tmax. 
Descriptive summary statistics (n, arithmetic mean, SD, CV%, median, min, max, and GM) will 
be reported for PK parameters. Individual plasma concentrations and PK parameter values will 
be included in by-subject listings. 
7.9.8 
Efficacy Analyses 
7.9.8.1 
Primary Efficacy Analysis 
There is no primary efficacy analysis. 
7.9.8.2 
Secondary Efficacy Analysis 
There is no secondary efficacy analysis. 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 7  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
7. 9. 8. 3  
E x pl or at or y Effic ac y A n al yses 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n
 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 8  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n
 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 1 9  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
7. 9. 8. 3. 4. 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 2 0  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
7. 9. 9  
S af et y A n al yses 
7. 9. 9. 1  
E xte nt of E x p os ure 
T he e xte nt of e x p os ure t o st u d y dr u g will be s u m m arize d b y t otal n u m ber of da ys of e x p os ure, 
t otal n u m ber of a p plicati o ns, perce nt c o m plia nce , a n d t otal a m o u nt of st u d y dr u g a p plie d. T otal 
n u m ber of a p plicati o ns will be deter mi ne d b y t he n u m ber of e ntries i n t he d osi n g diar y. T otal 
n u m ber of da ys of e x p os ure will be c o m p ute d as f oll o ws: 
Da ys of E x p os ure = D ate of L ast A p plicati o n  – Date of F irst A p plicati o n + 1. 
T o c o m p ute per ce nt c o m plia nce, t otal n u m ber of e x pecte d a p plicati o ns will be calc ulate d b y:  
E x pecte d a p plicati o ns = 2 *( St u d y C o m pleti o n/ Disc o nti n uati o n Date  – Dat e of First A p plicati o n).  
If t he t otal n u m ber of e x pecte d a p plicati o ns e x cee ds 5 8 t he n it will be set t o 5 8. Perce nt 
c o m plia nce will be calc ulate d fr o m t otal n u m ber of a p plicati o ns a n d t otal n u m ber of e x pecte d 
a p plicati o ns as f oll o ws: 
Perce nt C o m plia nce  = 1 0 0 *( T otal A p plicati o ns/ E x pecte d A p plicati o ns). 
Perce nt c o m plia nce will n ot be calc ulate d f or s u bj ects w h o are l ost t o f oll o w- u p. 
7. 9. 9. 2  
A d verse E ve nts  
C or p or at e C o nfi d e nti al I nf or m ati o n
Treat me nt -e mer ge nt A E s ( T E A Es) are defi ne d as AEs wit h a n o nset o n or after t he d ate of t he 
first st u d y dr u g a p plicati o n. Treat me nt -e mer ge nt AE s will be s u m marize d b y s yste m or ga n class 
a n d pref err e d ter m  a n d f urt her b y se verit y a n d rel ati o ns hi p t o st u d y dr u g. W he n s u m marizi n g 
A Es b y s e verit y a n d relati o ns hi p, eac h s u bject will be c o u nte d o nce w it hi n a s yste m or ga n class 


CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Medimetriks Pharmaceuticals, Inc. 
Page 21 
Protocol Number: MEDI-MM36-206 
May 18, 2017 
or preferred term by using the event with the highest severity and strongest relationship within 
each classification.  
Serious AEs (SAEs) will be summarized by system organ class, preferred term, severity, and 
relationship to study drug. Application site AEs and any TEAEs reported by ≥ 5% of subjects 
will be summarized by system organ class and preferred term. Adverse events leading to 
treatment or study discontinuation will be summarized by system organ class and preferred term. 
Listings will be presented for all adverse events as well as for serious adverse events, and 
adverse events leading to discontinuation from the study. 
7.9.9.3 
Clinical Laboratory Evalutions 
Laboratory test results will be summarized with descriptive statistics at Baseline and Day 29. 
Additionally, change from baseline values will be summarized at Day 29, and shifts from 
Baseline to Day 29 in laboratory test results based on normal ranges will be summarized with 
frequency counts and percentages. Individual laboratory test results, including urine and serum 
pregnancy test results, will be presented in a by-subject listing.  
7.9.9.4 
Other Observations Related to Safety 
7.9.9.4.1 
ECG Measurements 
ECGs will be performed in triplicate at Screening, Day 1, Day 15 and Day 29, and the following 
parameters will be measured for each ECG: heart rate, RR duration, QRS duration, PR duration, 
QT duration, QT interval corrected for heart rate using Bazett’s formula (QTcB), and QT interval 
corrected for heart rate using Fridericia’s formula (QTcF). For each parameter and each visit, the 
mean of all measurements collected at the visit will be calculated, so each subject will have one 
value associated with each ECG parameter at each visit.  
Descriptive statistics at Baseline, Day 15, and Day 29 will be provided for each ECG parameter. 
Change from baseline values will be summarized at Day 15 and Day 29. 
Individual ECG measurements, as well as means of triplicates, will be presented in a by-subject 
listing. 
7.9.9.4.2 
Vital Signs 
Temperature, respiratory rate, heart rate, blood pressure, and weight will be summarized at each 
visit, and change from baseline values will be presented for post-baseline visits. Weight will be 
summarized at Baseline, Day 15, and Day 29, and all other vital signs will be summarized at 
Baseline, Day 8, Day 15, Day 22, and Day 29. 
Heart rate and blood pressure measurements are collected in triplicate at each visit. Prior to 
computing summary statistics, the mean of each measurement will be calculated for each subject 


C O N FI D E N TI A L  
 
 
 
Statistical A nal ysis Pla n  f or Me di metri ks P har mace uticals, I nc. 
P a ge 2 2  
Pr ot oc ol N u m ber: M E DI -M M 3 6 -2 0 6  
Ma y 1 8, 2 0 1 7  
at eac h visit. S u m mar y stat istics will be c o m p ute d fr o m eac h s u bject’s mea n heart rate a n d bl o o d 
press ure v al ues at eac h visit.  
I n di vi d ual vital si g n data, as well as mea ns of heart rate a n d bl o o d press ure tri plicates, will be 
prese nte d i n a b y -s u bject listi n g. 
7. 9. 9. 4. 3  
P h ysic al E x a mi n ati o n 
P h ysical e x a mi nati o n data will be prese nt e d i n a b y -s u bject listi n g.  
8.  R E F E R E N C E S  
 
 
 
C or p or at e C o nfi d e nti al I nf or m ati o n