A Randomized, Prospective, Multicenter, Double Blind, Parallel Assignment, Placebo Controlled Bioequivalence Study of Pimecrolimus Cream, 1% and Elidel® (Pimecrolimus) Cream, 1% in Patients With Mild to Moderate Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Mylan Inc.

 
 
NCT #  
NCT03107611 
Study Identification Code  
CD-14-875  
Protocol Version  
2.0  
Protocol Issue Date  
14 October 2016  
Study Title  
A Randomized, Prospective, Multicenter, Double Blind, 
Parallel Assignment, Placebo Controlled Bioequivalence 
Study of Pimecrolimus Cream, 1% and Elidel® 
(Pimecrolimus) Cream, 1% in Patients with Mild to 
Moderate Atopic Dermatitis  
Sponsor  
DPT Laboratories, Ltd., an affiliate of Mylan Inc. 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 1 of 75 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Identification Code 
CD-14-875 
Protocol Version 
2.0 
Protocol Issue Date 
14 October 2016 
Study Title 
 
 
A Randomized, Prospective, Multicenter, Double Blind, 
Parallel Assignment, Placebo Controlled Bioequivalence 
Study 
of 
Pimecrolimus 
Cream, 
1% 
and 
Elidel® 
(Pimecrolimus) Cream, 1%  in Patients with Mild to 
Moderate Atopic Dermatitis 
Study Design 
Randomized, prospective, multicenter, double blind, 
parallel assignment, placebo-controlled, bioequivalence 
clinical endpoint study 
Study Population 
Mild to Moderate Atopic Dermatitis 
Study Drug  
Pimecrolimus Cream, 1% 
Sponsor 
DPT Laboratories, Ltd., an affiliate of Mylan Inc. 
318 McCullough  
San Antonio, TX 78215 
Contact Research 
Organization (CRO) & 
Protocol Author 
TKL Research, Inc.  
365 W. Passaic Street, Suite 550 
Rochelle Park, NJ 07662 
Phone: 201-587-0500 Fax: 201-336-1512 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 3 of 75 
 
 
INVESTIGATOR PROTOCOL AGREEMENT 
 
I have read and understood the Protocol No. CD-14-875. I have fully discussed the objectives 
and design of this study and the contents of this protocol with the Sponsor’s representative or 
designee. 
I agree to maintain a list of appropriately qualified persons to whom I shall delegate certain 
specified trial-related duties based on their training and experience. I shall ensure that all 
persons assisting me with the trial are adequately informed about the protocol and any 
amendments, and their trial-related duties and functions.  
I understand that the information in this protocol and all other information provided to or 
accessed by me relating to this study or its progress are the confidential property of the Sponsor 
and shall not be disclosed, other than to those authorized persons who are directly involved in 
the execution or the Institutional Review Board (IRB) and/or Ethics Committee review of the 
study, without prior written authorization from the Sponsor, and I agree to maintain all such 
information in strict confidence and to use such information solely pursuant to my conduct of 
the study. It is, however, permissible to provide information to a subject in order to obtain 
subject consent to participate in the study once IRB approval is obtained. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject ethical and safety considerations and guidelines, and to conduct the trial in accordance 
with ICH guidelines on Good Clinical Practice (GCP) and with the applicable regulatory 
requirements. I further agree to comply with local laws and regulations and the provisions of 
Declaration of Helsinki (Fortaleza, Brazil, October 2013) and the rules and regulations in force 
in this country at present. 
I understand that the Sponsor may decide to suspend or terminate the study at any time for 
whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from execution of the study I will communicate my intention immediately 
in writing to the Sponsor. 
 
 
 
 
Signature of Investigator 
 
Printed Name: 
 
Date: 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 5 of 75 
 
 
STUDY SYNOPSIS 
 
Study Title  
A Randomized, Prospective, Multicenter, Double Blind, Parallel 
Assignment, Placebo Controlled Bioequivalence Study of Pimecrolimus 
Cream, 1% and Elidel® (Pimecrolimus) Cream, 1% in Patients with 
Mild to Moderate Atopic Dermatitis 
Study Design  
Randomized, 
prospective, 
multicenter, 
double 
blind, 
parallel 
assignment, placebo controlled therapeutic equivalence study 
Sample Size 
648  Subjects  
Protocol Number 
CD-14-875 
Study Center 
Multi-center study 
Study Type  
Bioequivalence study with clinical endpoints 
Sponsor 
DPT Laboratories, Ltd., an affiliate of Mylan Inc. 
318 McCullough  
San Antonio, TX 78215 
Investigational  
Products & Study 
Arms 
Test drug: Pimecrolimus Cream, 1% 
Reference listed drug (RLD): Elidel® (Pimecrolimus) Cream 1% 
Placebo: Vehicle cream 
Dosage of 
Investigational 
Product 
A thin layer is to be applied to all affected skin areas twice daily for 2 
weeks (14 days) 
Objectives  
Primary Objective:  
 To establish the bioequivalence between test and reference listed 
drugs using the primary endpoint in the Per Protocol population 
 
Additional:  
 
To establish superiority of the each treatment over the placebo using the 
primary endpoint in the modified intent to treat (mITT) population and 
Last Observation Carried Forward (LOCF)  
 To assess individual signs and symptoms of Atopic Dermatitis (i.e., 
erythema, induration/papulation, lichenification and pruritus) in each 
treatment group 
 To compare the safety and tolerability between the test and reference 
drugs 
Study Population  
Non-immunocompromised males and females with mild to moderate 
atopic dermatitis who have failed to respond adequately to other topical 
prescription treatments, or when those treatments are not advisable. 
Age: 8 years and above  
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 6 of 75 
 
 
Patient Selection 
Screening Criteria: 
 Non-immunocompromised male or female aged 8 years and older 
 Clinical diagnosis of mild to moderate atopic dermatitis (AD), as 
defined by the criteria of Hanifin and Rajka 
 Failed to respond adequately to other topical prescription treatments 
for AD, or for whom those treatments are not advisable (The 
subject/guardian’s verbal report of failure to other topical 
prescription treatments for AD will be adequate.) 
 An Investigator’s Global Assessment (IGA) of disease severity of 
mild or moderate at baseline (score of 2 or 3)  
 Affected area of AD involvement at least 5% body surface area 
(BSA) 
 Expected to be able to meet inclusion and exclusion criteria after 
minimum 7 days of continuous treatment with a bland emollient 
(e.g. Cetaphil® Lotion) 
 
Inclusion Criteria: 
 Non-immunocompromised male or female aged 8 years and older 
 Clinical diagnosis of mild to moderate atopic dermatitis (AD), as 
defined by the criteria of Hanifin and Rajka 
 Failed to respond adequately to other topical prescription treatments 
for AD, or for whom those treatments are not advisable (The 
subject/guardian’s verbal report of failure to other topical 
prescription treatments for AD will be adequate.) 
 A diagnosis of AD for at least 3 months (Subject/guardian may 
verbally report signs and symptoms of atopic dermatitis with an 
onset at least 3 months prior.) 
 An Investigator’s Global Assessment (IGA) of disease severity of 
mild or moderate at baseline (score of 2 or 3)  
 Affected area of AD involvement at least 5% body surface area 
(BSA)  
 Treated with a bland emollient (e.g. Cetaphil® Lotion) for at least 7 
days continuously 
 Willing and able to give written informed consent (and assent as 
applicable) and willing to comply with the trial protocol 
 If female of childbearing age, willing to use an acceptable form of 
birth control, that is stable at least 3 months prior to baseline and 
throughout the study.  Acceptable forms of birth control include any 
of the following: (1) hormonal birth control, which must be stable 
for > 3 months prior to baseline; (2) abstinence; subject must use 
condom plus spermicide, if becomes sexually active; (3) double 
barrier method, such as condom plus spermicide. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 7 of 75 
 
 
 
Exclusion Criteria: 
a) Females who are pregnant, breast feeding, or who wish to become 
pregnant during the study period  
b) Active cutaneous bacterial or viral infection in any treatment area at 
baseline (e.g., clinically infected atopic dermatitis, impetigo)  
c) Sunburn, extensive scarring or pigmented lesion(s) in any treatment 
area at baseline, which would interfere with evaluations  
d) History of confounding skin conditions, e.g., psoriasis, rosacea, 
erythroderma, ichthyosis, or scabies  
e) History or presence of Netherton’s Syndrome, immunological 
deficiencies or diseases, HIV, diabetes, malignancy, serious active or 
recurrent infection, clinically significant severe renal insufficiency 
or severe hepatic disorders  
f) Concurrent disease or treatment likely to interfere with the study 
treatment or evaluations 
g) Use within one month prior to baseline  
 Oral or intravenous corticosteroids (Subjects on a stable and 
continued dose of nasal, or inhaled corticosteroids for 
conditions other than atopic dermatitis may be enrolled at 
the investigator’s discretion when the investigator considers 
that such will not affect the efficacy or safety evaluations of 
the study. Ophthalmic corticosteroids are not excluded.) 
 UVA/UVB therapy 
 PUVA (psoralen plus ultraviolet A) therapy 
 Tanning booths 
 Nonprescription UV light sources 
 Immunomodulators or immunosuppressive therapies 
 Interferon 
 Cytotoxic drugs 
 Tacrolimus 
 Pimecrolimus  
h) Use within 14 days of baseline of 
 Systemic antibiotics 
 Calcipotriene or other vitamin D preparations 
 Retinoids  
i) Use within 7 days prior to baseline of 
 Systemic antihistamines (Subjects on a stable and continued 
dose of systemic antihistamines may be enrolled at the 
investigator’s discretion when the investigator considers that 
such will not affect the efficacy or safety evaluations of the 
study.) 
 Topical antibiotics 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 8 of 75 
 
 
 Topical corticosteroids  
 Other topical drug products 
 Probiotics  
j) Use within 24 hours prior to baseline of any topical product 
(e.g., sunscreens, lotions, creams) in the areas to be treated, 
except for bland emollient (e.g. Cetaphil® Lotion)  
k) Known allergy or hypersensitivity to pimecrolimus or any other 
component of the test product or RLD  
l) Not willing to minimize or avoid natural and artificial sunlight 
exposure during treatment  
m) Currently enrolled in an investigational drug or device study or used 
an investigational drug or investigational device treatment within 30 
days prior to first application of the test article   
Study Treatment 
 Screening period: 
Up to 14 days before visit 2 
 Treatment period:  
The blinded treatment will be administered for two weeks for each 
subject. Apply a thin layer of cream to all affected skin areas twice 
daily.  
Randomization 
1:1:1 (Test: RLD: Placebo) 
Study Duration 
The study duration for each subject would be up to 32 days. There is a 
screening period of up to 14 days and a treatment period of 14 (± 3) 
days. 
 
Study Visits 
4 Visits: 
V1-Screening Visit (up to -14 days) 
V2-Baseline and Randomization Visit (Day 1) 
V3-Interim Visit (Day 8 ± 3 days) 
V4- End of Therapy Visit (Day 15 ± 3 days) 
 
Study 
Measurements 
Efficacy: 
Signs and Symptoms of Atopic Dermatitis will be scored per body 
region (Head and Neck; Trunk; Upper Limbs; Lower Limbs). Signs and 
Symptoms will be scored by the principal investigator or a qualified 
person delegated by the investigator. It is strongly preferred to have one 
evaluator for each of the visits per subject. A back up evaluator may be 
present at baseline in case the primary evaluator is unavailable at follow 
up.  
Pruritus will be assessed by questioning the subject or the subject’s 
guardian regarding the intensity in the 24 hours prior to the visit for the 
overall condition. 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 9 of 75 
 
 
Sign and 
Symptom 
Score Category 
Definition 
Erythema 
0 
None 
No erythema present  
1 
Mild 
Slight erythema: very light-pink  
2 
Moderate Dull red, clearly distinguishable  
3 
Severe 
Deep/dark red 
Induration/ 
Papulation 
0 
None 
None  
1 
Mild 
Slightly perceptible elevation  
2 
Moderate Clearly perceptible elevation but not 
extensive  
3 
Severe 
Marked and extensive elevation 
Lichenification 
0 
None 
None  
1 
Mild 
Slight 
thickening 
of 
the 
skin 
discernible only by touch and with 
skin markings minimally exaggerated  
2 
Moderate Definite thickening of the skin with 
skin marking exaggerated so that 
they form a visible criss-cross pattern  
3 
Severe 
Thickened indurated skin with skin 
markings 
visibly 
portraying 
an 
exaggerated criss-cross pattern 
Pruritus 
0 
None 
None 
1 
Mild 
Occasional, slight itching/scratching 
2 
Moderate Constant 
or 
intermittent 
itching/scratching/discomfort which 
is not disturbing sleep 
3 
Severe 
Bothersome 
itching/scratching/discomfort which 
is disturbing sleep  
 
Overall Body Surface Area (BSA) Involvement with AD will be 
assessed and recorded by the investigator or delegate.  
 
Investigator’s Global Assessment of Disease Severity Scoring will be 
scored for the investigator’s (or delegate’s) assessment of the subject’s 
overall condition as seen at the time of evaluation (static) as explained 
below: 
 
Score  Category  
Definition  
0  
Clear  
Minor residual discoloration, no erythema or 
induration/papulation, no oozing/crusting  
1  
Almost 
Clear  
Trace faint pink erythema with almost no 
induration/papulation and no oozing/crusting  
2  
Mild disease  Faint 
pink 
erythema 
with 
mild 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 10 of 75 
 
 
induration/papulation and no oozing/crusting  
3  
Moderate 
disease  
Pink-red 
erythema 
with 
moderate 
induration/papulation and there may be some 
oozing/crusting  
4  
Severe 
disease  
Deep/bright 
red 
erythema 
with 
severe 
induration/papulation with oozing/crusting  
 
Safety:  
Physical Examination: Must include a detailed skin examination. 
Additionally, examination of head, ears, nose and throat, eyes, central 
nervous 
system, 
respiratory 
system, 
cardiovascular 
system, 
gastrointestinal system, musculoskeletal system should be assessed. 
Vital Signs: Pulse rate, blood pressure and body temperature   
Urine Pregnancy Test 
Adverse Event Assessments 
Application site reactions such as dryness, burning/stinging, erosion, 
edema, and pain will be assessed scored (as per Appendix IV) and 
recorded. 
Study Endpoints 
Primary endpoint:  
 The proportion of subjects in each treatment group with treatment 
success (i.e., a grade of clear or almost clear; a score of 0 or 1, 
within the treatment area) based on the Investigator’s Global 
Assessment of Disease Severity at the end of treatment (Study Day 
15) 
 
Additional endpoints:  
 Change in severity from baseline to week 2 (study Day 15) of four 
individual 
signs 
and 
symptoms 
of 
AD 
(i.e., 
erythema, 
induration/papulation, lichenification and pruritus) are considered 
supportive information 
 Application site reactions will be compared between treatment 
groups.  
 
Safety Endpoints: 
Safety assessment through the incidences and severity of all adverse 
events (AEs) reported during the study and summarized by treatment 
group 
Statistical 
Analysis: 
 Therapeutic equivalence of the test product to the reference product 
will be evaluated in the PP population. To establish bioequivalence, 
if the 90% confidence interval (calculated using Yates’ continuity 
correction) of the test - reference difference between products for the 
primary endpoint (success proportion) is contained within [-0.20, 
+0.20], then bioequivalence of the test product to the reference 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 11 of 75 
 
 
product will be considered to have been demonstrated. 
 As a parameter for determining adequate study sensitivity, the test 
product and RLD will be compared to placebo with regard to the 
primary endpoint from baseline to week 2 (Day 15). Superiority of 
the test and reference products against the placebo will be tested at 
the 5% significance level (p < 0.05; using Fisher’s exact test) in the 
mITT population using last observation carried forward. 
 Supportive information will be presented describing the change in 
severity from baseline to week 2 (study Day 15) of four individual 
signs and symptoms of AD (i.e., erythema, induration/papulation, 
lichenification and pruritus).  
 Adverse events that occurred subsequent to the first dose of study 
drug will be summarized. The number and the proportion of subjects 
who experienced AEs will be computed by treatment group. AEs 
will also be summarized by each severity grade (mild, moderate, 
severe) and by each relationship grade (none, possibly, probably) in 
a similar way. 
 Application site reactions will be compared via a descriptive analysis 
between treatment groups. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 12 of 75 
 
 
TABLE OF CONTENTS 
SPONSOR / CRO APPROVAL PAGE ........................................................................ 2 
STUDY SYNOPSIS ..................................................................................................... 5 
1 
INTRODUCTION ............................................................................................ 16 
1.1 
Study Rationale .......................................................................................... 18 
1.2 
Risk-Benefit Assessment ............................................................................. 19 
2 
STUDY OBJECTIVES ..................................................................................... 19 
2.1 
Primary Objective ....................................................................................... 19 
2.2 
Additional Objectives .................................................................................. 19 
3 
INVESTIGATIONAL PLAN ............................................................................ 19 
3.1 
Overall Study Design and Data Collection ..................................................... 19 
3.1.1 Visit 1 - Screening Visit (-up to 14 days) .................................................. 20 
3.1.2 V2 - Baseline and Randomization Visit (Day 1) ....................................... 23 
3.1.3 V3 - Follow up visit (Day 8 ± 3 days) ....................................................... 24 
3.1.4 V4 - End of Therapy Visit (Day 15 ± 3 days) ............................................. 24 
3.1.5 Unscheduled Visits and Early Discontinuation Visit ................................ 25 
3.2 
Schedule of events ...................................................................................... 26 
3.3 
Evaluation Criteria ...................................................................................... 26 
3.3.1 Primary Endpoint: ................................................................................. 26 
3.3.2 Secondary Endpoints: ............................................................................ 27 
3.3.3 Safety Endpoints: ................................................................................... 27 
4 
STUDY POPULATION .................................................................................... 27 
4.1 
Subject Selection ........................................................................................ 27 
4.1.1 Inclusion Criteria ................................................................................... 27 
4.1.2 Exclusion Criteria .................................................................................. 28 
4.2 
Withdrawal of Subjects ............................................................................... 29 
4.3 
Protocol Deviations and Violations ............................................................... 29 
4.4 
Ethical and Regulatory Considerations .......................................................... 30 
4.4.1 Declaration of Helsinki and ICH-GCP .................................................... 30 
4.4.2 Protocol Amendments ............................................................................ 30 
4.4.3 Informed Consent and Assent ................................................................. 30 
4.4.4 Patient Information Sheet ....................................................................... 31 
5 
INVESTIGATIONAL PRODUCTS .................................................................. 31 
5.1 
Packaging, Labeling and Storage of Investigational Products .......................... 31 
5.2 
Retention of Study Records and Drug Samples .............................................. 32 
5.3 
Dispensing ................................................................................................. 32 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 13 of 75 
 
 
5.4 
Drug accountability ..................................................................................... 32 
6 
TREATMENT OF STUDY DRUG .................................................................... 33 
6.1 
Randomization ........................................................................................... 33 
6.2 
Dosing and Administration Information ........................................................ 33 
6.3 
Concomitant Medication ............................................................................. 33 
6.4 
Prohibited Medications and Treatments ......................................................... 34 
6.5 
Blinding and Unblinding ............................................................................. 34 
7 
SAFETY ASSESSMENT .................................................................................. 36 
7.1 
Intensity of Adverse Events ......................................................................... 37 
7.2 
Causality Assessment .................................................................................. 37 
7.3 
Frequency .................................................................................................. 38 
7.4 
Serious Adverse Events ............................................................................... 38 
8 
DATA HANDLING, RECORDING AND QUALITY ASSURANCE ................. 39 
8.1 
Data Handling and Record Keeping .............................................................. 39 
8.2 
Access to Source Data ................................................................................. 39 
8.3 
Source Data Verification and on-site Audits .................................................. 39 
8.4 
Monitoring ................................................................................................. 40 
8.5 
Data Management ....................................................................................... 40 
9 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ......................... 40 
9.1 
Determination of Sample Size ...................................................................... 40 
9.2 
Statistical Methods ...................................................................................... 40 
9.2.1 Study Population .................................................................................... 40 
9.2.2 Statistical analysis .................................................................................. 41 
9.3 
Presentation of Results ................................................................................ 42 
9.4 
Handling of Dropout or Missing Data ........................................................... 43 
10 
STUDY ADMINISTRATIVE PROCEDURES .................................................. 43 
10.1 
Regulatory Authority Approval .................................................................... 43 
10.2 
Confidentiality of Subjects........................................................................... 43 
10.3 
Delegation of Investigator Responsibilities .................................................... 44 
10.4 
Study Termination and Site Closure .............................................................. 44 
10.5 
Archiving and Record Retention................................................................... 44 
10.6 
Study Report and Publication Policy ............................................................. 45 
11 
REFERENCES ................................................................................................. 45 
12 
APPENDICES .................................................................................................. 48 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 14 of 75 
 
 
12.1 
Appendix I: Hanifin and Rajka Criteria ......................................................... 48 
12.2 
Appendix II: Scoring of signs and symptoms in AD ....................................... 49 
12.3 
Appendix III: IGA Scoring .......................................................................... 50 
12.4 
Appendix IV: Local Irritation Scale (LIS) ..................................................... 51 
12.5 
Appendix V: Instructions for the patients ...................................................... 52 
12.7 
Appendix VI:  Revision History Dated 14Oct2016 ......................................... 54 
12.8 
Appendix VII: US Reference Listed Drug Package Insert ............................... 56 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 15 of 75 
 
 
ABBREVIATIONS: 
  
AD 
Atopic Dermatitis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BSA 
Body Surface Area  
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DMP  
Data Management Plan 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices  
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGA 
Investigator Global Assessment  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
LOCF 
Last Observation Carried Forward 
mITT 
Modified Intention To Treat  
OGD 
Office of Generic Drugs  
PI 
Principal Investigator 
PIS 
Patient Information System 
PP 
Per Protocol 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAS 
Statistical Analyzing System 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 16 of 75 
 
 
1 
   INTRODUCTION 
 
STUDY DISEASE: 
Atopic dermatitis (AD) (eczema) is a skin disease affecting an estimated 35 million 
Americans, predominantly children.13 AD is a pruritic disease of unknown origin that starts 
in early infancy; an adult-onset variant is recognized14; it is characterized by pruritus, 
eczematous lesions, xerosis (dry skin) and lichenification. AD may be associated with 
other atopic (immunoglobulin E [Ig E]–associated) diseases (e. g., acute allergic reaction to 
foods, asthma, urticaria, and allergic rhinitis).  AD is the first disease to present in a series 
of allergic diseases such as food allergy, asthma, and allergic rhinitis, provoking the 
“atopic march” theory, which suggests that early or severe AD and cutaneous sensitization 
to environmental allergens may lead to subsequent allergic disease at other epithelial 
barrier surfaces (e.g., gastrointestinal or respiratory tract).14 This hypothesis is supported 
by cross-sectional and longitudinal studies.  
 
TREATMENT OPTIONS15 
Topical steroids in atopic dermatitis 
 Topical steroids are currently the mainstay of treatment in association with 
moisturization. 
Immunomodulators in atopic dermatitis 
 
Tacrolimus (topical FK506) is an immune modulator that acts as a calcineurin 
inhibitor. In the US, Tacrolimus is available as an ointment and is indicated as a 
second-line therapy for the short-term and non-continuous chronic treatment of 
moderate-to-severe atopic dermatitis. Topical Tacrolimus Ointment is available in 
2 strengths, 0.1% for adults and 0.03% for adults and children aged 2 years and 
older.  
 
Pimecrolimus cream, 1% is a calcineurin inhibitor immunosuppressant indicated 
as second-line therapy for the short-term and non-continuous chronic treatment of 
mild to moderate atopic dermatitis in non-immunocompromised adults and 
children 2 years of age and older, who have failed to respond adequately to other 
topical prescription treatments, or when those treatments are not advisable. It is 
not indicated for use in children less than 2 years of age. It is available in the US 
as Elidel®.  
Other treatments in atopic dermatitis 
 
UV-A, UV-B, a combination of both, psoralen plus UV-A (PUVA), or UV-B1 
(narrow-band UV-B) therapy may be used. 
 
In patients with severe disease and particularly in adults, phototherapy, 
methotrexate (MTX), azathioprine, cyclosporine and mycophenolate mofetil have 
been used. 
 
Hydroxyzine and diphenhydramine hydrochloride 
 
Barrier repair moisturizers 
 
Bleach baths 
 
Probiotics 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 17 of 75 
 
 
 
ABOUT STUDY DRUG:  
Pimecrolimus cream, 1% is a calcineurin inhibitor immunosuppressant indicated as 
second-line therapy for the short-term and non-continuous chronic treatment of mild to 
moderate atopic dermatitis in non-immunocompromised adults and children 2 years of age 
and older, who have failed to respond adequately to other topical prescription treatments, 
or when those treatments are not advisable.16 
 
Dosage & Administration 
Patients should apply a thin layer of pimecrolimus cream, 1% to all affected skin areas 
twice daily. Continuous long-term use of pimecrolimus cream, 1% should be avoided, and 
application should be limited to areas of involvement with atopic dermatitis. The safety of 
pimecrolimus cream, 1% under occlusion, which may promote systemic exposure, has not 
been evaluated. Use of pimecrolimus cream, 1% with occlusive dressings should be 
avoided.16 
 
Warning and Precautions16 
Long-term safety of topical calcineurin inhibitors has not been established. Although a 
causal relationship has not been established, rare cases of malignancy have been reported 
in patients treated with topical calcineurin inhibitors, including Elidel® Cream, 1%. 
Therefore: 
 Continuous long-term use of topical calcineurin inhibitors, including Pimecrolimus 
Cream, 1%, in any age group should be avoided, and application limited to areas of 
involvement with atopic dermatitis.  
 Pimecrolimus Cream, 1% is not indicated for use in children less than 2 years of age. 
Pimecrolimus Cream, 1% should not be used in immunocompromised adults and 
children, including patients on systemic immunosuppressive medications.   
 If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients 
should be reexamined by their healthcare provider and their diagnosis be confirmed. 
 The safety of Pimecrolimus Cream, 1% has not been established beyond one year of 
non-continuous use. 
Common Side Effects  
Anaphylactic reactions, ocular irritation after application of the cream to the eye lids or 
near the eyes, angioneurotic edema, facial edema, skin flushing associated with alcohol use 
and skin discoloration. 
 
The use of Pimecrolimus Cream, 1% may cause local symptoms such as skin burning 
(burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common 
during the first few days of Pimecrolimus Cream, 1% application and typically improve as 
the lesions of atopic dermatitis resolve. 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 18 of 75 
 
 
 
Drug Interactions 
Potential interactions between Pimecrolimus Cream, 1% and other drugs, including 
immunizations, have not been systematically evaluated. Due to low blood levels of 
pimecrolimus detected in some patients after topical application, systemic drug interactions 
are not expected, but cannot be ruled out. The concomitant administration of known 
CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease 
should be done with caution. Some examples of such drugs are erythromycin, itraconazole, 
ketoconazole, fluconazole, calcium channel blockers and cimetidine. 
 
1.1 
Study Rationale 
Atopic dermatitis (eczema) is a common skin disorder that affects an estimated 35 million  
Americans, most often beginning in infancy and childhood. The introduction of topical  
calcineurin inhibitors for the treatment of atopic dermatitis addresses a clear unmet medical 
need by offering an important alternative to topical corticosteroids for patients, care-givers 
and physicians.  
 
Atopic dermatitis (AD) is a common and chronic inflammatory skin disease that affects a 
large part of the population. Although atopic dermatitis responds well to twice daily mid-
strength corticosteroids, it is not optimal to expose a patient to the long term use of topical 
corticosteroids because of their side effects like skin atrophy, striae, tachyphylaxis, adrenal 
suppression, bacterial infections, and contact allergies. Pimecrolimus Cream 1% is an 
alternative topical therapy for use in patients with mild to moderate atopic dermatitis.  
 
The purpose of the study is to establish the bioequivalence of Pimecrolimus Cream, 1% 
with that of Elidel® (pimecrolimus) Cream 1% in patients with AD using clinical 
endpoints. The double blind parallel group randomized placebo controlled study design 
was chosen as an appropriate study design based on the recommendations from draft 
guidance on bioequivalence study for Pimecrolimus Cream, 1% and from prescribing 
information for Elidel® (pimecrolimus) Cream 1%. 
 
This trial uses the dose that has proven efficacy and safety in various clinical trials and 
approved strengths by developed countries.  
 
As per FDA guidelines for Pimecrolimus, a placebo control arm is recommended to 
demonstrate that the test product and RLD are active and as a parameter to establish that 
the study is sufficiently sensitive to detect differences between products.  
 
The study will commence after a written approval obtained from the IRB at respective 
sites. The study will be conducted as per the ICH-GCP (step 5) Guidelines and in 
accordance with the Declaration of Helsinki, (Fortaleza, Brazil, October, 2013). 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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       Page 19 of 75 
 
 
1.2 
Risk-Benefit Assessment  
Long-term safety of topical calcineurin inhibitors has not been established. Although a 
causal relationship has not been established, rare cases of malignancy have been reported 
in patients treated with topical calcineurin inhibitors, including Elidel® Cream 1%.  
Participation in this study may or may not benefit the subjects. The expected potential 
benefits of Pimecrolimus include improvement in signs and symptoms of AD. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary Objective is to establish the bioequivalence between test drug, Pimecrolimus 
Cream, 1% with that of reference listed drug, Elidel® (pimecrolimus) Cream 1%, listed as 
RLD in the Orange Book (NDA No. N021302), in the treatment of mild to moderate AD, 
using the primary endpoint in the Per Protocol population, as detailed in FDA Draft 
Guidance on Pimecrolimus 1% Topical Cream dated March 2012. 
2.2 Additional Objectives 
 To establish superiority of each active treatment over the placebo using the primary 
endpoint in the modified intent to treat (mITT) population and Last Observation Carried 
Forward (LOCF) 
 To assess individual signs and symptoms of Atopic Dermatitis (i.e., erythema, 
induration/papulation, lichenification and pruritus) in each treatment group 
 To compare the safety and tolerability between the test and reference drugs 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Data Collection 
The study is a randomized, double blind, active and placebo controlled, prospective 
multicenter, comparative therapeutic equivalence study in subjects with mild to moderate 
AD. The study consists of three treatment arms. As per FDA recommendations, this study 
will be a bioequivalence study with a clinical endpoint in the treatment of mild to moderate 
atopic dermatitis comparing the test product versus the reference listed drug and vehicle 
control, each applied as a thin layer twice daily to the affected area(s) for 14 days (2 
weeks). The primary endpoint is the proportion of subjects with treatment success (a grade 
of clear or almost clear; a score of 0 or 1, within the treatment area) based on the 
Investigator’s Global Assessment of Disease Severity at the end of treatment (study Day 
15).  
 
A placebo control arm (vehicle of test product) is used to demonstrate that the test product 
and RLD are active and as a parameter to establish that the study is sufficiently sensitive to 
detect differences between products.  
  

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
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       Page 20 of 75 
 
 
The study duration for each subject is up to 32 days. There is a screening period of up to 
14 days and a treatment period of 14 (± 3) days.  
 
A total of 648 subjects will be included in the study. The subjects will be randomized into 
three groups in 1:1:1ratio. 
 
         The study consists of a total of 4 visits: 
 
1. V1-Screening Visit, if required (-up to 14 days).  If one is already using bland emollient 
(e.g Cetalphil® Lotion) continuously for 7 days, there is no need to be dispensed study 
bland emollient.  In such case, procedures of Visit 1 (V1) and Visit 2 (V2) can be 
combined in one visit, if desired. 
2. V2-Baseline and Randomization Visit (Day 1) 
3. V3-Interim Visit (Day 8 ± 3 days) 
4. V4-End of Therapy Visit (Day 15 ± 3 days) 
 
It is strongly preferred to have one evaluator for each of the visits per subject. A back up 
evaluator may be present at baseline in case the primary evaluator is unavailable at follow 
up. 
 
3.1.1 Visit 1 - Screening Visit (-up to 14 days) 
3.1.1.1 Informed Consent and Assent (Assent as applicable):  
During the informed consent and assent process, complete information about the study, 
study procedures, potential risk and benefits, alternative treatments and study drug 
information will be provided to the subject and/or guardian, as applicable.   The subject 
and/or guardian will have sufficient time to consider the study aspects and ask questions. If 
the subject and/or guardian agree to participate in the study, they will confirm such via the 
study specific, IRB approved informed consent and assent (if applicable) form(s) and will 
receive a copy of such signed consent/assent form. All study related procedures will be 
undertaken, after obtaining informed consent from the subjects or guardian as applicable. 
Please see section 4.4.3 for additional details. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 21 of 75 
 
 
3.1.1.2 Demographics: Data including gender, birth date, age, ethnicity and race, body weight, 
height, and use of birth control (for females) will be recorded.  
3.1.1.3 Medical History: Detailed medical history, including the start date of atopic dermatitis 
will be obtained. (Subject/guardian may verbally report signs and symptoms of atopic 
dermatitis with an onset at least 3 months prior.) 
3.1.1.4 Vital Signs: Body temperature, blood pressure, and pulse rate will be performed and 
recorded.  
3.1.1.5 Diagnosis: Subjects will undergo a clinical examination for the diagnosis of AD using 
the Hanifin Rajka criteria as outlined in Appendix I.   
3.1.1.6 Signs and Symptoms: Signs and Symptoms of Atopic Dermatitis will be scored per 
body region (Head and Neck; Trunk; Upper Limbs; Lower Limbs). Signs and 
symptoms of AD (i.e., erythema, induration/papulation, and lichenification) will be 
scored objectively and recorded using the scale mentioned in Appendix II. The 
average/typical severity per sign/symptom of all lesions in the reported body region will 
be recorded. 
Signs and Symptoms will be scored by the principal investigator or a qualified person 
delegated by the investigator. It is strongly preferred to have one evaluator for each of 
the visits per subject. A back up evaluator may be present at baseline in case the 
primary evaluator is unavailable at follow up.  
The evaluator will score the sign and symptom per body region as it presents itself at 
the current visit, and not in comparison to any other visit.  
3.1.1.7 Body Surface Area (BSA) Assessment: An overall body surface area involved with 
atopic dermatitis will be assessed. The palmar method (surface area of the palm 
including fingers and thumb is considered roughly equal to 1% of body surface area) is 
recommended for assessment. Subjects must have at least 5% BSA to be included in the 
study. 
3.1.1.8 Investigator’s Global Assessment (IGA) 
At each visit, the investigator will assess the overall status of the subject’s skin for AD 
using the IGA as per the scale noted in Appendix III. The IGA is a static assessment of 
how the subject’s overall skin is observed at the time of the current visit. Scores or 
severity from prior visits should not be considered. The IGA scores for each visit will 
be documented on the source and the Case Report Form. Subjects must have a score of 
mild to moderate AD on IGA in order to be enrolled in the study. 
3.1.1.9 Pruritus Assessment: Pruritus will be assessed by questioning the subject or the 
subject’s guardian regarding the intensity of overall itching/scratching/discomfort in the 
24 hours prior to the visit using the scale mentioned in Appendix II.  
3.1.1.10 Local Application Site Reactions: Subjects will also be assessed at screening for 
evaluation of pre-treatment local application site reactions. At each study visit, the 
investigator will evaluate any application site reactions with separate severity scores for 
dryness, burning/stinging, erosion, edema, and pain. At each visit the reactions will be 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 22 of 75 
 
 
noted and classified as mild, moderate or severe. Refer to Appendix IV Local Irritation 
Scale (LIS) for scoring of application site reactions. 
3.1.1.11 Physical Examination: Subjects will undergo a general physical examination. A 
detailed dermatological examination is required. A full body dermatologic examination 
will assess if the subject has any dermatologic malignancies. If the subject does have a 
dermatologic malignancy, they should not be enrolled. The following systems should 
also be evaluated: head, ears, nose, throat, eyes, central nervous system, respiratory, 
cardiovascular, gastrointestinal, and musculoskeletal. 
3.1.1.12 Concomitant Medication: History concomitant medications used will be obtained for 
at least the past 30 days. The start and stop date of medication use will be collected in 
addition to the reason for use. See section 6.3. 
3.1.1.13 Screening Criteria:  
Subjects will be evaluated to confirm that they meet the following screening criteria.  
 
Non-immunocompromised male or female aged 8 years and older 
 
Clinical diagnosis of mild to moderate atopic dermatitis (AD), as defined by the criteria of 
Hanifin and Rajka 
 
Failed to respond adequately to other topical prescription treatments for AD, or for whom those 
treatments are not advisable (The subject/guardian’s verbal report of failure to other topical 
prescription treatments for AD will be adequate.) 
 
An Investigator’s Global Assessment (IGA) of disease severity of mild or moderate at baseline 
(score of 2 or 3)  
 
Affected area of AD involvement at least 5% body surface area (BSA) 
 
Expected to be able to meet inclusion and exclusion criteria (See section 4.1.) after minimum 7 
days of continuous treatment with a bland emollient (e.g. Cetaphil® Lotion).  
3.1.1.14 Bland emollient distribution: Subjects who meet Screening Criteria will receive a 
bland emollient (e.g. Cetaphil® Lotion) to use at least once per day over seven days.  
Those subjects who have already been using bland emollient as standard of care don’t 
need study bland emollient dispensation. In such case, procedures of Visit 1 (V1) and 
Visit 2 (V2) can be combined in one visit, if desired. 
 
3.1.1.15 Schedule Next Visit: Subjects will be instructed on care until their next visit. Subjects 
should return the provided bland emollient at the next visit. Subjects should be advised 
that they will be evaluated again at the next visit to confirm their eligibility for study 
treatment. 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 23 of 75 
 
 
3.1.2 V2 - Baseline and Randomization Visit (Day 1) 
The study specific procedures to be evaluated at baseline visit are: 
3.1.2.1 Vital signs (See section 3.1.1.4) 
3.1.2.2 Signs and symptoms evaluation (See section 3.1.1.6) 
3.1.2.3 Body surface area assessment (See section 3.1.1.7) 
3.1.2.4 Investigator’s Global Assessment (IGA) (See section 3.1.1.8) 
3.1.2.5 Pruritus Assessment (See section 3.1.1.9.) 
3.1.2.6 Local application site reactions (pre-treatment) (See section 3.1.1.10) 
3.1.2.7 Urine pregnancy test will be conducted for female subjects of child bearing age prior 
to dosing.  
3.1.2.8 Adverse Event Assessment: Subjects will be questioned regarding adverse events in 
the form of non-leading questions (e.g., “How are you feeling?”).  All adverse events 
will be assessed and documented and will be managed as per standard of care. 
3.1.2.9 Concomitant medication (See section 3.1.1.12) 
3.1.2.10 Bland emollient collection: Subjects will return with the bland emollient used over the 
past 7 days. The site staff will collect such as the subject should not use it while being 
treated with the study treatment. 
3.1.2.11 Inclusion / Exclusion Criteria Evaluation (See section 4.1.) 
3.1.2.12 Randomization: Subjects fulfilling inclusion and exclusion criteria will receive study 
product from the next available sequential randomized kit which contains one of the 
following three treatment arms:  
 Test drug: Pimecrolimus Cream, 1% 
 Reference listed drug: Elidel® (Pimecrolimus) Cream 1%  
 Placebo:   Vehicle of the test drug cream without Pimecrolimus 
Each study product kit will contain three 100 gram tubes of study cream from the same 
randomized treatment arm. The kits will be packaged in a block size of 6. Each block 
will contain 2 kits of each treatment arm (2:2:2).  
3.1.2.13 Study Drug Dispensing: Study drug tube(s) will be dispensed to each subject by a staff 
member delegated by the PI. The study drug dispenser will not participate in any 
clinical assessments. The delegated staff member will tear off the perforated label prior 
to dispensing to the subject. The perforated portion of the label contains the blinded 
treatment arm underneath an occlusive layer. The perforated label with blinded code 
will remain at the clinic site in case of emergency. (See section 6.5 regarding 
emergency unblinding.) The delegated staff member will dispense at least one tube of 
study cream.  
Subjects (or guardians) will be instructed to apply a thin layer to the affected areas 
twice daily for 2 weeks (14 days). Subjects/guardians will be instructed about the 
following: When applying assigned study treatment after a bath or shower, the skin 
should be dry. Caregivers applying study treatment to a subject, or subject who is not 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
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       Page 24 of 75 
 
 
treating their hands should wash their hands with soap and water after applying study 
treatment. Caregivers who are pregnant, breastfeeding or may become pregnant should 
consult their physicians and follow their recommendations relating to the potential 
exposure to Pimecrolimus 1% Cream.  Appendix V Instructions for the Patients will be 
reviewed with the subject or guardian. 
The subject will be instructed to return all tubes to the study clinic. 
3.1.2.14 Diary Card Instructions / Schedule Next Visit: Subjects or their guardians will be 
issued a diary card with instructions to record all applied and missed doses. 
  
3.1.3 V3 - Follow up visit (Day 8 ± 3 days) 
Subjects will return to the study site on day 8 with diary card. During this visit, the 
following procedures and evaluations will occur. 
3.1.3.1 Signs and symptoms evaluation (See section 3.1.1.6) 
3.1.3.2 BSA assessment (See section 3.1.1.7) 
3.1.3.3 Investigator’s global assessment (IGA) (See section 3.1.1.8)  
3.1.3.4 Pruritus Assessment (See section 3.1.1.9.) 
3.1.3.5 Local application site reactions (See section 3.1.1.10)  
3.1.3.6 Adverse event assessment (See section 3.1.2.8) 
3.1.3.7 Concomitant medication (See section 3.1.1.9) 
3.1.3.8 Assessment of Compliance: The treatment diary card will be used to verify 
compliance. Compliance is defined in the term of study drug dose applied i.e. subject 
should apply the cream twice daily. The subjects should be using at least 75% and no 
more than 125% of expected study drug doses. If this is not the case, please decide if 
further study participation is recommended or if the subject should be re-instructed on 
proper study cream use and continued in the study. 
3.1.3.9 Study Drug Collection and Dispensing: The delegated staff member will collect the 
used tube(s) from the subject. The used tube may be re-dispensed to the subject until 
fully used. A new tube from the subject kit may be provided if necessary. The subject 
should be reminded to return to the study clinic with all tubes at the next visit. 
Accountability of the dispensing of tubes will be recorded. 
3.1.3.10 Diary Card Instructions / Schedule Next Visit (See section 3.1.2.13.) 
 
3.1.4 V4 - End of Therapy Visit (Day 15 ± 3 days) 
At the end of 2 weeks, subjects will return to the study site with treatment diary card for 
the end of therapy visit. During this visit, the following procedures and evaluations will 
occur. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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       Page 25 of 75 
 
 
3.1.4.1 Vital signs (See section 3.1.1.4) 
3.1.4.2 Urine pregnancy test (See section 3.1.2.6) 
3.1.4.3 Signs and symptoms evaluation (See section 3.1.1.6) 
3.1.4.4 BSA assessment (See section 3.1.1.7) 
3.1.4.5 Investigator’s global assessment (See section 3.1.1.8)  
3.1.4.6 Pruritus Assessment (See section 3.1.1.9.) 
3.1.4.7 Local application site reactions (See section 3.1.1.10) 
3.1.4.8 Adverse event assessment (See section 3.1.2.8) 
3.1.4.9 Concomitant medication (See section 3.1.1.9) 
3.1.4.10 Assessment of compliance (See section 3.1.3.8) 
3.1.4.11 Study Drug Collection: The delegated staff member will collect all used and unused 
tube(s) from the subject. 
3.1.4.12 Diary card Collection: The delegated staff member will collect the completed diary card 
from the subject.  
 
3.1.5 Unscheduled Visits and Early Discontinuation Visit  
An unscheduled visit is allowed at any time, for any reason, if in the investigator’s opinion 
it is warranted. If the unscheduled visit is due to an AE, the investigator will determine 
whether additional visits are needed.   
If a subject is discontinued from the study during an unscheduled visit, the unscheduled 
visit will be referred to as an Early Discontinuation Visit and all procedures scheduled for 
Visit 4 will be performed.  
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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       Page 26 of 75 
 
 
3.2 
Schedule of events 
 
Details 
Screening  
 
Baseline 
& 
Randomization  
Follow up  
 
End of therapy#  
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Week 
NA 
NA 
End 
of 
week 1 
End of week 2 
Day/s 
(0-14 
days) 
(Day 1) 
(Day 8) 
(Day 15) 
Window period 
0-14 days 
NA 
± 3 days 
± 3 day 
Informed consent 
X 
 
 
 
Detailed medical history 
X 
 
 
 
Physical examination## 
X 
 
 
 
Vitals** 
X 
X 
 
 
Establish diagnosis of AD  
X 
 
 
 
Urine pregnancy test* 
 
X 
 
X 
Inclusion and exclusion criteria 
X 
X 
 
 
Signs and Symptoms, Overall Body Surface 
Area, Investigator’s Global Assessment, 
Pruritus  
X 
X  
X 
X  
Application Site Reactions 
X 
X  
X 
X 
Dispense bland emollient 
X 
 
 
 
Collect bland emollient 
 
X 
 
 
Dispensing of study drugs  
 
X 
X 
 
Issue of patient diary 
 
X 
X 
 
 
 
 
 
 
Assessment of drug compliance 
 
 
X 
X 
Assessment of AEs 
 
X 
X 
X 
Review of concomitant medications 
X 
X 
X 
X 
Collection of used and unused study drug 
tubes and completed patient diary 
 
 
X 
X 
 
*Urine pregnancy test for females in child bearing potential age only 
** Pulse rate, blood pressure and body temperature  
# Schedule of events performed for end of treatment is applicable for early termination 
##Physical examination: Head, ears, nose and throat, eyes, central nervous system, respiratory system, cardiovascular 
system, gastrointestinal system, musculoskeletal system and a detailed dermatological examination 
 
 
3.3 
Evaluation Criteria 
3.3.1 Primary Endpoint: 
The primary endpoint is the proportion of subjects in each treatment group with treatment 
success (i.e., a grade of clear or almost clear; a score of 0 or 1, within all treatment areas) 
based on the Investigator’s Global Assessment of Disease Severity at the end of treatment 
(week 2 visit; study Day 15).  
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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       Page 27 of 75 
 
 
3.3.2 Secondary Endpoints:  
 Change in severity from baseline to week 2 (study Day 15) of four individual signs and 
symptoms of AD (i.e., erythema, induration/papulation, lichenification and pruritus) are 
considered supportive information 
 Application site reactions will be compared between treatment groups.  
 
3.3.3 Safety Endpoints: 
The type of AE(s), number of AE(s) and proportion of subjects with AE(s). 
Safety assessment through the incidences and severity of all adverse events (AEs) reported 
during the study will be summarized by treatment group. 
Subjects will be asked about any changes in their health since the prior visit. As such, AE(s) 
monitored using information volunteered by the subject and as observed by the PI will be 
categorized descriptively by total number of AE(s) based on their causality, as well as severity 
and compared between the 3 study arms. 
 
4 
STUDY POPULATION 
4.1 
Subject Selection 
4.1.1 Inclusion Criteria 
a) Non-immuno compromised male or female aged 8 years and older  
b) Clinical diagnosis of mild to moderate AD, as defined by the criteria of Hanifin and 
Rajka (Appendix I) 
c) Failed to respond adequately to other topical prescription treatments for AD, or for whom 
those treatments are not advisable. (The subject/guardian’s verbal report of failure to 
other topical prescription treatments for AD will be adequate.) 
d) A diagnosis of AD for at least 3 months (Subject/guardian may verbally report signs and 
symptoms of atopic dermatitis with an onset at least 3 months prior.)  
e) An Investigator’s Global Assessment (IGA) of disease severity of mild or moderate at 
baseline (score of 2 or 3)  
f) Affected area of AD involvement at least 5% body surface area (BSA)  
g) Treated with a bland emollient (e.g. Cetaphil® Lotion) for at least 7 days continuously 
h) Willing and able to give written informed consent (and assent as applicable) and willing 
to comply with the trial protocol 
i) If female of childbearing age, willing to use an acceptable form of birth control, that is 
stable for at least 3 months prior to baseline and throughout  the study. Acceptable forms 
of birth control include any of the following: (1) hormonal birth control, which must be 
stable for > 3months prior to baseline; (2) abstinence; subject must use condom plus 
spermicide, if becomes sexually active; (3) double barrier method, such as condom plus 
spermicide. 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 28 of 75 
 
 
4.1.2 Exclusion Criteria 
a) Females who are pregnant, breast feeding, or who wish to become pregnant during the 
study period  
b) Active cutaneous bacterial or viral infection in any treatment area at baseline (e.g., 
clinically infected atopic dermatitis, impetigo).  
c) Sunburn, extensive scarring or pigmented lesion(s) in any treatment area at baseline, 
which would interfere with evaluations  
d) History or presence of confounding skin conditions, e.g., psoriasis, rosacea, 
erythroderma, ichthyosis, or scabies.  
e) History or presence of Netherton’s Syndrome, immunological deficiencies or diseases, 
HIV, diabetes, malignancy, serious active or recurrent infection, clinically significant 
severe renal insufficiency or severe hepatic disorders  
f) Concurrent disease or treatment likely to interfere with the study treatment or 
evaluations 
g) Use within one month prior to baseline of  
 Oral or intravenous corticosteroids (Subjects on stable and continued doses of nasal,   
or inhaled corticosteroids for conditions other than atopic dermatitis may be enrolled 
at the investigator’s discretion when the investigator considers that such will not 
affect the efficacy or safety evaluations of the study. Ophthalmic corticosteroids are 
not excluded.) 
 UVA/UVB therapy 
 PUVA (psoralen plus ultraviolet A) therapy 
 Tanning booths 
 Nonprescription UV light sources 
 Immunomodulators or immunosuppressive therapies 
 Interferon 
 Cytotoxic drugs 
 Tacrolimus 
 Pimecrolimus  
h) Use within 14 days of baseline of 
 Systemic antibiotics 
 Calcipotriene or other vitamin D preparations 
 Retinoids  
i) Use within 7 days prior to baseline of 
 Systemic antihistamines (Subjects on a stable and continued dose of systemic 
antihistamines may be enrolled at the investigator’s discretion when the investigator 
considers that such will not affect the efficacy or safety evaluations of the study.) 
 Topical antibiotics 
 Topical corticosteroids  
 Other topical drug products  
 Probiotics 
j) Use within 24 hours prior to baseline of any topical product (e.g., sunscreens, lotions, 
creams) in the areas to be treated, except for bland emollient (e.g. Cetaphil® Lotion). 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 29 of 75 
 
 
k) Known allergy or hypersensitivity to pimecrolimus or any other component of the test 
product or RLD  
l) Not willing to minimize or avoid natural and artificial sunlight exposure during 
treatment  
m) Currently enrolled in an investigational drug or device study or used an investigational 
drug or investigational device treatment within 30 days prior to first application of the 
test article   
 
4.2 
Withdrawal of Subjects  
A subject will be discontinued from the study under the following circumstances: 
 If the subject requests discontinuation or withdraws consent  
 If a subject experiences a serious adverse event that renders them incapable of further 
participation in the study 
 Any entry criteria are violated and the violation becomes apparent during the course 
of the study 
In the event of withdrawal of a subject, the Investigator should assess the primary cause for 
the subject’s withdrawal and document this in the Case Report Form (CRF). As far as 
possible all subjects should undergo all end of therapy visit assessments. 
Subjects will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care. Any withdrawal must be fully documented in the 
CRF and source documents. The Investigator may also withdraw a subject at any time if 
this is considered to be in the subject’s best interest. 
The subject will be discontinued from the study if the inclusion and exclusion criteria are 
not met, has withdrawn the informed consent, has not been compliant with the study 
medication, or if the Investigator considered such in the best interest of the subject due to 
an AE.   
4.3 
Protocol Deviations and Violations 
After a subject is enrolled into the study and is noticed to be noncompliant with inclusion 
and exclusion criteria, the same will be documented as a Protocol Violation(s). 
During the conduct of the study process if deviation(s) are noticed from the norm 
mentioned in the protocol, the same will be documented as Protocol Deviation(s).  
The severity of the protocol deviation will be graded as minor if the deviation is not 
altering the integrity of the study plan or its safety and efficacy outcome, as major if the 
deviation is altering the integrity of the study plan or its safety and efficacy outcome. 
Sponsor reserves the right to terminate the study at any time and bears the responsibility for 
informing applicable regulatory authorities. Whereas the investigator reserves the right to 
discontinue the study for safety reasons at any time and bears the responsibility to inform 
the IRB.  

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 30 of 75 
 
 
All violations or deviations from the approved protocol would be documented. The 
following details will be captured: 
 Description of deviation 
 Date of deviation 
 Date reported  
In case of a deviation, the investigator will inform CRO/Sponsor and seek approval for 
continuation/discontinuation of the concerned subject. The investigator should not deviate 
from the protocol. CRO will not assume any resulting responsibility or liability from 
unapproved deviations. The IRB will be informed of protocol deviations by the 
investigator, according to applicable regulations and the IRB’s established procedures. 
4.4 Ethical and Regulatory Considerations 
4.4.1 Declaration of Helsinki and ICH-GCP  
The study will be conducted according to the protocol and to guidelines from the 
International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) in 
clinical trials and in compliance with all relevant local guidelines. Written approval will 
be obtained from the IRB prior to recruitment of subjects into the study and for all 
relevant material like the protocol, written subject information and informed consent 
form prior to recruitment into the study. 
 
4.4.2 Protocol Amendments 
Proposed amendments to the protocol and aforementioned documents would be 
submitted to the sponsor / CRO for review and approval, and then to the IRB, as 
necessary.  Amendments may be implemented only after a copy of the IRB approval 
letter has been transmitted to the sponsor. Amendments that are intended to eliminate an 
apparent immediate hazard to subjects may be implemented prior to receiving sponsor or 
IRB approval. 
  
4.4.3 Informed Consent and Assent 
The written consent and assent document will embody the elements of informed consent 
and assent as described in the Declaration of Helsinki, and will also comply with local 
regulations. The principles of informed consent will be implemented before protocol 
specified procedures or interventions are carried out. Information will be given in written 
form.  Subjects, their relatives, guardians, if necessary legal representatives will be given 
ample opportunity and time to discuss any details of the study with trained local 
personnel. 
The Investigator will ensure that the subject has been given enough information, both 
written and oral, about the nature, possible risks, benefits and procedures that the study 
will entail, in a language that the subject can understand. They will be informed that 
participation is purely voluntary and withdrawal at any time is possible and that 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 31 of 75 
 
 
non-participation in the study will in no way affect their medical treatment. Ample time 
will be given for questions, discussion, and consideration. 
Informed Consent Forms (ICF) / Assent will be, in a language fully comprehensible to 
the prospective subjects and be completed by the subject with assistance if requested 
from trained local personnel. Informed consent / assent shall be documented by the use of 
written consent form approved by the IRB and signed by the subject. The dated signature 
of the subject will be documented in the informed consent form.  The signature confirms 
the consent is based on information that has been understood.  The investigator, for 
possible inspection by regulatory authorities and/or CRO and regulatory compliance, will 
maintain each subject’s signed informed consent form. A copy of the informed 
consent/assent forms will be given to the subject/parent/guardian and the original will be 
retained in the records of the investigator. Site will take an acknowledgement from the 
subject in the source document that the subject has received a copy of the completed and 
signed ICF / Assent from the site.  
 
4.4.4 Patient Information Sheet  
All subjects will be provided a signed copy of the informed consent that details the study 
procedures, the risk and benefits of the study, emergency contact numbers, procedures to 
be followed, voluntary participation and withdrawal, compensation etc. The informed 
consent will be provided in a language fully comprehensible to the prospective subjects. 
 
5 
INVESTIGATIONAL PRODUCTS 
The investigational products to be used for this study are: 
 
 Test drug: Pimecrolimus Cream, 1% 
 Reference listed drug (RLD): Elidel® (Pimecrolimus) Cream 1% 
 Placebo: Vehicle cream 
5.1 Packaging, Labeling and Storage of Investigational Products 
Sponsor will supply the drugs used in this study. The drug will be manufactured complying 
with all the required regulations. The medication assigned to each subject will be 
determined by a randomization list generated in SAS by a statistician of the CRO. The 
investigational product will be labeled and packaged accordingly.  
The following general information will be provided on the clinical trial supply label: 
 
• 
Caution: New Drug - Limited by Federal (or United States) law to 
investigational use  
• 
Study CD-14-875  

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 32 of 75 
 
 
• 
Kit # XXXX  
• 
Elidel® Cream, or Pimecrolimus Cream 1%, or Placebo Cream 
• 
Renaissance Pharma, Inc.                                                                     
• 
Store at 25°C (77°F);. excursions permitted to 15oC to 30oC (59oF to 86oF) Do 
not freeze.  
• 
Keep out of the reach of children. 
• 
Rx only.  
• 
FOR TOPICAL USE ONLY.  
• 
NOT FOR OPHTHALMIC USE.  
• 
Apply a thin layer of cream to the affected skin twice daily. 
 
The investigational products would be stored in a secured area that is access controlled and 
remains within the storage conditions mentioned in the product label or specified by the 
sponsor. Access to investigational products will be provided only to the pharmacist or 
authorized personnel.  
5.2 
Retention of Study Records and Drug Samples 
Retention of study drug samples will be done as per the guidelines presented in ‘21 CFR 
320.38, 320.63’ and the FDA Guidance for Industry, “Handling and Retention of BA and 
BE Testing Samples.” Randomized kits for subject use will be randomly selected from the 
drug supplies received prior to dispensing to subjects. The sponsor will instruct separately 
on the amount of kits required to be kept as bioequivalence samples and will not be 
returned to the sponsor at any time. 
Records of bioequivalence testing will be maintained as per ‘21 CFR 320.36’ guidelines. In 
addition, the investigators will follow the procedures of 21 CFR 58 and ICH E6, “Good 
Clinical Practice: Consolidated Guideline”, for retention of study records and data in order 
to conduct their studies in compliance with Good Laboratory Practices (GLP) and Good 
Clinical Practices (GCP).  
5.3 Dispensing 
The investigational products will be dispensed as tubes from kits received and in ascending 
order by the pharmacist or designee to the investigator/ delegated personnel.  See section 
3.1.2.12. 
5.4 Drug accountability 
Relevant forms will be provided to the investigator and the pharmacist/designee to 
maintain accurate written records of all investigational product from sponsor, dispensed to 
subjects and returned. At the end of the study the drug (with the exception of 
bioequivalence retention kits) will be returned to the sponsor and reconciliation of records 
will be performed. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 33 of 75 
 
 
 
6 
TREATMENT OF STUDY DRUG 
6.1 
Randomization 
Randomization will be performed using SAS® package (SAS Institute Inc., USA, Version 
9.2 or higher). 
Study kit numbers will be randomly assigned to one of the three treatment arms based on a 
randomization code list.  The statistician will generate the randomization code list; a copy 
of this list will be shared with the IP handling team.  
  6.2 Dosing and Administration Information 
Dosage of the study drugs: Apply a thin layer of Cream to the affected skin twice daily. 
Rub in gently and completely. Subjects will be advised to wash their hands before and 
after application of drugs (unless the hands are being treated) and to avoid accidental 
exposure of drug with eyes, nose, mouth and other mucus membrane. The use of occlusive 
dressings or wrappings over the lesions should be avoided.   
At any point of time, if there are signs or symptoms of intolerability or toxicity, the 
investigator, based on his/her medical discretion may delay further treatment with study 
medication, or terminate the subjects from further study participation. At the time of check 
out for visit 2 the subjects will be provided with sufficient amount of study medication and a 
treatment diary card. Subjects will be instructed to continue with the medications twice daily 
and contact the site if any problem arises. The used and unused medication tubes will be 
collected at the end of therapy visit at Day 8 and Day 15 visits. 
6.3 
Concomitant Medication  
Current medications and any medications taken in the 30 days prior to the start of the study 
(Screening/Baseline, Visit 1) will be recorded as prior/concomitant medications with the 
corresponding indication and dose. Prescription and over-the-counter (OTC) medications, 
including NSAIDs will be recorded. All medications taken on a regular basis should be 
recorded prior to commencing the use of the test article. If concomitant medication is 
required during the study, subjects will be treated accordingly and a decision to continue or 
discontinue the subjects will be made by the investigator, based on the pharmacology and 
pharmacokinetics of the study product and the concomitant medication. All prescription 
and over the counter medications and vaccinations will be recorded and reported. 
 
Subjects may continue during the study with the same cleansing regimen that they had 
prior to the study. If not medically required, any changes in such should occur after the 
study completion. Subjects should not use any moisturizers while using the study 
medication. 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 34 of 75 
 
 
6.4 
Prohibited Medications and Treatments 
The following prescription and over-the-counter drug products, procedures and activities 
are prohibited during or the entire study:  
 Treatment for atopic dermatitis, other than assigned treatment 
 Topical or systemic corticosteroid, topical or systemic antibiotic, topical or 
systemic antifungal, topical antihistamine, immunosuppressive drugs (e.g. 
cyclosporine, methotrexate, or azathioprine), immunomodulator (e.g., tacrolimus), 
calcipotriene or other vitamin D preparations, retinoids, interferon  
o Subjects on stable and continued doses of nasal or inhaled corticosteroids 
for conditions other than atopic dermatitis may be enrolled at the 
investigator’s discretion when the investigator considers that such will not 
affect the efficacy or safety evaluations of the study.  
o Ophthalmic corticosteroids are not excluded. 
 Systemic antihistamines (Subjects on a stable and continued dose of systemic 
antihistamines may be enrolled and continued in the study at the investigator’s 
discretion when the investigator considers that such will not affect the efficacy or 
safety evaluations of the study.) 
 CYP3A inhibitor, e.g., erythromycin, itraconazole, ketoconazole, fluconazole, 
calcium channel blockers cimetidine, grapefruit or grapefruit juice  
 Topical product, other than assigned treatment (e.g., sun screen, new brand of 
cosmetic or cleanser, cream, lotion, ointment, or powder) applied on or near the 
treatment area(s) 
 Phototherapy, e.g., PUVA, UVA or UVB therapy 
 Bathing, showering or swimming within 3 hours of applying study treatment 
 Prolonged baths (i.e., longer than 5 minutes), excessive exposure to sunlight, or 
use of tanning booths, sunlamps or nonprescription UV light sources. 
 Bleach baths 
 Covering any treated area with bandage(s), dressing(s) or wrap(s) 
 Allowing the study treatment to come in contact with the eyes, nose, mouth, 
vagina, or rectum (mucous membranes).  
 Probiotics 
 Vaccinations 
 
Subjects who require prohibited interventions during the study will be withdrawn from the 
study. The use of concomitant and prohibited medications will be recorded on the 
concomitant medications section of the CRF.  
6.5 
Blinding and Unblinding 
Blinding: 
This study will be conducted as a double-blind study. Subjects in three arms will receive 
either study medications or placebo from subject kits (IMP Kit) which are identical 
and labeled in a manner to maintain the blind.  

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 35 of 75 
 
 
 
Subjects entering the study will be randomized in ratio of 1:1:1 for 3 treatment arms. 
 
Knowledge of the randomization list will be limited to the persons responsible for the 
creation of the randomization list, labeling, packing & distribution of the IMP’s. 
 
Randomization schedule will be generated based on the randomization request details 
and study design outlined in the protocol using SAS by the statistician & will be used 
to assign subjects to treatment groups.  Randomization schedule will be shared with the 
unblinded team involved in labeling, packaging, distribution of investigational products by the 
statistician. Unblinded personnel at packaging site will pack the IMP’s based on the 
randomization schedule. All the IMP’s will be identified with their respective kit 
numbers. 
 
To maintain the blinding through packaging: 
a. Packing material should be similar in colour and size. 
b. Labelling and packaging shall be performed as per the instructions given in the 
batch packaging document. 
c. Uniformity shall be maintained during assembly of labels on units, placement of 
units in the carton & sealing of the subject kits. 
 
IMP’s will be distributed to sites along with corresponding respective blinded labels 
containing the randomized treatment. 
 
Site personnel will pick the appropriate next numbered IMP kit and complete the 
details on the IMP tube label dispensed. Site personnel will dispense to the 
subject/guardian specific IMP tube(s) and instruct the subject/guardian on the IMP 
usage. Subjects/guardians are advised to return the used & unused IMP tubes. 
 
Unblinding:  
In the case of an emergency, the investigator may learn the treatment arm the subject 
was randomized to by removing the occlusive tube label remaining in the subjects 
records stored at the investigator’s site. Except in the circumstances detailed in 
unblinding section (breaking the blind), the code will not be broken. The CRO shall be 
contacted before unblinding whenever possible. 
 
Unblinding a subject’s treatment is restricted to emergency situations and should only be 
done 
to 
facilitate 
the 
proper 
care 
of 
a 
subject. 
In-case 
of 
emergency, 
investigator/authorized personnel will contact the CRO for unblinding the subjects by 
submitting the Un-blinding Request Form. The investigator should always attempt to 
contact the medical monitor/designee before breaking the blind. 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 36 of 75 
 
 
In case of safety issues, a medical emergency where the identity of investigational product 
is essential for medical management of a subject, or an AE/SAE that requires expedited 
reporting, shall a subject become un-blinded as to the treatment they are receiving. The un-
blinding provides the information about the identity of study drug provided to the subject 
as per the randomization list. 
 
If there is a medical emergency with a subject, the Study PI will take the necessary medical 
action to address the emergency first, and then send an unblinding form to the unblinded 
person at CRO. Unblinded person sends this form to the medical monitor/designee for 
approval. If the medical monitor or designee, after careful consideration of the 
circumstances, feels that there is a need to know which treatment group the subject is in, 
he/she will approve the unblinding by signing this form. This signed /approved form will 
be sent to the site, upon which investigator can unblind the subject.  Based on the 
authorization from the unblinded authority of CRO, the study PI will access to unblind the 
particular subject ID. 
 
Should the unblinding happen, the same treatment kit should be withdrawn from the 
subject. The kit should be quarantined with proper status on site. 
An account of all broken or unbroken codes will be collected by the monitor at or after site 
closure. 
 
Every attempt will be made to maintain the blinding throughout the study. In any case 
treatment code is broken; the un-blinding procedure must be adequately documented in the 
subject’s study file.  
 
Before breaking the blind of an individual subject’s blinded treatment, the investigator 
should have determined that the information is necessary, i.e., that it will alter the 
subject’s immediate management.  Every attempt will be made to maintain the blind 
throughout the study. 
If the treatment blind is broken, the investigator will record the reason and date, time on 
the appropriate CRF. If the blind is broken because of an AE/SAE, an AE/SAE form will 
be completed and informed to CRO.  Randomization data are kept strictly confidential, and 
are accessible only to authorized personnel, until unblinding of the trial after database lock.  
 
7 
SAFETY ASSESSMENT 
Adverse event (or adverse experience, AE): Any untoward medical occurrence in a subject 
or clinical investigation subject administered the test and reference product which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including for example an abnormal laboratory 
finding), symptom or disease temporally associated with the use of the test and reference 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 37 of 75 
 
 
product, whether or not considered related to the test and reference product. Each subject 
will be carefully monitored for the development of any adverse events. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and 
from signs and symptoms detected during each examination, observations of the study 
personnel or spontaneous reports from the subjects. 
 
Subjects will be monitored for safety and tolerability during the study and until the 
completion of the study. Any AEs, including either observed or volunteered problems, 
complaints, signs or symptoms, occurring during the course of the study or designated 
follow-up periods, must be recorded on the subject’s CRF. This would include AEs 
resulting from concurrent illnesses, reactions to concomitant medications.  
 
Each AE will be evaluated for duration, intensity, and relationship to (or association with) 
the study treatment (or other causes). Additionally, the actions taken (e.g., discontinuation 
of study medication, administration of treatment) and the resulting outcome of the AE 
should be indicated on the CRF.  
 
Any subject who is withdrawn from the study due to an adverse event should be followed 
until the outcome of the event is determined, and the investigator will prepare a written 
summary of the event and document the available follow-up information in the study 
documents.  
7.1 
Intensity of Adverse Events  
The intensity of the AEs will be graded according to the following criteria:  
a. Mild: Events that are usually transient; require only minimal treatment or therapeutic 
intervention; do not generally interfere with usual daily activities. 
b. Moderate: Events that are alleviated with additional specific therapeutic intervention; 
interfere with usual daily activities, causing discomfort but pose no significant or 
permanent risk or harm to the subject. 
c. Severe: Events that require intensive therapeutic intervention; interrupt usual daily 
activities, or significantly affect clinical status; pose a significant risk or harm to the 
subject and hospitalization may be required. 
7.2 
Causality Assessment  
Causality denotes the relation of the event to the study drug and is classified as follows by 
the investigator:  
a. ‘Definitely Related’ when the AE is clearly related to the study drug or 
intervention and is defined as meeting all the following conditions: 
Has a reasonable temporal relationship to the investigational agent(s) or research 
intervention; could not have been readily produced by the subject’s clinical state or have 
been due to environmental or other intervention; disappears or decreases with reduction in 
investigational agent or cessation of intervention; recurs with re-exposure to the 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
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applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 38 of 75 
 
 
investigational agent(s) (in case of studies involving multiple administration of drug); no 
alternative cause is present; follows a known pattern of response to intervention 
 
b. ‘Probably Related’ when the AE is likely related to the investigational agent(s) or 
intervention and is defined as meeting any three of the following conditions: 
Has a reasonable temporal relationship to the investigational agents(s) or research 
intervention; Could not readily have been produced by the subject’s clinical state or have 
been due to environmental or other intervention; Follows known or suspected pattern of 
response to intervention; Disappears or decreases with reduction in investigational agent or 
cessation of intervention; Alternative cause may be present 
 
c. ‘Possibly Related’ when it may be related to the investigational agent(s) or 
intervention and is defined as meeting any two of the following conditions: 
Has a reasonable temporal relationship to the investigational agents(s) or research 
intervention; Could not have been produced readily by the subject’s clinical state or have 
been due to environmental or other intervention; Follows known or suspected pattern of 
response to intervention; Alternative cause is present 
 
d. ‘Unlikely Related’ when it is doubtfully related to the investigational agent(s) or 
intervention and is defined as meeting any two of the following conditions: 
Has a temporal relationship to the investigational agents(s) or research intervention; Could 
readily have been produced by the subject’s clinical state or have been due to 
environmental or other intervention; Does not follow a known pattern of response to 
intervention; Does not reappear or worsen with reintroduction of intervention (in case of 
studies involving multiple administration of drug); Alternative cause is present 
 
e. ‘Not related’ when the AE is clearly not related to the investigational agent(s) or 
intervention and is defined as meeting all of the following conditions: 
Has no temporal relationship to the investigational agents(s) or research intervention; 
Follows no known or suspected pattern of response; Alternative cause is present. 
7.3 
Frequency 
i.If the same type of AE occurs only once will be documented as ‘Single Episode’. 
ii.If the same type of AE occurs more than once, will be documented as ‘Recurrent’. 
iii.If an AE is still continuing (not resolved) will be documented as ‘Continuous Event’. 
 
7.4 
Serious Adverse Events  
A serious adverse event (SAE) is defined as any event that suggests a significant clinical 
hazard, contraindication, side effect, or precaution. This includes any event which:  
- Results in death. 
- Life threatening. 
- Results in persistent or significant disability / incapacity. 
- Requires repeated hospitalization or prolongation of existing hospitalization.  

Protocol Number: CD-14-875 
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Dated  14 Oct 2016 
 
CONFIDENTIAL 
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       Page 39 of 75 
 
 
- Results in congenital anomaly / birth defect. 
- Is an important medical event which includes other events, based on medical judgment, 
which jeopardize the subject and require medical or surgical intervention to prevent one of 
the outcomes listed above.  
 
The investigator or a suitable designee will record all adverse events observed, either 
queried or spontaneously reported by the subject(s).  
The Serious Adverse Event Reporting will be in compliance with the local legal and 
regulatory requirements. 
 
The adverse events will be followed until resolution or to the satisfaction of the 
investigator(s) unless the subject’s is deemed lost to follow-up. 
 
8 
DATA HANDLING, RECORDING AND QUALITY ASSURANCE 
8.1 
Data Handling and Record Keeping 
The investigator must ensure that proper source documentation for all activities performed 
in relation to this study are diligently maintained and securely kept.  The investigator will 
transfer all relevant data from the source documents to the CRF as stipulated in this study 
protocol and his/her signature on the CRF guarantees the completeness and integrity of 
these data.  All records and documents pertaining to the study will be maintained as 
documented for at least a period of 2 years following the date a marketing application is 
approved for the indication for which it is being investigated; or if no application is to be 
filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities are notified. These documents 
should be retained for a longer period if required by an agreement with the sponsor. In 
such an instance, it is the responsibility of the sponsor to inform the investigator / 
institution as to when these documents no longer need to be retained. 
8.2 
Access to Source Data 
The investigator must ensure that institutional regulations and the informed consent form 
clearly permit study-related monitoring, audits, IRB review, and regulatory inspections 
providing direct access to source data and documents by the sponsor, the sponsor’s 
delegates, the US FDA, local regulatory bodies, or the IRB. 
8.3 
Source Data Verification and on-site Audits 
Besides regular source data verification by the study monitor, regulatory authorities, the 
IRB, and/or the sponsor’s personnel or designate may request access to all source 
documents, CRFs, and other study documentation for on-site audit inspections.  The 
Investigator, who must provide support at all times for the activities, must guarantee direct 
access to these documents. 

Protocol Number: CD-14-875 
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CONFIDENTIAL 
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       Page 40 of 75 
 
 
8.4 
Monitoring 
The study will be monitored by the CRO, Sponsor, and/or Sponsor Delegate.    Monitoring 
may be done by personal visits by the site monitor who will review the CRFs and source 
documents, and/or by frequent communications (letter, email, telephone, and fax).  The site 
monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements. 
8.5 
Data Management 
Data management will ensure that clinical parameters collected on each subject throughout 
the study are as complete, accurate and of the highest quality possible and that the 
procedures are performed in accordance with all applicable guidelines and regulations 
(including ICH guidelines). CRFs, questionnaires and treatment diaries shall be made 
available to the data management site.   
9 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The following information provides an overview of the issues related to the analysis of 
data collected during the study.  
9.1 
Determination of Sample Size 
The primary statistical analysis of interest is the proportion of subjects in the PP population with a 
clinical response of treatment success (at least an Investigator’s Global Assessment of 
Clear or Almost Clear) at study Day 15. Considering the pivotal studies of the Reference 
Listed Drug, it is assumed that the active test and RLD will have approximate success rates 
at 21% and the vehicle cream will have an approximate success rate of 9%. A sample size of 
184 subjects per group will provide at least 99% power to demonstrate bioequivalence (i.e., the 
90% confidence interval (Yates’ continuity -corrected) of the absolute difference between the test 
and reference composite success rates is within a defined equivalence range [-0.20, +0.20]). Assuming the 
conversion rate from mITT to PP will be about 90%, 205 subjects in each of the groups of the mITT 
population will provide at least 85% power to demonstrate superiority of active over placebo. Under the 
above assumptions, the overall global study power to demonstrate bioequivalence and superiority is 
estimated to be approximately 85%. To allow for about 5% of subjects who may drop out from the 
study or are otherwise non-evaluable, approximately 648 subjects will be enrolled (216 in 
each active group and 216 in the placebo group). 
 
9.2 
Statistical Methods 
9.2.1 Study Population 
9.2.1.1 Intent-to-treat (ITT) 
The safety population includes all randomized subjects who applied the study 
product at least once.  
 

Protocol Number: CD-14-875 
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       Page 41 of 75 
 
 
9.2.1.2 Modified Intent-to-treat (mITT) 
The mITT population includes all randomized subjects who met all inclusion / 
exclusion criteria, applied at least one dose of assigned product and returned for 
at least one post-baseline evaluation visit.  
 
9.2.1.3 Per Protocol (PP) 
The PP population includes all randomized subjects who met all 
inclusion/exclusion criteria, applied 75% to 125% of the assigned product for 
the specified duration of the study, did not miss the scheduled applications for 
more than 3 consecutive days, and completed the evaluation within the 
designated visit window (+/- 3 day) with no protocol violations that would affect 
the treatment evaluation. The subject’s compliance will be verified by the use of 
subject diaries, and the protocol violations that would affect the treatment 
evaluation.  
 
9.2.2 Statistical analysis 
9.2.2.1 Efficacy Analysis 
Primary Efficacy Parameter: 
Equivalence Analysis  
The 90% confidence interval for the difference in success proportions between test and 
reference treatment must be contained within [-0.20, +0.20] in order to establish 
equivalence.  
The compound hypothesis to be tested is:  
H0:  PT - PR < -0.20 or PT - PR > 0.20  
 
Versus  
HA:  -0.20 ≤ PT - PR  ≤ 0.20  
where PT = success rate of test treatment and  PR = success rate of reference treatment.  
Let  
nT = sample size of test treatment group Tn  
cnT = number of successes in test treatment group Tn  
nR = sample size of reference treatment group Rn  
cnR = number of successes in reference treatment group Rn  
PT = cnT / nT , PR = cnR / nR,  
and se = ( PT (1 - PT ) / nT + PR (1 -  PR ) / nR ) ½.  
The 90% confidence interval for the difference in proportions between test and reference 
will be calculated as follows, using Yates’ correction:  
L = (PT - PR) – 1.645 se – (1/ nT  + 1/ nR ) / 2  
U = (PT - PR) + 1.645 se + (1/ nT  + 1/ nR ) / 2  

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       Page 42 of 75 
 
 
We reject H0 if L <  -0.20 or  U > 0.20  
Rejection of the null hypothesis H0 supports the conclusion of equivalence of the two 
products.  
 
Superiority of the treatment:  
Superiority of both treatments over the placebo will be evaluated for mITT population at 
week 2. Tests for superiority of each active treatment over the placebo will be conducted 
using two-sided Fisher exact test at the 5% level of significance.  
The efficacy analysis will be conducted in mITT population and Last Observation 
Carried Forward (LOCF) approach will be used to impute for missing data in the mITT 
population.  
 
Secondary Efficacy & Safety Parameters:  
The change in severity from baseline to week 2 (study Day 15) of four individual signs 
and symptoms of AD (i.e., erythema, induration/papulation, lichenification and pruritus; 
see Table 2) will be evaluated as supportive information. 
The type of AE(s), number of AE(s) and proportion of subjects with AE(s) 
Safety assessment through the incidences of all adverse events (AEs) reported during the 
study and summarized by treatment group. 
 
 
Main Variables Assessed for Safety & Tolerability:  
AE(s) monitored using information volunteered by the subject and as observed by the PI 
will be categorized descriptively by total number of AE(s) based on their causality, as 
well as severity and compared between the 3 study arms. 
 
9.2.2.2 Safety Analysis 
Subjects will be monitored for safety and tolerability throughout the study (as explained 
above) and until the completion of the study.  
Adverse events will be tabulated for each and summary statistics will be statistically 
evaluated using Fisher’s exact test. 
9.3 
Presentation of Results 
Summary statistics will be presented for actual values and changes from the baseline. If the 
values are raw measurements or derived totals from raw measurements, then the statistical 
measures; mean and median will be presented to single decimal place more than the 
maximum number of decimal places to which the raw measurements are collected. 
Minimum and maximum will be presented to the same number of decimal places as the 
maximum of decimal places to which the raw measurements are collected. 

Protocol Number: CD-14-875 
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CONFIDENTIAL 
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       Page 43 of 75 
 
 
Standard deviation (SD) will be presented two decimal places more than the raw data. If 
the values are derived values then an extra decimal place will be added to all these 
measures. Percentages will always be presented in two decimal place. Zero counts will be 
reported as '0' with '0.0%' percentages and 100 percentages will be presented as 100.00% 
counts will be presented as integer values.  
Confidence intervals and percentiles will be presented with two decimal place. All p-
values will be reported to four decimal points and p-values less than 0.0001 will be 
reported as <0.0001. 
 
Interim Evaluation: 
No interim evaluation is planned for this study.  
 
9.4 
Handling of Dropout or Missing Data 
No missing imputations will be done for either efficacy or safety parameters estimations. 
Subjects whose condition worsens and require alternate or supplemental therapy for the 
treatment of their AD during the study should be discontinued, included in the PP 
population analysis as treatment failures, and provided with effective treatment. Subjects 
discontinued early for other reasons should be excluded from the PP population, but 
included in the mITT population, using Last Observation Carried Forward (LOCF). For 
example, subjects who develop a skin infection in the treated area requiring treatment 
should be discontinued, excluded from the PP population, but included in the mITT 
population, using LOCF.   
10 STUDY ADMINISTRATIVE PROCEDURES 
10.1 Regulatory Authority Approval 
The Sponsor / CRO will obtain approval to conduct the study at each site from the relevant 
local regulatory authorities, in accordance with applicable regulatory requirements prior to 
initiating a site. The study will be performed in compliance with ICH-GCP guidelines and 
local guidelines. 
10.2 Confidentiality of Subjects 
The records of the subject’s medical history, physical examination, clinical examination 
results and any other information or data generated during the study will be made available 
to the sponsor or its designees (auditors, monitors), ethics committee, and will be made 
available to the local drug regulatory bodies and other participating countries, formulary 
committees of hospitals, at the opinion of sponsor. A pre-condition for entry into this study 
will be subject’s agreement to release all of the above-mentioned documentation and data 
for any lawful purpose.  

Protocol Number: CD-14-875 
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CONFIDENTIAL 
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written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 44 of 75 
 
 
10.3 Delegation of Investigator Responsibilities 
The investigator will ensure that all persons assisting with the trial are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their trial 
related duties and functions. The investigator should maintain a list of co-investigators and 
other appropriately qualified persons to whom he or she has delegated significant trial 
related duties.  
10.4 Study Termination and Site Closure 
Upon completion of the study, the CRO will conduct the following activities in 
conjunction with the Investigator or site staff, as appropriate, including but not limited to 
the following: 
 Return of all study data to the sponsor or sponsor authorization for safe and 
adequate disposition by the site 
 Data queries 
 Review of site study records for completeness 
 
In addition, the sponsor reserves the right to temporarily suspend or prematurely 
discontinue this study at any time for reasons including, but are not limited to, ethical 
issues or severe non-compliance.  If the sponsor determines such action is needed, the 
sponsor will discuss this with the Investigator (including the reasons for taking such 
action) at that time.  When feasible, the sponsor will provide advance notification to the 
Investigator of the impending action prior to it taking effect. The sponsor will also inform 
the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action.  The Investigator must inform the IRB promptly and provide the reason for 
the suspension or termination. If the study is prematurely discontinued, all study data must 
be returned to sponsor. 
10.5 Archiving and Record Retention 
The investigator will maintain adequate records for the study, including medical records, 
laboratory reports (if any), signed informed consent forms, drug disposition records, 
correspondence with the IRB, adverse event reports and information regarding subject 
discontinuation and completion of the study. Laboratory investigation reports, logbooks 
and data forms based on in-house procedures will be the primary data collection 
documents for this study.  
Study documents should be retained for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or planned 
marketing applications in an ICH region (that is at least 15 years) or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the product by 
Sponsor. The Investigator/institution should take measures to prevent accidental or 
premature destruction of these following documents. 
 
 Signed informed consent documents for all subjects 

Protocol Number: CD-14-875 
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CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
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       Page 45 of 75 
 
 
 Subject identification code list, screening log (if applicable), and enrolment log 
 Record of all communications between the Investigator and the IRB 
 Composition of the IRB 
 Record of all communication between the Investigator and the CRO 
 List of co-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles 
in the study and their signatures 
 Copies of CRFs, questionnaires, treatment diaries and of documentation of 
correction for all subjects 
 All other source documents (subject records, hospital records, laboratory records, 
etc.) 
 All other documents deemed relevant for this study from those listed in Section 8 
of the ICH consolidated guideline on GCP (Essential Documents for the conduct 
of a clinical trial) 
 
Normally, these records will be held in the investigator’s archives.  If the Investigator is 
unable to meet this obligation, he or she must ask the sponsor for permission to make 
alternative arrangements.  Details of these arrangements must be documented. 
10.6 Study Report and Publication Policy 
The publication policy will be at the sole discretion of the Sponsor. If published the 
subjects identity will not be revealed.   
 
11 REFERENCES  
1. Luger TA, Van Leent E, Graeber M, Hedgecock S, Thurston M, Kandra A,  
Berth-Joness J, Bjerke J, Christophers E, Knop J, et al. SDZ ASM 981: An emerging safe 
and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-94 
 
2. Van Leent EJM, Graber M, Thurston M, Wagenaar A, Spuls Phi, Bos JD. Effectivenesss 
of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. 
Arch Dermatol 1998; 134:805-9 
  
3. Van Leent E, Ebelin ME, Burtin P, Dorobek B, Spuls P, Bos JD. Low systemic exposure 
after repeated topical application of pimecrolimus (Elidel, SDZZ ASM 981) in patients 
with atopic dermatitis. Dermatology 2002; 204:63-8 
  
4. Hanifin JM, Rajka G . Diagnostic features of atopic dermatitis. Acta Derm Venereoll 
(Stockh) 1980; Suppl. 92:44-7 
  

Protocol Number: CD-14-875 
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CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
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       Page 46 of 75 
 
 
5. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area 
and severity index (EASI): Assessment of reliability in atopic dermatitis. EASI Evaluator 
Group. Exp Dermatol 2001; 10(1): 11-8 
 
6. Atopic dermatitis: A practice parameter update 2012 Lynda Schneider, MD, Stephen 
Tilles, MD, Peter Lio, MD, Mark Boguniewicz, MD, Lisa Beck, MD, Jennifer LeBovidge, 
PhD, and Natalija Novak, MD  
https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%
20Parameters/Atopic-dermatitis-2013.pdf  
 
 7. ISRN Allergy Volume 2014 (2014), Article ID 354250, Review Article, Atopic 
Dermatitis: Natural History, Diagnosis, and Treatment Simon Francis Thomsen 
Department of Dermatology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen 
NV, 
Denmark, 
Published 
2 
April 
2014 
http://www.hindawi.com/journals/isrn/2014/354250/  
 
8. FDA draft guidance on Pimecrolimus; Recommended Mar 2012 
 
9. Safety and Efficacy of Pimecrolimus in Atopic Dermatitis: A 5-Year Randomized Trial 
Bardur Sigurgeirsson, Et al; PEDIATRICS Volume 135, number 4, April 2015 
 
 10. Eichenfield LF, Lucky AW, Langley RG, Lynde C, Kaufmann R, et al. (2005) Use of 
pimecrolimus cream 1% (Elidel) in the treatment of atopic dermatitis in infants and 
children: the effects of ethnic origin and baseline disease severity on treatment outcome. 
International journal of dermatology 44: 70–75. doi: 10.1111/j.1365-4632.2004.02234.  
 
11. Wellington K, Noble S (2004) Pimecrolimus: a review of its use in atopic dermatitis. 
American journal of clinical dermatology 5: 479–495. doi: 10.2165/00128071-200405060-
00013 
 
12. Papp KA, Werfel T, Folster-Holst R, Ortonne JP, Potter PC, et al. (2005) Long-term 
control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a 
two-year study. Journal of the American Academy of Dermatology 52: 240–246. doi: 
10.1016/ j.jaad. 2004.09.016 
 
13. Elidel (pimecrolimus) Cream 1% NDA 21-302 Briefing Document: FDA Pediatric 
Advisory Committee Meeting: Office of Pediatric Therapeutics: Meeting date: Tuesday, 
February 
15, 
2005; 
Release 
Date: 
January 
25, 
2005 
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4089b2_03_04_Elidel%20Novartis%20Briefing%20Bookredacted.pdf  

Protocol Number: CD-14-875 
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CONFIDENTIAL 
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       Page 47 of 75 
 
 
 
14. Atopic Dermatitis: Author: Brian S Kim, MD; Chief Editor: William D James, MD 
 
http://emedicine.medscape.com/article/1049085-overview  
 
15.  Atopic Dermatitis Treatment & Management, Author: Brian S Kim, MD; Chief 
Editor: William D James, MD  
http://emedicine.medscape.com/article/1049085-treatment  
 
16. Elidel Package Insert Valeant Pharmaceuticals North America LLC; Revised 08/2014 
 
 
 

Protocol Number: CD-14-875 
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       Page 48 of 75 
 
 
12 APPENDICES 
12.1 Appendix I: Hanifin and Rajka Criteria 
The diagnosis of atopic dermatitis using the Hanifin and Rajka criteria requires that 
subjects have the following: at least 3 of the 4 major criteria and 3 of the 23 minor criteria. 
 
Major criteria: At least 3 or more of the following 
 Pruritus 
 Typical morphology and distribution 
o Facial and extensor involvement in infants and children 
o Flexural lichenificaiton or linearity in adults 
 Chronic or chronically relapsing dermatitis 
 Personal or family history of atopy 
o Allergic rhinitis 
o Asthma 
o Atopic dermatitis 
 
Minor criteria: At least 3 or more of the following 
 Anterior neck folds 
 Anterior subcapsular cataracts 
 Chelitis 
 Course influenced by environmental or emotional factors 
 Dennie-Morgan infraorbital fold 
 Early age onset 
 Facial pallor or facial erythema 
 Food intolerance 
 Keratoconus 
 Ichthyosis, palmar hyperlinearity, or keratosis pilaris (Please note that ichthyosis is 
exclusionary.) 
 Immediate skin test reactivity 
 Intolerance to wool and lipid solvents 
 Itch when sweating 
 Nipple eczema 
 Orbital darkening 
 Perifollicular accentuation 
 Pityriasis alba 
 Raised serum IgE 
 Recurrent conjunctivitis 
 Tendency toward cutaneous infections (especially S. aureus and herpes simplex) or 
impaired-cell immunity 
 Tendency toward nonspecific hand or foot dermatitis 
 White dermatographism or delayed blanch 
 Xerosis 

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       Page 49 of 75 
 
 
 
12.2 Appendix II: Scoring of signs and symptoms in AD 
Individual Signs and Symptoms of AD 
Sign and Symptom 
Score 
Category 
Definition 
Erythema 
0 
None 
No erythema present  
1 
Mild 
Slight erythema: very light-pink  
2 
Moderate 
Dull red, clearly distinguishable  
3 
Severe 
Deep/dark red 
Induration/ 
Papulation 
0 
None 
None  
1 
Mild 
Slightly perceptible elevation  
2 
Moderate 
Clearly perceptible elevation but not extensive  
3 
Severe 
Marked and extensive elevation 
Lichenification 
0 
None 
None  
1 
Mild 
Slight thickening of the skin discernible only by 
touch 
and 
with 
skin 
markings 
minimally 
exaggerated  
2 
Moderate 
Definite thickening of the skin with skin marking 
exaggerated so that they form a visible criss-cross 
pattern  
3 
Severe 
Thickened indurated skin with skin markings 
visibly portraying an exaggerated criss-cross 
pattern 
Pruritus 
0 
None 
None 
1 
Mild 
Occasional, slight itching/scratching 
2 
Moderate 
Constant 
or 
intermittent 
itching/scratching/discomfort 
which 
is 
not 
disturbing sleep 
3 
Severe 
Bothersome itching/scratching/discomfort which 
is disturbing sleep  
 
 
 
 
 
 
 

Protocol Number: CD-14-875 
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       Page 50 of 75 
 
 
12.3 Appendix III: IGA Scoring 
 
Investigator Global Assessment (IGA) of Disease Severity 
Score 
Category  
Definition  
0 
Clear  
Minor residual discoloration, no erythema or induration / 
papulation, no oozing / crusting  
1 
Almost Clear  
Trace faint pink erythema with almost no induration / 
papulation and no oozing / crusting  
2 
Mild disease  
Faint pink erythema with mild induration / papulation and no 
oozing / crusting  
3 
Moderate disease  Pink-red erythema with moderate induration / papulation and 
there may be some oozing / crusting  
4 
Severe disease  
Deep / bright red erythema with severe induration / papulation 
with oozing / crusting  
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number: CD-14-875 
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       Page 51 of 75 
 
 
12.4 Appendix IV: Local Irritation Scale (LIS) 
 
 
Dryness 
 
0 
None 
 
 
1 
Mild 
 
2 
Moderate 
 
3 
Severe 
 
Stinging/burning 
 
0 
None 
 
 
1 
Mild 
 
2 
Moderate 
 
3 
Severe 
 
Erosion 
 
0 
None 
 
 
1 
Mild 
 
2 
Moderate 
 
3 
Severe 
 
Edema 
 
0 
None 
 
 
1 
Mild 
 
2 
Moderate 
 
3 
Severe 
 
Pain 
 
0 
None 
 
 
1 
Mild 
 
2 
Moderate 
 
3 
Severe 

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12.5 Appendix V: Instructions for the patients 
WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS HAS 
NOT BEEN ESTABLISHED 
Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and 
lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including 
ELIDEL Cream, 1%. 
Therefore:  
 
Continuous long-term use of topical calcineurin inhibitors, including ELIDEL Cream, 1%, in 
any age group should be avoided, and application limited to areas of involvement with atopic 
dermatitis.  
 
ELIDEL Cream, 1% is not indicated for use in children less than 2 years of age. 
                                                                                                                                                                              
ELIDEL Cream, 1% may cause serious side effects. It is not known if ELIDEL Cream, 1% is 
safe to use for a long period of time. A very small number of people who have used ELIDEL 
Cream, 1% have had cancer (for example, skin or lymphoma). However, a link with ELIDEL 
Cream, 1% use has not been shown. Because of this concern: 
 
A patient should not use the study cream continuously for a long time. 
 
Study cream should be used only on areas of skin that have eczema. 
 
A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light 
therapy during the study. 
 
A patient should limit sun exposure during the study and even when the study cream is 
not on the skin. If a patient needs to be outdoors after applying the study cream, the 
patient should wear loose fitting clothing that protects the affected area from the sun. The 
physician should advise the patient about other types of protection from the sun. It is not 
known how the study cream may affect your skin with exposure to ultraviolet light. 
 
A patient should not cover the affected skin with bandages, dressings or wraps. A patient 
can wear normal clothing. 
 
The study cream is for topical use on the skin only. Do not get the study cream in your 
eyes, nose, mouth, vagina, or rectum (mucous membranes). If you get the study cream in 
any of these areas, burning or irritation can happen. Wipe off any study cream from the 
affected area and then rinse the area well with cold water. The study cream is for external 
use only.  
 
Wash hands before using the study cream. When applying the study cream after a bath or 
shower, the skin should be dry. 
 
Apply a thin layer of the study cream only to the affected skin areas, twice a day, as 
directed by the physician. Use the smallest amount of cream needed. 
 
A patient should not bathe, shower or swim for at least 3 hours after applying the study 
cream. This could wash off the cream.  In addition, please avoid prolonged bathing (i.e. 
longer than 5 minutes). 

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Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 53 of 75 
 
 
 
If you apply the study cream to another person, or if you have eczema and are not treating 
your hands, it is important for you to wash your hands with soap and water after applying 
the cream. This should remove any cream left on your hands. Caregivers who are pregnant, 
breastfeeding or may become pregnant should consult their physicians and follow their 
recommendations relating to the potential exposure to Pimecrolimus 1% Cream. 
 
Do not cover the skin being treated with bandages, dressings or wraps. You can wear 
normal clothing. 
 
Do not swallow the study cream. If you do, call your doctor. 
 
Do not use the study cream if you are allergic to pimecrolimus or any of the ingredients 
in cream.  
 
Avoid using the study cream on skin areas that have cancers or pre-cancers. 
 
Call your doctor if your symptoms get worse.  
Before using the study cream, tell your doctor about all of your medical conditions, including if 
you:  
 
have a skin disease called Netherton's syndrome (a rare inherited condition) 
 
have any infection on your skin including chicken pox or herpes 
 
have been told you have a weakened immune system 
 
are pregnant or plan to become pregnant. It is not known if the study cream will harm 
your unborn baby. 
 
are breastfeeding or plan to breastfeed. It is not known if the study cream passes into your 
breast milk.  
Tell your doctor about all the medicines you take, including prescription and over-the-counter 
medicines, vitamins, and herbal supplements. In addition, please avoid eating grapefruit or 
drinking grapefruit juice while using the study medication as it may interfere with its activity.  
Tell your doctor about all the skin medicines and products you use. 
 
Store at 25°C (77°F); excursions permitted to 15oC to 30oC (59oF to 86oF). 
 Do not freeze the study cream. 
 Keep the study cream out of the reach of children.  
Please return for study visits at the doctor’s office as follows:  
Visit 2 on ______________at ____________ am  
Visit 3 on ______________at ____________ am  
Visit 4 on ______________ at ____________am  
Please return with your study diary and any tubes of study cream that you may have. 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 54 of 75 
 
 
12.7 Appendix VI:  Revision History Dated 14Oct2016 
Section  
Revisions  
Title Pages 
CRO and Sponsor contact information was updated 
Title Pages and Protocol 
Approval Signature Pages 
Administrative Structure section was deleted and will be 
replaced with the Contact List to be distributed separately 
Investigator Protocol 
Agreement 
Investigator Protocol Agreement was updated to include 
mention of training and experience for delegation 
consideration as well as Ethics Committee as one of the 
bodies that may have access to the study information 
Study Synopsis and  
Section 3.1 
Screening criteria clarified: 
 
using Cetaphil for minimum of 7 days 
continuously  
 
as well as having affected area of AD 
involvement at least 5% body surface area 
(BSA), removing requirement of having this 
criteria be met at baseline 
 
Study Synopsis and  
Section 3.1 
Inclusion/Exclusion criteria was updated to include specific 
recommendation relating to the birth control 
Study Synopsis and  
Section 3.1 
Screening Period was extended to up to 14 days 
Section 3.1 
 
Clarified that if one is already using bland emollient (e.g 
Cetalphil® Lotion) continuously for 7 days, there is no need 
to be dispensed study bland emollient. In such case, 
procedures of Visit 1 (V1) and Visit 2 (V2) can be combined 
in one visit, if desired. 
Section 3.1.2 and Instructions to 
Patients 
Caregivers who are pregnant, breastfeeding or may become 
pregnant should consult their physicians and follow their 
recommendations relating to the potential exposure to 
Pimecrolimus 1% Cream. 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 55 of 75 
 
 
Section  
Revisions  
Section 3.2 
Clarified screening period/window as 0-14 days 
Section 4.4.3 
Added “assent” to section 4.4.3 
Section 6.4 
Clarified immunosuppressive drugs criteria. 
Section 9.2.1 
Clarified “safety” population instead of ITT 
Patient Instructions 
Clarified that prolonged baths (longer than 5 minutes) as 
well as grapefruit and grapefruit juice should be avoided 
while on the study. 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 56 of 75 
 
 
12.8 Appendix VII: US Reference Listed Drug Package Insert 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 57 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 58 of 75 
 
 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 59 of 75 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 60 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 61 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 62 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 63 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 64 of 75 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 65 of 75 
 
 
 
 
 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 66 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 67 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 68 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 69 of 75 
 
 
 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 70 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 71 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 72 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 73 of 75 
 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 74 of 75 
 
 
 

Protocol Number: CD-14-875 
Version 2.0 
Dated  14 Oct 2016 
 
CONFIDENTIAL 
This document is confidential and should be distributed for review only to investigators, potential investigators, consultants, study staff and 
applicable institutional ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from sponsor. Protocol is the property of the sponsor. 
 
 
       Page 75 of 75