Clinical trial NCT02120898
Conditions: Actinic Keratosis
Keywords: Actinic Keratosis Imiquimod Zyclara
Sponsor: Actavis Inc.
Start date: 2013-10-10; Completion date: 2014-04-30
Enrollment: 467 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study it so compare the safety and efficacy profiles of a generic imiquimod 2.5% cream to the reference listed Zyclara® (imiquimod) cream in the treatment of actinic keratosis (AK).

Detailed description:
Aldara® (imiquimod) Cream, 5% was the first imiquimod product approved by the Food and Drug Administration (FDA) for the topical treatment of AK, superficial basal cell carcinoma and external genital and perianal warts. The FDA approved regimen for the treatment of AK is application of 250 milligrams (mg) of cream twice a week for 16 weeks to a 25 square centimeters (cm\^2) area. In 2011, a lower strength imiquimod cream, Zyclara (imiquimod) Cream, 2.5% was approved by the FDA. When used for the treatment of AK, Zyclara is applied for a shorter duration and in an expanded treatment area (for example, face or scalp) in comparison to Aldara®. This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirement(s). Marketed by Medicis, Zyclara® (imiquimod) cream 2.5% is a safe and effective topical therapy for the treatment of AK of the face and scalp. Actavis has developed a generic formulation of imiquimod 2.5% cream and the current study is designed to evaluate the safety and efficacy of this formulation.

Arms: arm 1: Generic imiquimod cream 2.5% will be applied once daily approximately 1 to 2 hours before bedtime to the skin of the treatment area (either full face \[excluding the ears\] or balding scalp) for two, 2-week treatment cycles separated by a 2-week no-treatment period. Participants will apply test article for 14 consecutive days for each treatment cycle. arm 2: Zyclara® (imiquimod) cream 2.5% will be applied once daily approximately 1 to 2 hours before bedtime to the skin of the treatment area (either full face \[excluding the ears\] or balding scalp) for two, 2-week treatment cycles separated by a 2-week no-treatment period. Participants will apply test article for 14 consecutive days for each treatment cycle. arm 3: Vehicle cream will be applied once daily approximately 1 to 2 hours before bedtime to the skin of the treatment area (either full face \[excluding the ears\] or balding scalp) for two, 2-week treatment cycles separated by a 2-week no-treatment period. Participants will apply test article for 14 consecutive days for each treatment cycle.
Interventions: intervention 1: Imiquimod intervention 2: Zyclara® intervention 3: Vehicle Cream
Intervention descriptions: intervention 1: Cream, generic formulation of the brand product. intervention 2: Cream, brand product. intervention 3: Vehicle cream in the same image of the generic imiquimod. Has no active ingredient.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Clinical Study Protocol 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, 
PARALLEL GROUP COMPARISON STUDY TO DETERMINE THE THERAPEUTIC 
EQUIVALENCE OF GENERIC IMIQUIMOD CREAM, 2.5% AND ZYCLARA® 
(IMIQUIMOD) CREAM, 2.5% IN SUBJECTS WITH ACTINIC KERATOSES 
 
 
Study Number 094-3153-301 
 
NCT02120898 
 
Protocol Approval Date: 30 July 2013  
 


CONFIDENTIAL 
Page 1 of 55 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, VEHICLE-
CONTROLLED, PARALLEL GROUP COMPARISON STUDY TO DETERMINE 
THE THERAPEUTIC EQUIVALENCE OF GENERIC IMIQUIMOD CREAM, 
2.5% AND ZYCLARA® (IMIQUIMOD) CREAM, 2.5% IN SUBJECTS WITH 
ACTINIC KERATOSES 
 
PROTOCOL NUMBER: 
094-3153-301 
 PROJECT NUMBER: 
094-3153-301 
ORIGINAL PROTOCOL:  
July 30, 2013 
FILE NAME: 
094-3153-301_pro_30July2013_v1.0   
SPONSOR: 
Actavis, LLC 
SPONSOR REPRESENTATIVE: 
 
 
MEDICAL MONITOR: 
 
 
 
 
 (office) 
 (cell) 
 (fax) 
 (email) 
CLINICAL PROJECT MANAGER: 
 
 
 
 
 (office) 
(fax) 
 (email) 
 
24 Hour Emergency Telephone Number 
 
 
 
 
 
The information contained in this document is confidential and proprietary 
property of Actavis, LLC. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 2 of 55 
 
PROTOCOL APPROVAL 
The following individuals approve version 1.0 of the 094-3153-301 protocol dated July 
30, 2013. All changes to this version of the protocol must have prior written approval and 
require an amendment or administrative letter. 
 
Actavis Representative(s): 
 
 
 
Signature: ______________________________________ Date: _______________ 
 
 
 
 
 
Signature: ______________________________________ Date: _______________ 
 
 
 
 
Signature: ______________________________________ Date: _______________ 
 
 
 
 
Signature: ______________________________________ Date: _______________ 
 
 
 
 
Signature: ______________________________________ Date: _______________ 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 3 of 55 
 
STUDY ACKNOWLEDGEMENT 
I understand this protocol contains information that is confidential and proprietary to 
Actavis, LLC. 
 
I have read this protocol and agree that it contains all the details necessary to conduct the 
study as described. I will conduct this study following this protocol and will make a 
reasonable effort to complete the study in the time noted. 
 
I will provide the contents of this protocol to study staff under my direct supervision that 
need to know the contents to conduct the study. I will discuss this information with the 
study staff to ensure they are fully informed about the study and the test articles. I will 
provide the contents of the protocol to the responsible Institutional Review Board(s). 
These disclosures may be made; providing the contents are not used in any other clinical 
study and they are not disclosed to any other person or entity without prior written 
consent from Actavis, LLC. This condition does not apply to disclosure required by 
government regulations or laws; however, I agree to give prompt notice to Actavis, LLC 
of any such disclosure. 
 
I understand the study may be terminated or enrollment suspended at any time by 
Actavis, LLC, with or without cause, or by me if it becomes necessary to protect the 
interests of the study subjects. 
 
Any additional information added to this protocol is also confidential and proprietary to 
Actavis, LLC and must be treated in the same manner as the contents of this protocol. 
 
____________________________________ 
Printed Name of Principal Investigator 
 
____________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
 
Date 
 
 
Protocol number: 094-3153-301 
 
 
 
Site number:              
 
Version: 1.0 
 
DATE OF FINAL VERSION: July 30, 2013 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 4 of 55 
 
PROTOCOL SYNOPSIS 
Title 
A Multicenter, Randomized, Double-Blind, Vehicle-Controlled, Parallel 
Group Comparison Study to Determine the Therapeutic Equivalence of 
Generic Imiquimod Cream, 2.5% and Zyclara® (imiquimod) Cream, 2.5% 
in Subjects with Actinic Keratoses 
Study Type 
Bioequivalence with Clinical Endpoint 
Test Articles 
1. 
Imiquimod cream, 2.5% (Actavis) (generic imiquimod) 
2. 
Zyclara® (imiquimod) Cream, 2.5% (Medicis) (Reference Listed 
Drug) 
3. 
Vehicle cream (Actavis) 
Study Objective 
To evaluate the safety and therapeutic equivalence of generic imiquimod 
cream, 2.5% to Zyclara (imiquimod) Cream, 2.5% and to establish the 
superiority of the efficacy of these two products over the vehicle cream in 
the treatment of actinic keratoses (AK). 
Study Design 
Multicenter, randomized, double-blind, vehicle-controlled, parallel group 
comparison. 
Treatment Groups 
After enrollment in the study, each subject will be randomized 
 to 
treatment with Zyclara, generic imiquimod, or vehicle control.  
Duration of Treatment 
Two 2-week treatment cycles separated by a 2-week no-treatment period 
and an 8-week follow-up period.  
Duration of Study 
Approximately 14 weeks (not including up to 30-day screening period). 
Study Population 
Male or female subjects, age 18 years or older with actinic keratoses on the 
face or balding scalp. 
Total Number of 
Subjects 
Approximately 435 subjects will be enrolled. 
Number of Sites 
Approximately 25 sites will participate in the study. 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
 
1. Subject is a male or female, 18 years of age or older. 
2. Subject has provided written informed consent. 
3. Subject is willing and able to apply the test article as directed, comply 
with study instructions and commit to all follow-up visits for the 
duration of the study. 
4. Subject has a clinical diagnosis of actinic keratoses (AK) with at least 
five (5) and no more than twenty (20) clinically typical, visible or 
palpable AK lesions, each at least 4 mm in diameter, in an area greater 
than 25 cm2 on the face (excluding ears) or balding scalp, but not both.  
5. Subject is in good general health and free of any disease state or 
physical condition that might impair evaluation of AK lesions or 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 5 of 55 
 
which, in the investigator’s opinion, exposes the subject to an 
unacceptable risk by study participation.  
6. Females must be post-menopausal1, surgically sterile2 or use an 
effective method of birth control3,4 with a negative urine pregnancy 
test (UPT)5 at the Baseline Visit. 
Exclusion Criteria 
A subject is ineligible to enter the study if he/she meets one or more of the 
following criteria:  
 
1. Subject is pregnant, lactating, or is planning to become pregnant 
during the study. 
2. Subject has hyperkeratotic, hypertrophic or atypical AKs (e.g., AK > 1 
cm2 in size) in the treatment area. 
3. Subject is currently enrolled in an investigational drug or device study. 
4. Subject plans to be exposed to artificial tanning devices or excessive 
sunlight during the trial. 
5. Subject is immunosuppressed (e.g., HIV, systemic malignancy, graft 
vs. host disease, etc.). 
6. Subject has experienced an unsuccessful outcome from previous 
imiquimod therapy (an unsuccessful outcome is defined as after a 
reasonable therapeutic trial with no compliance issues and the topical 
drug did not work). 
7. Subject has used an investigational drug or investigational device 
within 30 days prior to the Baseline Visit. 
8. Subject has had dermatologic procedures or surgeries such as: laser 
resurfacing, PUVA (Psoralen + ultraviolet A) therapy, UVB therapy, 
chemical peels or dermabrasion on the face or balding scalp within six 
(6) months prior to the Baseline Visit. 
9. Subject has had cryodestruction or chemodestruction, curettage, 
photodynamic therapy, surgical excision or other treatments for actinic 
keratosis on the designated treatment area (face or scalp) within one 
month prior to the Baseline Visit. 
10. Subject has used oral corticosteroid therapy, interferon, cytotoxic 
drugs, immunomodulators, immunosuppressive therapies or retinoids 
within one month prior to the Baseline Visit. 
11. Subject has used topical medications; corticosteroids, alpha hydroxy 
                                                 
1 Defined as amenorrhea greater than 12 consecutive months. 
2 Hysterectomy, bilateral tubal ligation (at least 6 months prior to initiation of baseline treatment) or 
bilateral oophorectomy. 
3 Effective forms of birth control include hormonal contraceptives [oral, injectable, transdermal or 
intravaginal], intrauterine device (IUD), condom and spermicidal or diaphragm and spermicidal). IUD must 
be in place for at least one week prior to the Baseline Visit. Other acceptable forms of birth control include: 
a) abstinence for subjects who are not sexually active or b) if the subject is in a monogamous relationship 
with a partner who is sterile (e.g., vasectomy performed at least 6 months prior to the Baseline Visit). 
Subjects who become sexually active or begin to have relations with a partner who is not sterile during the 
trial must agree to use an effective form of birth control for the duration of the study.  
4 Women of childbearing potential (WOCBP) taking hormonal therapy must be on treatment for at least 12 
weeks prior to the Baseline Visit and must not change their dosing regimen during the study.  
5 Urine pregnancy tests must have a minimum sensitivity of 25mIU ß-hCG/mL. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 6 of 55 
 
acids (e.g., glycolic acid, lactic acid etc. >5%), beta hydroxy acid 
(salicylic acid >2%), urea >5%, 5-fluorouracil, diclofenac, imiquimod, 
ingenol mebutate or prescription retinoids (e.g., tazarotene, adapalene, 
tretinoin) to the face or balding scalp within one month prior to the 
Baseline Visit. 
12. Subject has used topical creams, lotions or gels of any kind to the 
selected treatment area within one day prior to the Baseline Visit.  
13. Subject has lesions suspicious for skin cancer (skin cancer not ruled 
out by biopsy) or untreated skin cancers within the selected treatment 
area (face or scalp). 
14. Subject has a history of sensitivity to any of the ingredients in the test 
articles (see Section 6.1). 
15. Subject has any skin pathology or condition (e.g., facial/scalp 
psoriasis, atopic dermatitis, acne, rosacea, etc.) that, in the 
investigator’s opinion, could interfere with the evaluation of the test 
article, worsen due to the treatment or requires the use of interfering 
topical, systemic or surgical therapy. 
16. Subject has any condition which, in the investigator’s opinion, would 
make it unsafe or precludes the subject’s ability to fully participate in 
this research study. 
17. Subject is known to be noncompliant or is unlikely to comply with the 
requirements of the study protocol (e.g., due to alcoholism, drug 
dependency, mental incapacity) in the opinion of the investigator. 
Study Procedures 
Subjects can be screened for the study up to 30 days before Visit 1. During 
screening, the study requirements will be reviewed, written informed 
consent obtained, and eligibility confirmed. If applicable, the washout from 
prohibited medications or treatments will be determined and implemented. 
These procedures may be combined with the Baseline Visit. 
 
1. 
Visit 1 - Screening/Baseline Visit (-30 to Day 1): The following will 
be obtained at this visit: signed written informed consent (or re-
consent if washout period exceeds 30 days), confirmation of 
eligibility, medical history, review of concomitant medications, brief 
physical exam including dermatologic exam and vital sign 
assessment, urine pregnancy test (if applicable), identification of 
treatment area (the entire face excluding the ears, or the entire 
balding scalp, but not both), % body surface area (BSA) of the 
treatment area, AK count, and local skin reaction (LSR) assessment. 
Qualified subjects will be randomly assigned to one of three 
treatment groups. Test article application will be demonstrated using 
the non-medicated samples provided to the site. Test article will be 
dispensed, along with application instructions and a subject diary to 
document any applied, held or missed doses. The subjects will be 
instructed to apply up to two (2) pump actuations of test article once 
daily in the evening for 14 days to the entire treatment area. Subjects 
will be scheduled for Visit 3.  
 
NOTE: The subject will apply the assigned test article once daily for 14 
consecutive days followed by a two week no treatment period followed 
by a second once daily regimen for 14 consecutive days. 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 7 of 55 
 
2. 
Visit 2 - Phone Call (Day 8 ± 2): The site staff will contact the 
subject on Day 8 to confirm the next visit appointment, review 
application instructions and query about adverse events (AEs). 
Remind the subject to continue to apply up to two (2) pump 
actuations of test article once daily in the evening and to stop after 
the Day 14 application, even if Visit 3 is scheduled on Day 16 
through 18. 
 
3. 
Visit 3 (Day 15 + 3): Subjects will return for LSR and AE 
assessment. 
Compliance 
with 
test 
article 
application 
and 
concomitant medications will be reviewed. The subject diary card 
will be reviewed and collected. Test article will be returned and 
collected. Subjects will be scheduled for the next visit.   
 
NOTE: Day 15 (+ 3 days) through Day 29 (± 2 days): Subject will not 
apply test article.  
 
4. 
Visit 4 (Day 29 ± 2): Subjects will return for LSR and AE 
assessment. Concomitant medications will be reviewed. The subject 
diary card for treatment cycle 2 will be dispensed. Test article for 
treatment cycle 2 will be dispensed. Any uncollected test article 
from treatment cycle 1 will be collected. Subjects will be scheduled 
for the next visit. NOTE: Visit 6 should be scheduled 14 to 17 days 
after Visit 4. 
 
5. 
Visit 5 - Phone Call (Day 36 ± 2): The site staff will contact the 
subject on Day 36 to confirm the next visit appointment, review 
application instructions and query about AEs. Remind the subject to 
continue to apply up to two (2) pump actuations of test article once 
daily in the evening and to stop after the subject has treated for 14 
consecutive days after Visit 4, even if Visit 6 is scheduled after 14 
consecutive application days have elapsed.  
 
6. 
Visit 6 (14-17 Days after Visit 4): Subjects will return for an AK 
lesion count, LSR and AE assessment. Compliance with test article 
application and concomitant medications will be reviewed. The 
subject diary card and test article will be reviewed and collected. 
Subjects will be scheduled for the next visit.  
 
7. 
Visit 7 (Day 99 ± 4): Subjects will return for the final AK lesion 
count, LSR and AE assessment. Concomitant medications will be 
reviewed. A UPT, if applicable, will be obtained. Any uncollected 
test article or diaries will be collected. 
Study Measurements 
Efficacy: 
The primary efficacy parameter is the number of all visible or palpable 
AK(s) (baseline and new lesions) in the treatment area as enumerated at 
Visits 1, 6 and 7 by the investigator.  
 
Safety: 
All AEs will be recorded. At each visit, subjects will also be questioned 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 8 of 55 
 
specifically about any AEs associated with the application of the test article 
as well as the status of any AEs. In addition, LSRs including erythema, 
edema, 
weeping/exudate, 
flaking/scaling/dryness, 
scabbing/crusting, 
erosion/ulceration, pain and pruritus) will be assessed separately at each 
visit by the investigator as detailed in Section 10.2. 
Study Endpoints 
Efficacy Endpoint(s) 
Complete clearance rate (treatment success), defined as the proportion of 
subjects in each treatment group at Visit 7 (Week 14/ End of Study Visit) 
in the per-protocol (PP) population with a count of zero AK lesions in the 
treatment area. All AKs (baseline and new lesions) independent of size 
within the treatment area will be included in the efficacy lesion count for 
each visit. 
 
Safety Endpoint(s) 
Dosing Compliance: 
Measures of test article compliance will include the total number of 
applications recorded in the case report forms (CRFs) and verified from the 
data in the subject diaries. Compliant subjects are defined as those who 
apply at least 75% and no more than 125% of the test article applications 
and no other evidence of material dosing noncompliance. 
 
Adverse Events: 
Assessment of the severity and frequency of adverse events including LSRs 
in the three treatment groups. 
Sample Size 
Calculations 
 
 
 
 
Bioequivalence was concluded if the 90% continuity-corrected confidence 
interval on the difference in active treatment complete clearance rates was 
between -0.20 and +0.20 in the per protocol (PP) population, and each 
active treatment was found to be statistically superior to the vehicle by 
independent continuity-corrected Z-tests in the intent-to-treat (ITT) 
population. 
 
 
A total of 435 ITT subjects 
 
for 
demonstrating superiority of each active treatment over the vehicle 
treatment. 
 
 
 
Statistical Methods 
All statistical processing will be performed using SAS® unless otherwise 
stated. 
 
 
 
 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 9 of 55 
 
 
 
 
 
 
 
 
Efficacy summaries and analyses will be carried out in the ITT and PP 
populations. All summaries of safety will be carried out in the Safety 
population. Last-observation-carried-forward (LOCF) will be used to impute 
missing values for efficacy variables in the ITT population.  
 
Demographic and baseline characteristics will be summarized by treatment 
group for the ITT and PP populations. The size of the treatment area (in 
centimeters) at baseline will be determined from an estimate of the % BSA 
treated. BSA will be determined from the subject’s height and weight using 
the Mosteller formula. Frequency counts and percentages will be reported 
for categorical data. Sample size, mean, standard deviation, and minimum 
and maximum will be reported for the continuous variables. 
 
Efficacy Analyses: 
The 90% Wald’s confidence interval with Yate’s continuity correction will 
be constructed on the difference between the proportions of subjects with 
AK lesion clearance in the Test and Reference treatments to evaluate the 
therapeutic comparability of the two active treatments. Two-sided, 
continuity-corrected Z-tests will be used to evaluate the superiority of each 
active treatment’s clearance proportion over that of the Vehicle treatment. 
 
If the 90% confidence interval on the difference between the Test and 
Reference lesion clearance proportions are contained within the 
interval -0.20 to +0.20, and each of these proportions is greater than, and 
statistically different (p<0.05) from, the Vehicle proportion, then the Test 
and Reference products will be considered to be therapeutically equivalent. 
 
The therapeutic comparability evaluations in the PP population will be 
considered primary while those in the ITT population will be considered 
supportive. The superiority comparisons in the ITT population will be 
considered primary while those in the PP population will be considered 
supportive. 
 
Safety Analyses: 
All subjects in the safety population will be included in summaries of safety 
data.  
 
Dosing Compliance 
Descriptive statistics will be used to summarize test article compliance for 
the ITT and PP populations. Measures of test article compliance will 
include the total number of applications as determined from the data 
recorded in the subject diaries. Compliant subjects are defined as those who 
apply at least 75% and no more than 125% of the test article applications 
and no other evidence of material dosing noncompliance. 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 10 of 55 
 
Adverse Events 
All adverse events will be coded using the MedDRA coding dictionary. 
The number and percent of unique subjects reporting each treatment-
emergent AE will be summarized by MedDRA system organ class (SOC), 
MedDRA preferred term (PT), and treatment group. AEs will also be 
similarly summarized by SOC, PT, maximum severity, and treatment group 
as well as by SOC, PT, closest relationship to study drug, and treatment 
group. All AEs reported during the study will be listed, documenting 
course, severity, investigator assessment of the relationship to the test 
articles, and outcome.  
 
Local Skin Reactions 
LSRs will be summarized by treatment group by the most intense score for 
each LSR and by the sum score at each visit and over the course of the 
study. The frequency of the individual LSRs will be tabulated by severity 
and treatment group at each visit. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 11 of 55 
 
SCHEDULE OF EVENTS 
Visit 
Visit 1 
Visit 2 
Telephone 
Visit 3 
Visit 4 
Visit 5 
Telephone  
Visit 6 
Visit 7 
Week 
Screening/ 
Baseline 
Week 1 
Week 2 
Week 4 
Week 5 
Week 6 
Week 14/ 
EOS 
Day 
 
Day 1 
Day 8 
(± 2 days) 
Day 15 
(+ 3 days) 
Day 29 
(± 2 days) 
Day 36 
(± 2 days) 
14-17 
Days After 
Visit 4 
Day 99 
(± 4 days) 
Treatment Period 
Treatment Cycle = Test Article Application Once Daily for 14 Consecutive Days  
Treatment Cycle 1-Visit 1 to Visit 3 Treatment Cycle 2-Visit 4 to Visit 6 
Informed Consent1 
X 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
 
X 
X 
 
X 
X 
Brief Physical Exam including 
Dermatologic Exam and Vital 
Sign Assessment 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Treatment Area (Face or Balding 
Scalp) ID - Location & Size 
X 
 
 
 
 
 
 
AK Lesion Count 
X 
 
 
 
 
X 
X 
Local Skin Reaction Assessment 
X 
 
X 
X 
 
X 
X 
Confirm Next Visit Appointment, 
Review Dosing Instructions and 
Query About AEs. 
 
X 
 
 
X 
 
 
Pregnancy Testing2for WOCBP3 
X 
 
 
 
 
 
X 
Issue Subject Diary 
X 
 
 
X 
 
 
 
Collect & Review Subject Diary 
for Compliance 
 
 
X 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Dispense/Return/Weigh Test 
Article (Perform Drug 
Accountability) 
X 
 
X 
X 
 
X 
 
 
 
                                                 
1 Informed consent may be obtained within 30 days prior to the Baseline Visit. 
2 Urine pregnancy tests must have a minimum sensitivity of 25 mIU ß-hCG/mL of urine and must be performed within 
24 hours prior to the start of test article at baseline. 
3 See Section 14.4 for definition of woman of childbearing potential (WOCBP).  


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 12 of 55 
 
ABBREVIATIONS 
5-FU 
5-Fluorouracil 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AHA 
Alpha Hydroxy Acid 
AK 
Actinic Keratosis or Keratoses 
BSA 
Body Surface Area 
CLIA 
Clinical Laboratory Improvement Amendments 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
EOS 
End of Study 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
Interferon  
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
LOCF 
Last Observation Carried Forward 
LSR 
Local Skin Reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NFκB 
Nuclear Factor κB 
OTC 
Over-the-Counter 
PDT 
Photodynamic Therapy 
PP 
Per-Protocol 
PT 
Preferred Term 
PUVA 
Psoralen + Ultraviolet A 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
 
 
TLR 
Toll-like Receptor 
TNF 
Tumor Necrosis Factor  
UPT 
Urine Pregnancy Test 
UVB 
Ultraviolet B 
WHO 
World Health Organization 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 13 of 55 
 
WOCBP 
Women of Childbearing Potential 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 14 of 55 
 
TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis................................................................................................................ 4 
Schedule of Events ............................................................................................................ 11 
Abbreviations .................................................................................................................... 12 
Table of Contents .............................................................................................................. 14 
1. 
Background ............................................................................................................... 17 
2. 
Rationale ................................................................................................................... 17 
3. 
Objective ................................................................................................................... 18 
4. 
Study Design ............................................................................................................. 18 
4.1 
Estimated Duration of Study ............................................................................. 18 
5. 
Study Population ....................................................................................................... 18 
5.1 
Subject Eligibility ............................................................................................. 19 
5.1.1 
Inclusion Criteria ....................................................................................... 19 
5.1.2 
Exclusion Criteria ...................................................................................... 19 
5.1.3 
Subject Withdrawal Criteria ...................................................................... 21 
6. 
Test Articles and Regimen ........................................................................................ 21 
6.1 
Description ........................................................................................................ 21 
6.2 
Instructions for Use and Application ................................................................ 21 
6.3 
Investigator Prescribed Rest Periods ................................................................ 22 
6.4 
Warnings, Precautions and Contraindications .................................................. 22 
7. 
Randomization Assignment ...................................................................................... 23 
8. 
Prior and Concomitant Therapies ............................................................................. 23 
8.1 
Prohibited Medications or Therapies ................................................................ 24 
8.2 
Allowed Medications or Therapies ................................................................... 24 
9. 
Study Procedures ...................................................................................................... 25 
9.1 
Visit 1 (Screening/Baseline, -30 to Day 1) ....................................................... 25 
9.2 
Visit 2 - Phone Call (Week 1/ Day 8 ± 2) ......................................................... 26 
9.3 
Visit 3 (Week 2/ Day 15 + 3) ............................................................................ 27 
9.4 
Visit 4 (Week 4/ Day 29 ± 2) ............................................................................ 27 
9.5 
Visit 5 - Phone Call (Week 5/ Day 36 ± 2) ....................................................... 28 
9.6 
Visit 6 (Week 6/14-17 Days after Visit 4) ........................................................ 28 
9.7 
Visit 7 (Week 14/ Day 99 ± 4) .......................................................................... 28 
9.8 
Unscheduled Visits ........................................................................................... 29 
10. 
Clinical Evaluations .............................................................................................. 29 
10.1 
AK Lesion Counts............................................................................................. 29 
10.2 
Local Skin Reactions (LSR) Assessment ......................................................... 30 
11. 
Photography .......................................................................................................... 30 


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12. 
Laboratory Tests ................................................................................................... 31 
12.1 
Urine Pregnancy Tests ...................................................................................... 31 
13. 
End of Study Criteria ............................................................................................ 31 
13.1 
Completion of the Study ................................................................................... 31 
13.2 
Subject Discontinuation .................................................................................... 31 
13.3 
Study Termination ............................................................................................ 32 
14. 
Adverse Event Reporting ...................................................................................... 32 
14.1 
Definitions......................................................................................................... 32 
14.2 
Reporting of Adverse Events ............................................................................ 33 
14.2.1 
Adverse Event and SAE Reporting Period ................................................ 34 
14.2.2 
Assessment of AEs .................................................................................... 34 
14.2.2.1 
Severity ................................................................................................ 34 
14.2.2.2 
Causal Relationship ............................................................................. 34 
14.2.2.3 
Outcome............................................................................................... 35 
14.2.2.4 
Treatment Required ............................................................................. 36 
14.2.3 
Procedure for Reporting of Serious Adverse Events ................................. 36 
14.2.3.1 
Notification by Investigator to TI ........................................................ 36 
14.2.4 
IRB/IEC Notification by Investigator........................................................ 37 
14.2.5 
FDA Notification by Sponsor .................................................................... 37 
14.3 
Laboratory Test Abnormalities ......................................................................... 37 
14.4 
Pregnancy .......................................................................................................... 38 
14.4.1 
Reporting Procedure .................................................................................. 39 
15. 
Blinding/Unblinding ............................................................................................. 39 
16. 
Clinical Supplies ................................................................................................... 39 
16.1 
Test Article Information ................................................................................... 39 
16.2 
Additional Supplies Provided by 
 ........................................ 39 
16.3 
Supplies Provided by Investigator .................................................................... 40 
16.4 
Supplies Provided by Actavis, LLC.................................................................. 40 
17. 
Statistical Considerations ...................................................................................... 40 
17.1 
Sample Size ....................................................................................................... 40 
17.2 
Endpoints .......................................................................................................... 40 
17.2.1 
Efficacy Endpoint(s) .................................................................................. 40 
17.2.2 
Safety Endpoint(s) ..................................................................................... 41 
17.2.2.1 
Dosing Compliance ............................................................................. 41 
17.2.2.2 
Adverse Events .................................................................................... 41 
17.3 
Statistical Methods ............................................................................................ 41 
17.3.1 
Efficacy Analyses ...................................................................................... 42 
17.3.2 
Safety Analyses ......................................................................................... 42 
17.3.2.1 
Dosing Compliance ............................................................................. 42 
17.3.2.2 
Adverse Events .................................................................................... 42 


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17.3.2.3 
Local Skin Reactions ........................................................................... 43 
17.3.3 
Other Analyses .......................................................................................... 43 
17.3.3.1 
Medical History ................................................................................... 43 
17.3.3.2 
Concomitant Medications .................................................................... 43 
17.4 
Subgroup Analyses ........................................................................................... 43 
17.5 
Interim Analyses ............................................................................................... 43 
18. 
Ethical and Regulatory Considerations ................................................................. 43 
18.1 
Compliance with Good Clinical Research Practice .......................................... 43 
18.2 
Institutional Review Board (IRB) and Informed Consent ................................ 44 
18.3 
Protocol Compliance ......................................................................................... 44 
18.4 
Protocol Revisions ............................................................................................ 44 
18.5 
Study Monitoring .............................................................................................. 44 
18.6 
Case Report Form Requirements ...................................................................... 45 
18.7 
Reports to Institutional Review Board .............................................................. 45 
18.8 
Quality Assurance Audits ................................................................................. 45 
18.9 
Records Retention ............................................................................................. 46 
18.10 Record Confidentiality ...................................................................................... 46 
19. 
References ............................................................................................................. 47 
Appendix 1 
Subject Instruction sheet ........................................................................... 48 
Appendix 2 
Test Article Information ............................Error! Bookmark not defined. 
  


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1. 
BACKGROUND 
Actinic keratoses (AKs) are common skin lesions which appear as scaly or crusty 
growths on the bald scalp, face, ears, lips, backs of the hands and forearms, shoulders, 
neck or any other areas of the body frequently exposed to the sun. The lesions appear as 
invisible or subclinical lesions as well as visible ones on the skin surface. Without 
treatment, AK(s) may spontaneously regress or progress to squamous cell carcinoma. It is 
unknown which AK(s) will develop into cancer so preventative treatment strategies are 
warranted. AK treatments include: topical medications, cryosurgery, combination 
therapies, chemical peels, laser surgery, and photodynamic therapy (PDT). Topical 
medications include: 5-fluorouracil (5-FU), imiquimod cream 5%, 3.75% and 2.5%, 
ingenol mebutate and diclofenac.  
 
Imiquimod is an immune response modifier that acts via stimulation of toll-like receptor 
7 (TLR-7) on plasmacytoid and myeloid dendritic cells. TLR-7 is part of a family of 11 
TLRs that are important in the innate immune system’s recognition of various microbial 
antigens. Stimulation of TLR-7 most notably results in dissociation of nuclear factor κB 
(NFκB) away from its inhibitor, thereby freeing it to diffuse into the nucleus and 
transcribe genes for various cytokines including tumor necrosis factor α (TNFα), 
interferon γ (IFNγ), interferon α (IFNα), and interleukin-12 (IL–12), among others. 
These cytokines upregulate cell mediated Th1 responses that have antitumor and antiviral 
effects and downregulate Th2 (humoral) responses. Imiquimod may also directly affect 
cell death through various pathways including via IFNγ modulation of the p53 apoptotic 
pathway. 
 
Aldara® (imiquimod) Cream, 5% was the first imiquimod product approved by the FDA 
and is now available in a generic formulation. Imiquimod cream 5% is approved for the 
topical treatment of AK(s), superficial basal cell carcinoma and external genital and 
perianal warts. The FDA approved regimen for the treatment of AK is application of 250 
mg of cream twice a week for 16 weeks to a 25-cm2 area. In 2010, a lower strength 
imiquimod cream, Zyclara (imiquimod) Cream, 3.75% was approved by the FDA. In 
2011, Zyclara (imiquimod) Cream, 2.5% was approved by the FDA. When used for the 
treatment of AK, both of these Zyclara formulations are applied for a shorter duration and 
in an expanded treatment area (e.g., face or scalp) in comparison to Aldara®.  
 
A generic imiquimod cream, 2.5% has been developed by Actavis, LLC for the topical 
treatment of clinically typical, visible or palpable actinic keratoses (AK) of the full face 
or balding scalp.  
2. 
RATIONALE 
Actavis, LLC has developed a generic imiquimod cream, 2.5% formulation and the 
current clinical study is designed to evaluate the therapeutic equivalence of this 


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Protocol: 094-3153-301, v1.0 
 
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formulation with the currently marketed Zyclara (imiquimod) cream, 2.5% formulation 
(Medicis).  
3. 
OBJECTIVE 
The objective is to evaluate the safety and therapeutic equivalence of generic imiquimod 
cream, 2.5% to Zyclara (imiquimod) Cream, 2.5% and to establish the superiority of the 
efficacy of these two products over the vehicle cream in the treatment of actinic keratoses 
(AK). 
4. 
STUDY DESIGN 
This is a multicenter, double-blind, vehicle-controlled, parallel group comparison study 
of a generic imiquimod cream, 2.5% and Zyclara (imiquimod) cream, 2.5% (Medicis) in 
subjects with actinic keratoses on the full face or balding scalp. Approximately 435 
subjects with at least five (5) but no more than 20 clinically typical, visible or palpable 
AK lesions at least 4 mm in diameter involving the face (excluding the ears) or the 
balding scalp who fulfill the inclusion/exclusion criteria will be enrolled at approximately 
25 U.S. study sites. Subjects will be randomized to one of three treatment groups on a 
 basis as follows:  
• Imiquimod cream, 2.5% (Actavis) 
• Zyclara (imiquimod) cream, 2.5% (Medicis)  
• Vehicle cream (Actavis) 
 
All subjects will apply the assigned test article to the designated treatment area (full face 
or balding scalp) identified by the investigator at Visit 1. The assigned test article will be 
applied once daily for two, 2-week treatment cycles separated by a 2-week no treatment 
interval. Subjects will also return for an End of Study (EOS) Visit, 8 weeks post-
treatment. At the end of the study, safety and efficacy outcome measures will be 
compared to a) determine if dosing with generic imiquimod cream, 2.5% is clinically 
equivalent to the currently marketed Zyclara (imiquimod) cream, 2.5% and b) both 
imiquimod 2.5% creams are superior in comparison to the vehicle cream. 
4.1 
Estimated Duration of Study 
The duration of the study as a whole will vary based upon the relative rates of recruitment 
and completion of subjects at all sites within the study. It is anticipated that each subject 
will participate for approximately 14 weeks or longer if the subject requires a medication 
washout period.  
5. 
STUDY POPULATION 
Approximately 435 adult male and female subjects with 5 (five) to 20 AKs that are at 
least 4 mm in diameter on the full face or balding scalp who meet the entry criteria will 
be enrolled into the treatment phase of the study. 


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5.1 
Subject Eligibility 
To be included in the study, subjects must meet the following inclusion criteria and none 
of the exclusion criteria.  
5.1.1 Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
1. Subject is a male or female, 18 years of age or older. 
2. Subject has provided written informed consent. 
3. Subject is willing and able to apply the test article as directed, comply with study 
instructions and commit to all follow-up visits for the duration of the study. 
4. Subject has a clinical diagnosis of actinic keratoses (AK) with at least five (5) and 
no more than twenty (20) clinically typical, visible or palpable AK lesions, each 
at least 4 mm in diameter, in an area greater than 25 cm2 on the face (excluding 
ears) or balding scalp, but not both.  
5. Subject is in good general health and free of any disease state or physical 
condition that might impair evaluation of AK lesions or which, in the 
investigator’s opinion, exposes the subject to an unacceptable risk by study 
participation.  
6. Females must be post-menopausal1, surgically sterile2 or use an effective method 
of birth control3,4 with a negative urine pregnancy test (UPT)5 at the Baseline 
Visit. 
5.1.2 Exclusion Criteria 
A subject is ineligible to enter the study if he/she meets one or more of the following 
criteria:  
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has hyperkeratotic, hypertrophic or atypical AKs (e.g., AK > 1 cm2 in 
size) in the treatment area. 
3. Subject is currently enrolled in an investigational drug or device study. 
                                                 
1 Defined as amenorrhea greater than 12 consecutive months. 
2 Hysterectomy, bilateral tubal ligation (at least 6 months prior to the Baseline Visit) or bilateral 
oophorectomy. 
3 Effective forms of birth control include hormonal contraceptives [oral, injectable, transdermal or 
intravaginal], intrauterine device (IUD), condom and spermicidal or diaphragm and spermicidal). IUD must 
be in place for at least one week prior to the Baseline Visit. Other acceptable forms of birth control include: 
a) abstinence for subjects who are not sexually active or b) if the subject is in a monogamous relationship 
with a partner who is sterile (e.g., vasectomy performed at least 6 months prior to the Baseline Visit). 
Subjects who become sexually active or begin to have relations with a partner who is not sterile during the 
trial must agree to use an effective form of birth control for the duration of the study.  
4 Women of childbearing potential (WOCBP) taking hormonal therapy must be on treatment for at least 12 
weeks prior to the Baseline Visit and must not change their dosing regimen during the study.  
5 Urine pregnancy tests must have a minimum sensitivity of 25mIU ß-hCG/mL. 


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4. Subject plans to be exposed to artificial tanning devices or excessive sunlight 
during the trial. 
5. Subject is immunosuppressed (e.g., HIV, systemic malignancy, graft vs. host 
disease, etc.). 
6. Subject has experienced an unsuccessful outcome from previous imiquimod 
therapy (an unsuccessful outcome is defined as after a reasonable therapeutic trial 
with no compliance issues and the topical drug did not work). 
7. Subject has used an investigational drug or investigational device within 30 days 
prior to the Baseline Visit. 
8. Subject has had dermatologic procedures or surgeries such as: laser resurfacing, 
PUVA (Psoralen + Ultraviolet A) therapy, UVB therapy, chemical peels or 
dermabrasion on the face or balding scalp within six (6) months prior to the 
Baseline Visit.  
9. Subject has had cryodestruction or chemodestruction, curettage, photodynamic 
therapy, surgical excision or other treatments for actinic keratosis on the 
designated treatment area (face or scalp) within one month prior to the Baseline 
Visit. 
10. Subject has used oral corticosteroid therapy, interferons, cytotoxic drugs, 
immunomodulators, immunosuppressive therapies or retinoids within one month 
prior to the Baseline Visit.  
11. Subject has used topical medications; corticosteroids, alpha hydroxy acids (e.g., 
glycolic acid, lactic acid etc. >5%), beta hydroxy acid (salicylic acid >2%), urea 
>5%, 5-fluorouracil, diclofenac, imiquimod, ingenol mebutate or prescription 
retinoids (e.g., tazarotene, adapalene, tretinoin) to the face or balding scalp within 
one month prior to the Baseline Visit. 
12. Subject has used topical creams, lotions or gels of any kind to the selected 
treatment area within one day prior to the Baseline Visit.  
13. Subject has lesions suspicious for skin cancer (skin cancer not ruled out by 
biopsy) or untreated skin cancers within the selected treatment area (face or 
scalp). 
14. Subject has a history of sensitivity to any of the ingredients in the test articles (see 
Section 6.1). 
15. Subject has any skin pathology or condition (e.g., facial/scalp psoriasis, atopic 
dermatitis, acne, rosacea, etc.) that, in the investigator’s opinion, could interfere 
with the evaluation of the test article, worsen due to the treatment or requires the 
use of interfering topical, systemic or surgical therapy. 
16. Subject has any condition which, in the investigator’s opinion, would make it 
unsafe or precludes the subject’s ability to fully participate in this research study. 
17. Subject is known to be noncompliant or is unlikely to comply with the 
requirements of the study protocol (e.g., due to alcoholism, drug dependency, 
mental incapacity) in the opinion of the investigator. 


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5.1.3 Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 13.2. Subjects who are discontinued will not be replaced. 
6. 
TEST ARTICLES AND REGIMEN 
6.1 
Description 
Reference product name: 
Zyclara (imiquimod) cream, 2.5% 
Active ingredient: 
 
Imiquimod 
Other ingredients: 
isostearic acid, cetyl alcohol, stearyl alcohol, white 
petrolatum, 
polysorbate 
60, 
sorbitan 
monostearate, 
glycerin, xanthan gum, purified water, benzyl alcohol, 
methylparaben, and propylparaben. 
 
Test article name: 
 
Generic imiquimod cream, 2.5%  
Active ingredient: 
 
Imiquimod 
Other ingredients: 
 
 
 
 
Placebo name:  
 
Vehicle cream  
Active ingredient: 
 
None 
Other ingredients: 
 
 
 
6.2 
Instructions for Use and Application 
Subjects will be instructed to apply test article once daily approximately 1 to 2 hours 
before bedtime to the skin of the treatment area (either full face (excluding the ears) or 
balding scalp) for two, 2-week treatment cycles separated by a 2-week no-treatment 
period. Subjects will apply test article for 14 consecutive days for each treatment cycle, 
regardless of the visit window. However, if a subject did not apply for 14 consecutive 
days due to a dose held or missed, and 14 consecutive days has elapsed from baseline, 
then no additional test article will be applied to make up for missed or held doses. Test 
article should be applied as a thin film to the entire treatment area and rubbed until the 
cream is no longer visible. Up to two (2) full actuations of the pump may be dispensed 
and applied to the treatment area at each application. Subjects will be cautioned to avoid 
applying the cream to the lips, nostrils and periocular areas. The test article should be left 
on the skin for approximately eight (8) hours, after which time the test article should be 
removed by washing the area with mild soap and water. Treatment should continue for 


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the full treatment course even if all AKs appear to be gone. The study staff should 
demonstrate the proper use of the pump and application technique using the pumps 
containing the vehicle cream provided for subject training. See Appendix 1 for the 
complete Subject Instructions. 
6.3 
Investigator Prescribed Rest Periods 
Rest periods of several days may be prescribed by the investigator or designee to manage 
intense local skin reactions (LSRs). Treatment should resume as soon as possible after the 
skin reaction has subsided as determined by the investigator or designee. Neither 2-week 
treatment cycle should be extended beyond the 14 consecutive days due to rest periods or 
missed doses. 
6.4 
Warnings, Precautions and Contraindications 
Intense local skin reactions including skin weeping or erosion can occur after a few 
applications of imiquimod cream, 2.5% and may require an interruption of dosing (see 
Section 6.3). Imiquimod cream, 2.5% has the potential to exacerbate inflammatory 
conditions of the skin, including chronic graft versus host disease. 
 
Administration of imiquimod cream, 2.5% is not recommended until the skin is healed 
from any previous drug or surgical treatment.  
 
Concomitant use of any other imiquimod creams is not allowed in this study. The use of 
any other imiquimod cream in the same treatment area may increase the risk for and 
severity of local skin reactions. 
 
Flu-like signs and symptoms may accompany, or even precede, local skin reactions and 
may include fatigue, nausea, fever, myalgias, arthralgias, and chills. An interruption of 
dosing and an assessment of the patient should be considered. See Section 6.3 
(Investigator Prescribed Rest Periods). 
 
Lymphadenopathy occurred in 2% of subjects treated with imiquimod cream, 2.5%. This 
resolved in all subjects by four (4) weeks after completion of treatment. 
 
The safety of concomitant use of imiquimod cream, 2.5% and any other imiquimod 
creams has not been established and should be avoided since they contain the same active 
ingredient (imiquimod) and may increase the risk for and severity of systemic reactions. 
 
Exposure to sunlight (including sunlamps) should be avoided or minimized during use of 
imiquimod cream, 2.5% because of concern for heightened sunburn susceptibility. 
Patients should be warned to use protective clothing (e.g., a hat) when using imiquimod 
cream, 2.5%. Patients with sunburn should be advised not to use imiquimod cream, 2.5% 
until fully recovered. Patients who may have considerable sun exposure (e.g., due to their 


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occupation, and those patients with inherent sensitivity to sunlight) should exercise 
caution when using imiquimod cream, 2.5%. 
 
In an animal photo-carcinogenicity study, imiquimod cream shortened the time to skin 
tumor formation. The enhancement of ultraviolet carcinogenicity is not necessarily 
dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid 
natural or artificial sunlight exposure. 
 
Other Considerations 
  
The test articles are for topical use only (not for oral, ophthalmic, or intravaginal use). 
Contact with eyes, lips, and nostrils should be avoided. If contact with the mouth or eyes 
occurs, rinse thoroughly with water right away.  
 
The test articles should not be applied to open wounds, infections or exfoliative 
dermatitis.  
 
Areas treated with the test article should not be covered with any type of bandage or 
occlusive dressings. 
 
Subjects with a known sensitivity to any of the ingredients in the test articles should not 
participate in this study. 
 
In case of accidental ingestion, subjects should contact the investigator immediately. 
 
The effects of the test article in nursing mothers, pregnant women and their unborn 
children are unknown. Women of childbearing potential must not be pregnant or planning 
a pregnancy during the study period.  
7. 
RANDOMIZATION ASSIGNMENT 
Subjects who are eligible for enrollment into the study will be randomized by assigning 
the lowest subject kit number available at the site. Subjects will be randomized to one of 
three treatments 
 [Imiquimod cream, 2.5% (Actavis), Zyclara 
(imiquimod) cream, 2.5% (Medicis), Vehicle cream (Actavis), respectively].  
8. 
PRIOR AND CONCOMITANT THERAPIES 
Current medications and any medications taken within 30 days prior to the start of the 
study (Screening/Baseline, Visit 1) will be recorded as prior/concomitant medications 
(using the generic name, if known) with the dose and corresponding indication. The 
medications to be recorded include prescription and over-the-counter (OTC) medications 
(except vitamins and dietary supplements). All medications taken on a regular basis 
should be recorded on this page prior to commencing the use of the test article. 
 


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Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used during the study for the treatment or prevention of disease or to maintain good health. 
Vitamins and mineral supplements are permitted at dosages considered by the investigator 
as reasonable for maintaining good health. Non-prohibited chronic therapies being used at 
Visit 1 may be continued. All concomitant therapies during the study must be recorded on 
the Concomitant Therapy case report form. Any changes in concomitant medications during 
the study must be recorded on the case report forms. The reason for any change in 
concomitant therapies should be evaluated and, if appropriate, reported as, or in conjunction 
with, an adverse event.  
8.1 
Prohibited Medications or Therapies 
Prohibited medications or therapies during the study include:  
  
• Topical corticosteroids on the head. [NOTE: If treatment with topical steroids in the 
head area is deemed to be a material medical necessity for the subject by the 
investigator, this will be reviewed on a case by case basis with the Medical Monitor, 
requiring his approval.]  
• Subjects should not apply moisturizers, sunscreen, make-up, creams, lotions, powders 
or any topical product other than the assigned treatment to the treatment area. 
• Subjects should not use any type of bandage or occlusive dressing on the treatment 
area or apply the assigned cream to any skin diseases (e.g., open skin wounds, 
infections or inflammatory skin diseases). 
• Systemic use of immunomodulators or immunosuppressive therapies, interferon, 
corticosteroid therapy, chemotherapeutic agents, photodynamic therapy, cytotoxic 
drugs or retinoids. 
• Topical application of 5-FU, imiquimod, ingenol mebutate, diclofenac sodium, 
bichloroacetic acid, trichloroacetic acid, photodynamic therapy, prescription topical 
retinoids (e.g. tazarotene, adapalene, tretinoin), alpha-hydroxyacids [e.g. glycolic 
acid, lactic acid, etc. greater than 5%], beta-hydroxyacid [salicylic acid greater than 
0.5%], or [urea greater than 5%] or other treatments for AK or photodamage at any 
body site. See Section 8.2 for the limited treatment of AKs deemed to be a medical 
necessity at a body site exclusive of the head. 
• Any AK therapy on the head including but not limited to topicals (e.g. 5-FU, 
imiquimod, diclofenac sodium, etc.), laser ablation or resurfacing, electrocautery, 
photodynamic therapy, chemical peels, dermabrasion, cryotherapy, chemodestruction, 
surgical excision, curettage. 
• Sunlamps, tanning beds or booths, non-prescription UV light sources, and excessive 
sunlight. 
8.2 
Allowed Medications or Therapies 
The use of any of the following allowed medications or therapies should be documented 
in the subject’s CRF. 


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• Any medications not intended or beneficial for the treatment of actinic keratosis may be 
used unless specifically excluded or prohibited by this protocol (see Prohibited 
Medications above).  
• NOTE: Ideally, treatment of AKs at a body site exclusive of the HEAD should be 
avoided during the study period unless the treatment is deemed to be a material 
medical necessity for the subject by the investigator. In such cases, the ONLY allowed 
treatments for AKs, at any body site exclusive of the HEAD, are focal and limited 
treatment to the AK site only using surgical excision, cryotherapy and curettage ± pin 
point focal electrodessication. Use of any other treatment methods are prohibited (see 
Section 8.1) as are the treatment of any AKs on the HEAD using any method. 
• Intranasal, inhaled, and ophthalmic corticosteroids used for the management of allergies, 
pulmonary disorders or other conditions.  
• Protective clothing (e.g., a hat) is encouraged to reduce exposure of the treatment area 
to sunlight.  
• Use of a light bodied bland moisturizer in the treatment area as an aid to managing 
local skin reactions is allowed ONLY with the approval of the Medical Monitor. 
Examples of light bodied moisturizers are Cetaphil, Lubriderm (without alpha 
hydroxy acid [AHA]) and other bland moisturizers that do not contain any “active” 
ingredients (e.g., salicylic acid, lactic acid, pyruvic acid, urea or any other ingredient 
that could irritate or cause a keratolytic effect). Moisturizers should not be applied 
within 8 hours of test article application. 
9. 
STUDY PROCEDURES 
Specific activities for each study visit are listed below. 
9.1 
Visit 1 (Screening/Baseline, -30 to Day 1) 
Informed consent may be collected from study subjects up to 30 days before Visit 1. If 
applicable, qualified subjects can washout from prohibited medications or treatments 
prior to their Screening/Baseline Visit once informed consent has been obtained. If 
washout period exceeds 30 days, re-consent is required. The Screening and Baseline Visit 
may be completed on the same day, if no washout is required. 
 
At this visit, the investigator or designee will: 
 
• Obtain a signed, written informed consent and update the Subject Screening and 
Enrollment Log. 
• Confirm the subject meets the inclusion/exclusion criteria. 
• Document the information required on the Medical History form. 
• Document the information required on the Demographics form. 
• Record the subject’s prior and/or concomitant therapies.  
 


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If the subject requires washout from previous medications, the remaining activities 
will be performed after washout is complete. 
 
• Perform a limited physical exam including a brief dermatologic exam and vital 
sign assessment. Consistent with Exclusion Criterion #13, any subject with a 
suspicious lesion within the treatment area should not be enrolled prior to 
confirmation that the lesion is not skin cancer. In the event that a biopsy is 
warranted to make such a determination per the investigator, such a procedure is 
considered outside the scope of this study and therefore will be the responsibility 
of the potential subject. In the event that a biopsy is needed and it is not available 
for review, the subject shall be considered a screen failure. 
• Identify the treatment area; either the full face or balding scalp. 
• Estimate %BSA of the treatment area. 
• Perform the AK lesion count (≥ 4 mm in diameter as well as any smaller lesions) 
and estimate the surface area of the entire treatment area (full face or balding 
scalp) to be treated as described in Section 10.1. (Note: A minimum of 5 to a 
maximum of 20 AKs ≥ 4 mm in diameter in the treatment area is required to 
qualify). 
• Document the diameter of each AK lesion in the treatment area. 
• Perform the LSR assessment as described in Section 10.2. 
• Reaffirm the Inclusion/Exclusion criteria. 
• Perform a UPT for all WOCBP. The UPT must be negative for subjects to 
continue. 
• Assign the subject the next available (lowest) subject number in ascending order. 
Assign the subject the lowest available test article kit number and dispense two 
test article pumps from the kit. NOTE: The pumps will be weighed prior to being 
dispensed. 
• Review and dispense a Subject Instruction Sheet to the subject (see Appendix 1). 
Instruct the subjects to apply test article for 14 consecutive days and demonstrate 
proper use of the pump and test article application using vehicle cream pumps 
provided for subject training. 
• Issue the subject diary. 
• Confirm the next visit. 
9.2 
Visit 2 - Phone Call (Week 1/ Day 8 ± 2) 
The investigator or designee will contact the subject by phone and document the 
following: 
 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Review the application instructions (see Appendix 1). 


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• Instruct the subject to continue to apply up to two (2) pump actuations of test 
article once daily in the evening and to stop after the Day 14 application, even if 
Visit 3 is scheduled on Day 16 through 18. 
• Confirm the next visit.  
 
If necessary, an unscheduled visit may occur at the discretion of the investigator, see 
Section 9.8. 
9.3 
Visit 3 (Week 2/ Day 15 + 3) 
At this visit, the investigator or designee will: 
 
• Perform the LSR assessment as described in Section 10.2. 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Review subject study compliance requirements, emphasizing to the subject they 
will not apply test article and other prohibited medications for the next two-week 
period until Visit 4. 
• Collect and review the subject diary. Pay particular attention to proper test article 
use and application per protocol, providing the subject feedback as required. 
• Collect used and unused test article pumps and document the number returned on 
the Accountability Log as described in Appendix 2. Do not re-dispense test 
article. 
 
• Record any changes in the subject’s concomitant therapies.  
• Confirm the next visit.  
9.4 
Visit 4 (Week 4/ Day 29 ± 2) 
At this visit, the investigator or designee will: 
 
• Perform the LSR assessment as described in Section 10.2. 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Review the application instructions (see Appendix 1). 
• Issue a new subject diary. 
• Dispense two test article pumps from the kit number assigned to the subject and 
complete the Test Article Accountability Log as described in Appendix 2. 
 
 
• 
 
 
 
 
• Record any changes in the subject’s concomitant therapies.  


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• Confirm the next visit. NOTE: Visit 6 should be scheduled 14 to 17 days after 
Visit 4. 
9.5 
Visit 5 - Phone Call (Week 5/ Day 36 ± 2) 
The investigator or designee will contact the subject by phone and document the 
following: 
 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Review the application instructions (see Appendix 1).  
• 
 
 
 
 
• Confirm the next visit.  
 
If necessary, an unscheduled visit may occur at the discretion of the investigator, see 
Section 9.8. 
9.6 
Visit 6 (Week 6/14-17 Days after Visit 4) 
At this visit, the investigator or designee will: 
 
• Perform the AK lesion count as described in Section 10.1. NOTE: New AK 
lesions need to be identified, counted and recorded. A new AK lesion is one that 
was not present at the Baseline Visit. 
• Perform the LSR assessment as described in Section 10.2. 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Collect and review the subject diary. 
• Review subject study compliance requirements, emphasizing to the subject they 
will remain off test article for the duration of the study. 
• Collect used and unused test article pumps and document on the Test Article 
Accountability Log as described in Appendix 2. Do not re-dispense test article. 
 
• Record any changes in the subject’s concomitant therapies.  
• Confirm the next visit.  
9.7 
Visit 7 (Week 14/ Day 99 ± 4) 
At this visit, the investigator or designee will: 
 


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• Perform the AK lesion count as described in Section 10.1. NOTE: New AK 
lesions need to be identified, counted and recorded. A new AK lesion is one that 
was not present at the Baseline Visit. 
• Perform the LSR assessment as described in Section 10.2. 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Collect any used or unused test article pumps and diaries not returned at the 
previous visit and document on the Test Article Accountability Log as described 
in Appendix 2. 
• Record any changes in the subject’s concomitant therapies.  
• Perform a UPT, if applicable. 
• Complete the End of Study Form. 
9.8 
Unscheduled Visits 
The investigator may see the subject at an unscheduled visit to manage any AEs or LSRs. 
During this visit, the investigator or designee will: 
 
• Query the subject about any changes in health status or any adverse events since 
the last visit. Document in the AE section of the CRF, as appropriate. 
• Perform the LSR assessment as described in Section 10.2. 
• Record any changes in the subject’s concomitant therapies. 
• Review subject diary and the requirements for test article application, if 
applicable.  
• Confirm the next visit.  
10. 
CLINICAL EVALUATIONS 
The following clinical evaluations will be performed according to the schedules indicated 
during the study. The same investigator should complete the evaluations for a given 
subject throughout the study. If this becomes impossible a sub-investigator with 
overlapping experience with the subject and the study should complete the evaluations. 
10.1 
AK Lesion Counts 
AK lesion counts will be performed at Visit 1, 6 and 7. 
 
 
he number and location of AK lesions to be treated that are ≥ 4 mm in 
diameter and the diameter of each AK lesion in the treatment area will also be 
documented at the Baseline Visit. The suggested procedure for AK counting and 
definition of full face and balding scalp will be detailed in a separate document. At the 
Baseline Visit, the treatment area must include at least 5 and no more than 20 clinically 
typical, visible or palpable AKs, each at least 4 mm in diameter, in an area greater than 
25 cm2 on either the face (excluding ears) or the balding scalp, but not both. At Visits 6 


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and 7, the number of total AK lesions in the treatment area will be counted and the 
number of new AKs will be identified. A new AK is defined as a lesion that was not 
present at the Baseline Visit. 
 
If the subject has a LSR that prevents the investigator or designee from performing the 
AK count at a visit, the investigator or designee should document in the source document 
and CRF that the AK count was unable to be obtained due to a LSR.  
 
At the Baseline Visit, estimate the surface area of the entire treatment area (full face or 
balding scalp) to be treated with the test article as a percentage of the total body surface 
area (BSA). For this assessment, the subject’s palmar surface of the hand (palm and 
fingers/thumb held together) is 1% BSA. 
10.2 
Local Skin Reactions (LSR) Assessment 
At Visit 1, 3, 4, 6, 7 and Unscheduled Visits, if applicable (prior to test article 
application), the investigator or designee will assess the treatment area and rate on a scale 
of 0 = none, 1= mild, 2 =moderate and 3 = severe (through observation and subject 
query) the following LSRs:  
• Erythema  
• Edema  
• Erosion/ulceration 
• Scabbing/crusting 
• Weeping/exudate 
• Flaking/scaling/dryness 
• Pain (within the last 24 hours) 
• Pruritus (within the last 24 hours) 
 
These LSRs will be collected independently of adverse events. Any LSR that occurs 
within the treatment area (full face [excluding the ears] or balding scalp) and 
extends to adjacent surrounding skin (defined to be up to a 5 cm border around the 
treatment area) will be considered LSRs. LSRs that require medical intervention 
(prescription medication) or extend beyond the 5 cm surrounding skin should be 
documented as an adverse event. LSRs may be of such intensity that the subject may 
require rest periods (see Section 6.3 for details on rest periods). 
11. 
PHOTOGRAPHY 
Photography documentation is not required in this study. The investigator may elect to 
photograph the subject’s treatment area to document the effects of treatment, adverse 
events or other findings during the trial. All photographs taken as part of this study are 
for informational purposes only and are not to assist in grading or for any other 
assessment. 


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12. 
LABORATORY TESTS 
12.1 
Urine Pregnancy Tests 
Urine pregnancy tests must be performed on all WOCBP at baseline prior to 
randomization and at the EOS visit. All WOCBP must have a negative pregnancy test at 
baseline to be eligible for study entry. The urine pregnancy testing will be performed at 
the study site if the site is registered and conforms to CLIA regulations for such testing or 
at an appropriately registered reference laboratory. The investigator will report the urine 
pregnancy test results on the case report forms, in the subject’s medical records and in 
independent records maintained at the study site. The urine pregnancy test used must 
have a minimum sensitivity of 25mIU of β-HCG/mL of urine. 
13. 
END OF STUDY CRITERIA 
At the end of each subject’s participation in the study, the investigator will complete an 
End of Study form for all completed and discontinued subjects.  
13.1 
Completion of the Study 
Subjects who complete the two, 2-week cycles of treatment and all of the Visit 7 follow-
up evaluations at Week 14 will be considered to have completed the study.  
13.2 
Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any of the following 
reasons: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Noncompliance with study drug 
• Physician decision 
• Pregnancy 
• Progressive disease 
• Protocol violation 
• Study terminated by Sponsor 
• Withdrawal by subject 
 
If a subject withdraws prematurely for any reason, the site should make every effort to 
have the subject return for; a) their next scheduled visit to perform all required visit 
activities and to collect and reconcile all test article AND b) return for the EOS visit 
(Week 14) to perform all required visit activities and complete the EOS Case Report 
Forms. If the subject will not agree to return for the EOS visit, the site should complete 


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the EOS CRFs during the last visit that the subject will complete. Subjects who withdraw 
prematurely will not be replaced. When a subject is withdrawn from the study for a 
treatment-related adverse event, when possible, the subject should be followed until 
resolution of the adverse event. If a subject is discontinued from the study due to 
pregnancy, the pregnancy and its outcome should be followed (see Section 14.4).  
13.3 
Study Termination 
The study may be terminated by the investigator or the Sponsor. If, in the opinion of the 
investigator, clinical observations made during the study suggest that it may be unwise to 
continue, he or she may stop the study. A study termination by the investigator will be 
reported to the Sponsor. 
 
In addition, a written statement fully documenting the reasons for this action will be 
submitted to the Sponsor by the investigator within five working days. 
 
In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 
14. 
ADVERSE EVENT REPORTING 
14.1 
Definitions 
The following definitions will be utilized: 
 
Adverse Event (AE) - Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a test article, 
whether or not considered related to the test article. 
 
Adverse Drug Reaction (ADR) - Any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to 
conclude that the drug caused the event. 
 
Suspected Adverse Reaction (SAR) – Any AE for which there is a reasonable 
possibility that the drug caused the event. A “reasonable possibility” means that there is 
evidence to suggest a causal relationship between the drug and the adverse reaction. 
 
Serious Adverse Event (SAE) - Any untoward medical occurrence that at any dose in 
the view of either the investigator or the Sponsor:  
• Results in death 
• Is life-threatening (i.e., its occurrence places the patient or subject at immediate 
risk of death),  


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• Requires inpatient hospitalization or prolongation of existing hospitalization with 
the following exceptions: 
 Hospitalization for preplanned treatment for an existing condition 
 Hospitalization for social reasons (in countries which permit such 
hospitalization) 
 Hospitalization required for protocol-required-testing or efficacy 
measurement. 
• Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or  
• Is a congenital anomaly/birth defect 
• Important medical event 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or patient may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in hospitalization, or the development of drug dependency or drug abuse. 
 
Unexpected adverse drug reaction: An AE, whether serious or non-serious, is 
designated an unexpected (unlabeled) drug related event if it is not consistent with the 
risk information in the Investigator Brochure, general investigational plan or Package 
Insert (marketed drugs) or if the event is shown to have a materially greater frequency or 
severity than previously reported; then such event(s) will be reported to the investigators 
if, in the opinion of the medical monitor, such findings represent a material drug related 
event. 
 
Test article: A pharmaceutical form of an active ingredient (or “primary operational 
component” for devices) or vehicle/placebo being tested or used as a reference in the 
study, whether blinded or unblinded.  
14.2 
Reporting of Adverse Events 
Throughout the clinical trial the clinical trial staff will question the subject in a non-
directive way as to the occurrence of adverse events. All adverse events which were not 
present at screening must be recorded in the subjects’ case report forms, whether 
observed by the investigator, the investigator’s staff, or spontaneously reported by the 
subjects. If known, the investigator should report the diagnosis of the underlying illness 
or disorder, rather than its individual symptoms. Follow-up of adverse events will 
continue through the last day of the study, until the investigator determines outcome, 
stabilization, and/or resolution of the event, or not-relatedness to study medication, or up 
to 30 days after the last dose of study drug. For SAEs this can occur before or after day 


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30. In the event of death, if an autopsy is performed, a copy of the report should be sent 
to 
 
 
The most common AEs reported with the use of imiquimod cream, 2.5% include LSRs 
listed by decreasing frequency: erythema, scabbing/crusting, flaking/scaling/dryness, 
edema, erosion/ulceration and weeping/exudate. Other application site reactions that have 
been reported include pruritus, irritation, pain, bleeding and swelling. LSRs may range in 
severity from mild to severe and may extend beyond the treatment area to the 
surrounding skin. LSRs occurring within the treatment area will be assessed at each visit 
and documented as detailed in Section 10.2. Any LSR that requires medical intervention 
(prescription medication) or extends beyond the 5 cm surrounding skin should be 
documented as an adverse event. Other reported AEs occurring in ≥ 2% of imiquimod 
cream, 2.5% treated subjects are listed in the Package Insert for Zyclara.  
14.2.1 Adverse Event and SAE Reporting Period 
The AE and SAE reporting period starts following the subject’s written consent to 
participate in the clinical trial with the first trial related procedure and ends after the last 
treatment dose.  
Adverse events classified as “serious” require expeditious handling and reporting to TI to 
comply with regulatory requirements. All SAEs whether related or unrelated to test 
article must be immediately reported to TI by email, telephone or confirmed facsimile 
transmission to the Medical Monitor or Project Manager listed on the first page of the 
protocol. Follow-up of AEs and SAEs is to occur as described in Section 14.2. 
14.2.2 Assessment of AEs 
The investigator must assess all AEs using the following criteria: 
14.2.2.1 
Severity 
The term severity is described as the intensity grade or level for a specific event, i.e., 
mild, moderate, severe. Importantly, severity is not the same as seriousness, which is 
based on participant/event outcome or action criteria usually associated with events that 
pose a threat to a subject’s life or functioning (ICH E2A). The following definitions 
should be used to assess the severity of adverse events: 
 
• 
Mild: an AE that is easily tolerated  
• 
Moderate: an AE sufficiently discomforting to interfere with daily activity  
• 
Severe: an AE that prevents normal daily activities 
14.2.2.2 
Causal Relationship 
The relationship between an adverse event and the test article will be determined by the 
investigator on the basis of his/her clinical judgment using the following definitions: 


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Certain - A clinical event that definitely: 
• follows a reasonable time relationship to drug administration. 
• follows a known or expected response pattern to the suspected medicine. 
• cannot be explained by an alternate factor (e.g. concurrent disease, drug, 
chemicals). 
• follows a clinically reasonable response on withdrawal of the suspected drug. 
• reappears on re-challenge with the offending drug. 
 
Probable - A clinical event where association of the event with the study drug seems 
likely and that: 
• follows a reasonable time relationship to drug administration. 
• follows a known or expected response pattern to the suspected medicine. 
• is unlikely to be attributed to an alternate factor (e.g. concurrent disease, drug, 
chemicals). 
• follows a clinically reasonable response on withdrawal of the suspected drug. 
 
(Re-challenge information is not required to fulfill this definition). 
 
Possible - A clinical event where a relationship between drug and event cannot be ruled 
out and that: 
• follows a reasonable time relationship to drug administration. 
• follows a known or expected response pattern to the suspected medicine. 
• can be produced by a number of other factors (e.g. concurrent disease, drug, 
chemicals). 
 
Not Related- A clinical event that is clearly not related to the use of the study drug and 
that: 
• does not follow a reasonable time relationship to drug administration. 
• does not follow a known or expected response pattern to the suspected medicine. 
14.2.2.3 
Outcome 
An AE outcome is defined as follows: 
• Fatal - Termination of life as a result of an AE. 
• Not Recovered/Not Resolved - AE has not improved or recuperated. 
• Recovered/Resolved with Sequelae - Subject recuperated but retained the 
pathological conditions resulting from the prior disease or injury. 
• Recovered/Resolved - AE has improved or recuperated. 
• Recovering/Resolving - AE is improving. 
• Unknown - Not known, not observed, not recorded or refused. 


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14.2.2.4 
Treatment Required 
• Yes (if yes, specify on concomitant therapy page of the CRF) 
• No 
14.2.3 Procedure for Reporting of Serious Adverse Events 
14.2.3.1 
Notification by Investigator to 
 
A Serious Adverse Event (SAE) form must be completed by the investigator and faxed to 
the Medical Monitor or Project Manager noted on page 1 of the protocol within 24 hours 
after becoming aware of the event. The investigator will keep the original of this SAE 
form on file at the study site. The Medical Monitor will inform the Sponsor within 24 
hours of their notification of the event. At the time of the initial report, the following 
information should be provided at a minimum: 
 
o Study identifier 
o Study Center 
o Subject Number 
o A description of the event 
o Date of onset 
o Date investigator was informed of 
the event 
o Current status 
 
o Whether study treatment was 
discontinued 
o The reason why the event is classified as 
serious 
o Investigator assessment of the association 
between the event and trial treatment 
o Blinding status (randomization code 
broken or not) of subject 
o If the Test Article was administered and 
date of the administration 
Even if all the information is not known, an initial report should be made. The 
investigator is obliged to provide follow-up information within 3 days of the initial report 
on a Serious Adverse Event form, and any other diagnostic information that will assist 
the understanding of the event. 
 
Significant new information on ongoing serious adverse events should be provided 
promptly to the Medical Monitor or Project Manager as a follow-up report.  
 
Documents relevant to the diagnosis, treatment and course of the event must be submitted 
(e.g. technical investigation reports, histology findings, case report forms, hospital 
discharge documents). All documents must be blinded with respect to subject’s name. 
 
When the investigator determines that there is no more information likely to be available, 
a final report should be provided. 
 
Serious adverse events that are still ongoing at the end of the study period must be 
followed up to determine the final outcome, if possible (see Section 14.2). Any serious 


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adverse event that occurs after the study period and is considered to be possibly related to 
the study treatment or study participation should be recorded and reported to the Medical 
Monitor within 24 hours. 
14.2.4 IRB/IEC Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
according to local requirements. Copies of each report and documentation of IRB/IEC 
notification and receipt will be kept in the Clinical Investigator’s Regulatory binder. 
As required, 
 will notify investigators of all AEs that are serious, unexpected, and 
certainly, probably or possibly related to the test article. This notification will be in the 
form of a Safety Update to the Investigator Brochure (i.e., “15-day letter”).  
 
Upon receiving such notices, the investigator must review and retain the notice with the 
Investigator’s Brochure and immediately submit a copy of this information to the 
responsible IRB according to local regulations. The investigator and IRB will determine 
if the informed consent requires revision. The investigator should also comply with the 
IRB procedures for reporting any other safety information. Where required, submission 
of Safety Updates by the investigator to Health Authorities should be handled according 
to local regulations. 
14.2.5 FDA Notification by Sponsor 
The study Sponsor shall notify the FDA of any unexpected fatal or life-threatening 
experience associated with the use of the drug as soon as possible but no later than seven 
(7) calendar days from the Sponsor’s original receipt of the information followed by as 
complete a report as possible within 8 additional calendar days. This report must include 
an assessment of the importance and implication of the findings, including relevant 
previous experience with the same or similar medicinal products. 
 
Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed 
as soon as possible but no later than 15 calendar days after first knowledge by the 
Sponsor that the case meets the minimum criteria for expedited reporting. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit 
the criteria for reporting, the study Sponsor will submit the adverse event in a written 
report to the FDA as soon as possible, but no later than 15 calendar days from the time 
the determination is made. 
14.3 
Laboratory Test Abnormalities 
Although there are no specific labs required in this study, any laboratory test result that 
meets the criteria for a Serious Adverse Event (see Section 14.2) must also be reported as 


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a SAE so 
 can collect additional information about that abnormality, including 
information regarding relationship to test article or other causes, any action taken, and 
resolution. 
14.4 
Pregnancy 
Women of childbearing potential (WOCBP) include any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation or bilateral ovariectomy) or is not postmenopausal (defined as 
amenorrhea >12 consecutive months and for women on hormone replacement therapy, 
only with a documented plasma follicle stimulating hormone level greater than 35 
mIU/mL). In cases where a woman’s partner is sterile (e.g., vasectomy), she is considered 
to be of childbearing potential. Even women who are using oral, implanted or, injectable 
contraceptive hormones, an intrauterine device (IUD), barrier methods (diaphragm and 
spermicidal, condom and spermicidal) to prevent pregnancy, or practicing abstinence 
should be considered to be of childbearing potential. Post-menopausal women who have 
fertilized eggs implanted are considered to be of childbearing potential. 
 
All WOCBP participating in the clinical trial must use appropriate method of birth 
control or continuous abstinence from heterosexual sexual contact during the course of 
the clinical trial until the onset of the first menses after the last dose of trial medication, 
in a manner such that risk of failure is minimized  
 
Any of the following methods of birth control are acceptable: oral contraceptives, 
contraceptive patches/implants, Depo-Provera®, double barrier methods (e.g., condom 
and spermicide) or IUD. Female subjects must have a negative urine pregnancy test at 
baseline. 
 
Prior to clinical trial enrollment, all WOCBP must be advised of the importance of 
avoiding pregnancy during clinical trial participation and the potential risk factors for an 
unintentional pregnancy. The subject must sign an informed consent form (ICF) 
documenting this discussion.  
 
WOCBP should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period). The test article must 
immediately be withheld if it can be done safely until the result of pregnancy testing 
having a minimum sensitivity of at least 25 mIU/mL for hCG is known. If pregnancy is 
confirmed, the test article must be permanently discontinued if this can be done safely 
and in an appropriate manner (e.g., dose tapering if necessary for subject safety) and the 
subject must be withdrawn from the clinical trial. Exceptions to clinical trial 
discontinuation may be considered for life-threatening conditions only after consultation 
with the Medical Monitor. The investigator must follow the subject to determine the 
outcome and follow up the neonate for 8 weeks post -delivery to know the outcome and 
health status of the neonate. 


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Protocol-required procedures for clinical trial discontinuation and follow-up must be 
performed unless contraindicated by pregnancy (e.g., x-ray studies). Appropriate 
pregnancy follow-up procedures should be considered if indicated. 
14.4.1 Reporting Procedure 
The investigator must report any pregnancy associated with exposure to test article within 
24 hours of becoming aware of the pregnancy using the appropriate 
 pregnancy 
surveillance form(s) to the Medical Monitor or Project Manager listed on page 1 of the 
protocol. If pregnancy was associated with an AE, procedures for AE reporting should be 
followed. If pregnancy was associated with a SAE, procedures for SAE reporting must be 
followed. Spontaneous abortion is always considered a serious adverse event. The 
investigator must report information regarding the course of the pregnancy, including 
perinatal and neonatal outcome on the 
 pregnancy surveillance form(s). The 
investigator must notify the IRB of any pregnancy associated with the study therapy and 
keep careful source documentation of the event. 
15. 
BLINDING/UNBLINDING 
This is a double-blind, randomized, vehicle-controlled study. Blinding is important for 
the integrity of this clinical drug trial. However, the blind may be broken in the event of a 
medical emergency in a subject, in which knowledge of the test article identity is critical 
to the subject’s management. Before breaking the blind for a subject, the investigator 
should determine that the information is necessary (i.e., that it will alter the subject’s 
immediate management). In many cases, particularly when the emergency is clearly not 
test article related, the problem may be effectively managed by assuming that the subject 
is receiving active product without the need for unblinding. If possible, before breaking 
the blind, contact the responsible Medical Monitor. 
16. 
CLINICAL SUPPLIES 
16.1 
Test Article Information 
Test articles will be packaged and labeled by the Sponsor or designee. Detailed 
information on the packaging/labeling, blinding/unblinding, storage and preparation, 
dispensing, accountability etc. is included in Appendix 2. 
16.2 
Additional Supplies Provided by 
 
 will provide the following additional supplies to the study sites: 
• Case report forms. 
• Site Regulatory Binder or document filing system. 
• Urine pregnancy test kits. 


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• Large plastic bags for subjects to transport study drugs, diary and instruction 
sheet. 
• Miscellaneous supplies such as markers for AK counting. 
16.3 
Supplies Provided by Investigator 
• Urine collection containers. 
16.4 
Supplies Provided by Actavis, LLC 
• Pumps containing vehicle cream for demonstration to subjects of test article 
application. 
17. 
STATISTICAL CONSIDERATIONS 
17.1 
Sample Size 
 
 
 
ioequivalence was concluded if the 90% continuity-corrected confidence 
interval on the difference in active treatment complete clearance rates was between -0.20 
and +0.20 in the per protocol (PP) population, and each active treatment was found to be 
statistically superior to the vehicle by independent continuity-corrected Z-tests in the 
intent-to-treat (ITT) population. 
 
 
 total of 435 ITT subjects 
 
for demonstrating superiority of each active treatment 
over the vehicle treatment. 
 
 
. 
17.2 
Endpoints 
17.2.1 Efficacy Endpoint(s) 
Complete clearance rate (treatment success), defined as the proportion of subjects in each 
treatment group at Visit 7 (Week 14/ End of Study) in the per-protocol (PP) population 
with a count of zero AK lesions in the treatment area. All AKs (baseline and new lesions) 
independent of size within the treatment area will be included in the efficacy lesion count 
for each visit. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 41 of 55 
 
17.2.2 Safety Endpoint(s) 
17.2.2.1 
Dosing Compliance 
Measures of test article compliance will include the total number of applications as 
determined from the data recorded in the subject diaries. 
17.2.2.2 
Adverse Events 
Safety endpoints will also include assessment of the severity and frequency of adverse 
events including local skin reactions (LSRs) in the three treatment groups. 
17.3 
Statistical Methods 
All statistical processing will be performed using SAS® unless otherwise stated. The 
Safety population will include all randomized subjects who received the test article.  
 
The Intent-to-Treat (ITT) population will include all randomized subjects who applied at 
least one dose of test article and returned for at least one post-baseline evaluation visit. 
 
Subjects will be included in the PP efficacy analyses if they met all the inclusion/exclusion 
criteria, were compliant with the assigned test articles (applied at least 75% and no more 
than 125% of the test article applications and no other evidence of material dosing 
noncompliance), completed the evaluation at Week 14 within the designated visit window 
(± 4 days) with no protocol violations that would affect treatment evaluation. Subjects who 
are discontinued from the study due to lack of treatment effect or due to worsening 
condition that requires alternate or supplemental therapy for the treatment of AK should be 
included in the PP population as treatment failures (non-responders). Subjects discontinued 
prematurely for other reasons should be excluded from the PP population, but included in 
the ITT population using the Last Observation Carried Forward (LOCF) to impute missing 
values for efficacy variables. 
 
Efficacy summaries and analyses will be carried out in the ITT and PP populations. All 
summaries of safety will be carried out in the safety population.  
 
Demographic and baseline characteristics will be summarized by treatment group for the 
ITT and PP populations. The size of the treatment area (in centimeters) at baseline will be 
determined from an estimate of the % BSA treated. BSA will be determined from the 
subject’s height and weight using the Mosteller formula. Frequency counts and 
percentages will be reported for categorical data. Sample size, mean, standard deviation, 
and minimum and maximum will be reported for the continuous variables. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 42 of 55 
 
17.3.1 Efficacy Analyses  
The primary efficacy endpoint is the complete clearance rate (treatment success), defined 
as the proportion of subjects at the EOS visit in the PP population with a count of zero 
AK lesions in the treatment area. All AKs (baseline and new lesions) independent of size 
within the treatment area will be included in the efficacy lesion count for each visit. 
 
The 90% Wald’s confidence interval with Yate’s continuity correction will be 
constructed on the difference between the proportions of subjects with lesion clearance in 
the Test and Reference treatments to evaluate the therapeutic comparability of the two 
active treatments. Two-sided, continuity-corrected Z-tests will be used to evaluate the 
superiority of each active treatment’s clearance proportion over that of the Vehicle 
treatment. 
 
If the 90% confidence interval on the difference between the Test and Reference lesion 
clearance proportions is contained within the interval -0.20 to +0.20, and each of these 
proportions is greater than, and statistically different (p<0.05) from, the Vehicle 
proportion, then the Test and Reference products will be considered to be therapeutically 
equivalent. 
 
The therapeutic comparability evaluations in the PP population will be considered 
primary while those in the ITT will be considered supportive. The superiority 
comparisons in the ITT population will be considered primary while those in the PP 
population will be considered supportive. 
17.3.2 Safety Analyses 
All subjects in the safety population will be included in summaries of safety data.  
17.3.2.1 
Dosing Compliance 
Descriptive statistics will be used to summarize test article compliance for the ITT and 
PP populations. Measures of test article compliance will include the total number of 
applications as determined from the subject diaries. Compliant subjects are defined as 
those who apply at least 75% and no more than 125% of the test article applications and 
no other evidence of material dosing noncompliance. 
17.3.2.2 
Adverse Events 
Adverse events will be coded using the MedDRA coding dictionary. The number and 
percent of unique subjects reporting each treatment-emergent AE will be summarized by 
MedDRA system organ class (SOC), MedDRA preferred term (PT), and treatment group. 
AEs will also be similarly summarized by SOC, PT, maximum severity, and treatment 
group as well as by SOC, PT, closest relationship to study drug, and treatment group. All 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 43 of 55 
 
adverse events (AEs) reported during the study will be listed, documenting course, 
severity, investigator assessment of the relationship to the test articles, and outcome.  
17.3.2.3 
Local Skin Reactions 
LSRs will be summarized by treatment group by the most intense score for each LSR and 
by the sum score at each visit and over the course of the study. The frequency of the 
individual LSRs will be tabulated by severity and treatment group at each visit. 
17.3.3 Other Analyses 
17.3.3.1 
Medical History 
Medical history events will be coded using the MedDRA dictionary. The number and 
percent of unique subjects reporting each medical history will be summarized by 
MedDRA system organ class (SOC), MedDRA preferred term (PT), and treatment group.  
17.3.3.2 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary and will be 
summarized by treatment group, drug class (pharmacological level) and drug name 
(chemical substance level). 
17.4 
Subgroup Analyses 
No subgroup analyses are planned.  
17.5 
Interim Analyses 
No interim analyses are planned.  
18. 
ETHICAL AND REGULATORY CONSIDERATIONS 
18.1 
Compliance with Good Clinical Research Practice 
This study will be conducted in compliance with the principles of the Declaration of 
Helsinki, with the current Good Clinical Practice (GCP) guidelines and with other 
applicable regulations. The investigator and all study staff will conduct the study in 
compliance with this protocol. The protocol, informed consent documents, recruitment 
advertisements and any amendments to these items will have Institutional Review Board 
(IRB) approval prior to study initiation. Voluntary informed consent will be given by 
every subject prior to the initiation of any study-related procedures. The rights, safety and 
well-being of the study subjects are the most important considerations and prevail over 
the interests of science and society. All personnel involved in the conduct of this study 
must be qualified by education, training and experience to perform their assigned 
responsibilities. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 44 of 55 
 
18.2 
Institutional Review Board (IRB) and Informed Consent 
Before study initiation, the investigator must have written and dated approval from the 
IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The 
investigator should also provide the IRB with a copy of the product labeling, information 
to be provided to subjects and any updates. The investigator will submit documentation 
of the IRB approval to 
  
 
The IRB approved consent form must include all elements required by FDA, state, and 
local regulations, and may include appropriate additional elements. 
 
The investigator/designee will explain the study to each potential subject and the subject 
must indicate voluntary consent by signing and dating the approved informed consent 
form. The investigator must provide the subject with a copy of the consent form, in a 
language the subject understands.  
 
The investigator will maintain documentation that informed consent was obtained prior to 
the initiation of any study-specific procedures. 
18.3 
Protocol Compliance 
The IRB approved protocol must be followed except in the case of a change that is 
intended to eliminate an immediate risk to subjects. All protocol deviations must be 
documented.  
18.4 
Protocol Revisions 
 must prepare all protocol revisions. All protocol amendments must 
receive IRB approval prior to implementation. All administrative letters must be 
submitted to the IRB for their information. Copies of all correspondence with the IRB 
regarding this study must be sent to 
 
 
New or altered consent forms required by the IRB due to a protocol change must be 
signed by all subjects currently enrolled in the study and must be used for any subsequent 
subject enrollment. 
18.5 
Study Monitoring 
Representatives of 
. and/or the Sponsor must be allowed to visit all 
study sites, to review study records and to directly compare them with source documents 
(including, but not limited to patient and hospital records), to discuss the study conduct 
with the investigator and study staff and to verify that the investigator, study staff and 
facilities remain acceptable for the conduct of the study. 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 45 of 55 
 
Representatives of the Food and Drug Administration and other government regulatory 
authorities may also evaluate the study records, source documents, investigator, study 
staff and facilities. 
 
The investigator should immediately notify 
 of any audits of this study 
by any regulatory agency, and must promptly provide copies of any audit reports. 
 will notify the Sponsor of any audits of the study by any regulatory 
agency.  
18.6 
Case Report Form Requirements 
The study will utilize validated 21CFR Part 11 compliant electronic data capture (EDC) 
software to collect CRF data. All requested information must be entered on the CRFs in 
the areas provided in a timely manner. When changes or corrections are made in the 
CRF, the EDC system will maintain a complete audit trail of the person making the 
changes, the date and time of the change and the reason for the change. Only individuals 
listed on the Delegation of Responsibilities Log with responsibility for CRF completion 
may make entries on the CRFs. Usernames and passwords will be provided to each 
authorized user to allow access to the training module. Access to additional features and 
functions will not be enabled until the user has successfully completed the training. 
 
The investigator or physician sub-investigator must electronically sign and date each 
subject’s CRF. Individuals who will be providing electronic signatures must first submit 
documentation with a handwritten signature acknowledging that their electronic signature 
is a legally binding equivalent to their handwritten signature. 
18.7 
Reports to Institutional Review Board 
The investigator should provide the IRB with reports, updates, and other information 
(e.g., safety updates, protocol amendments, and administrative letters) according to 
regulatory requirements or Institution procedures. 
18.8 
Quality Assurance Audits 
Representatives from 
 and/or the Sponsor or a third party selected by 
the Sponsor may conduct a quality assurance (QA) audit of this study. During the audit, 
the investigator must provide the auditor with direct access to all relevant documents and 
discuss any findings with the auditor. 
 
In the event of an inspection by the FDA or other regulatory authorities, the investigator 
must give the inspector direct access to relevant documents and to discuss any findings 
with the inspector.  


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 46 of 55 
 
18.9 
Records Retention 
According to Title 21 of the Code of Federal Regulation § 312.62, an investigator is 
required to maintain study records for a period of two (2) years following the date a 
marketing application is approved for the drug 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 two (2) years after the investigation is discontinued and the FDA is 
notified. 
 
In accordance with 21CFR § 320.38, each reserve sample (retain) shall be stored under 
conditions consistent with product labeling and in an area segregated from the area where 
testing is conducted and with access limited to authorized personnel. Each reserve sample 
shall be retained for a period of at least five (5) years following the date on which the 
application or supplemental application is approved, or, if such application or 
supplemental application is not approved, at least five (5) years following the date of 
completion of the bioavailability study in which the sample from which the reserve 
sample was obtained was used. 
 
The investigator must contact 
 or the Sponsor prior to destroying any 
records or reserve samples associated with this study. 
 
If the investigator withdraws from the study, the records shall be transferred to a mutually 
agreed upon designee. Written notification of such a transfer must be given to 
 
18.10 Record Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified 
in a manner designed to maintain subject confidentiality. All records will be kept in a 
secure storage area with limited access. Clinical information will not be released without 
the written permission of the subject or the subject’s guardian, except as necessary for 
monitoring by 
 or the Sponsor, the FDA or other regulatory authority, 
or the IRB/IEC. 
 
The investigator and all employees and coworkers involved with this study shall not 
disclose or use for any purpose other than performance of the study, any data, records, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from 
 or the Sponsor must be 
obtained for the disclosure of any said confidential information to other parties. 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 47 of 55 
 
19. 
REFERENCES 
1. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% 
and 3.75% for the treatment of actinic keratoses: Results of two placebo-controlled 
studies of daily application to the face and balding scalp for two 2-week cycles. J Am 
Acad Dermatol 2010; 4:582-90.  
2. Zyclara® (imiquimod) Cream, 2.5% Prescribing Information, Issued February 2012, 
Distributed by Medicis, The Dermatology Company. 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 48 of 55 
 
APPENDIX 1 
SUBJECT INSTRUCTION SHEET 
Copies of the following subject instructions will be provided to the study site. The 
investigator must give each subject a copy of this instruction sheet at Visit 1. 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 49 of 55 
 
Sample Subject Instruction Sheet 
 
 
 ⁭
 ⁭
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please follow these instructions carefully. Contact the study staff at the telephone number below, 
if you have any questions about the study. 
 
Name:_______________________________ 
Phone: ____________________________ 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 50 of 55 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 51 of 55 
 
SUBJECT INSTRUCTIONS FOR THE PREPARATION 
(PRIMING), DISPENSING AND APPLICATION OF 
CREAMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 52 of 55 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 53 of 55 
 
A 2.1 Test Article Packaging and Labeling 
 
 
 
 
 
 
  
 
Carton Label 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Kit Label 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 54 of 55 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Pump Label 
 
 
 
 
 
 
 
 
 
 
 
 
A 2.2 Retains 
 
 
 
A 2.3 Test Article Storage and Preparation 
Test article should be stored at room temperature [25°C (77°F); excursions permitted 
from 15°C to 30°C (59°F to 86°F)] in a secure area according to local regulations.  
A 2.4 Dispensing Test Article 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 by authorized personnel as required by applicable regulations and 
guidelines. 
A 2.5 Test Article Supply Records at Study Sites 
It is the responsibility of the investigator to ensure that a current record of disposition is 
maintained. Records or logs must comply with applicable regulations and guidelines, and 
should include: 
• Amount received placed in storage area. 
• Amount currently in storage area. 
• Label ID number or batch number. 
• Dates and initials of the person responsible for each product inventory 
entry/movement. 


Product Name: Generic Imiquimod, 2.5% 
 
 
Sponsor Name: Actavis, LLC 
 
Protocol: 094-3153-301, v1.0 
 
CONFIDENTIAL 
Page 55 of 55 
 
• Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
• Amount transferred to another area for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount returned to Sponsor. 
• Amount destroyed at study site, if applicable. 
• Retain samples sent to third party for bioavailability/bioequivalence, if applicable. 
A 2.6 Dose Interruptions 
Temporary dosing interruptions (rest periods) may be instituted by the investigator as 
needed to manage LSRs or AEs. Treatment should be resumed upon adequate resolution 
as determined by the investigator. However, doses missed due to rest periods or for other 
reasons will not be made up and the duration of each dosing cycle must remain at 14 
days. Dosing interruptions should be noted on the subject diary and documented in the 
subject’s CRF (see Section 6.3). 
A 2.7 Documentation of Test Article Application and Compliance 
Subjects will be instructed to document the application of test article and any missed or 
held doses on the subject diary.  
A 2.8 Return and Destruction of Test Article Supplies 
At the completion or termination of the study, all unused and/or partially used test articles 
must be returned by a traceable method. All missing pumps must be explained on the 
completed Test Article Accountability Log. The investigator must keep the original Label 
pages and Test Article Accountability Log in the site study file. Photocopies of the 
original Test Article Accountability Log and Label pages will be kept with the study 
records at 
. All shipment of returned test article must be labeled with the investigator’s 
name, address, and the protocol number. Return all test article in the original containers 
by a traceable means (e.g., 2-day FedEx shipping) to: 
 
Watson Laboratories, Inc. 
 
 
 
Upon receipt of the test articles, a Sponsor representative will perform a final 
reconciliation. 
will be notified of any missing test article. 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
A Multicenter, Randomized, Double-Blind, Vehicle-Controlled, Parallel Group 
Comparison Study to Determine the Therapeutic Equivalence of Generic Imiquimod 
Cream, 2.5% and ZyclaraTM (Imiquimod) Cream 2.5% in Subjects with Actinic Keratoses 
 
 
Study Number 094-3153-301 
 
NCT02120898 
 
Statistical Analysis Plan Approval Date: 08 April 2014  
 


Appendix 16.1.9 
Documentation of Statistical Methods 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
 
 
 
STATISTICAL ANALYSIS PLAN 
Statistical Analysis Plan 
 
 
 
Title: 
 A Multicenter, Randomized, Double-Blind, Vehicle-Controlled, 
Parallel Group Comparison Study to Determine the Therapeutic 
Equivalence of Generic Imiquimod Cream, 2.5% and Zyclara™ 
(Imiquimod) Cream 2.5% in Subjects with Actinic Keratoses 
Protocol Number: 
094-3153-301 
Sponsor: 
Actavis Elizabeth LLC 
TI Project Number: 
094-3153-301 
Date: 
08 April 2014 
Status: 
vl.0 
 
 
 
 
 
 
 
 
 
 
 
094-3153-301- SAP- 08APR2014- vl. 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 16 


 
Generic lmiquimod Cream. 2.5% 
Protocoi 094-3153-30 l 
Actavis Elizabeth. LLC _     
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This statistical analysis plan has been reviewed and approved by: 
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094-3153-301 --SAP·---08APR2014 vl. 0-2 
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Page 2 or 16 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
Statistical Analysis Plan 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................... 5 
2 
PURPOSE OF THE ANALYSES .................................................................................. 5 
3 
STUDY OBJECTIVES ................................................................................................... 5 
4 
STUDY DESIGN ............................................................................................................ 5 
5 
STUDY SCHEDULE AND PROCEDURES ................................................................ 7 
5.1 
Study Schedule .......................................................................................................... 7 
5.2 
Procedures at Study Assessment Time Points......................................................... 7 
6 
EFFICACY AND SAFETY MEASUREMENTS ......................................................... 9 
6.1 
Efficacy Measurements ............................................................................................ 9 
6.1.1 
AK Lesion Counts ............................................................................................. 9 
6.2 
Safety Measurements ................................................................................................ 9 
6.2.1 
Laboratory ......................................................................................................... 9 
6.2.2 
Local Skin Reactions (LSR) Assessments ..................................................... 10 
6.2.3 
Adverse Events ................................................................................................ 10 
6.2.4 
Concomitant Medications and Concurrent Therapies/Procedures ............... 11 
7 
DATA SETS ANALYZED ........................................................................................... 11 
8 
STATISTICAL METHODS ......................................................................................... 11 
8.1 
General Considerations .......................................................................................... 11 
8.2 
Efficacy Endpoints .................................................................................................. 12 
8.2.1 
Primary Endpoint ............................................................................................ 12 
8.3 
Safety Endpoints ..................................................................................................... 12 
8.3.1 
Dosing Compliance ......................................................................................... 12 
8.3.2 
Adverse Events and LSRs .............................................................................. 12 
8.4 
Subject Disposition ................................................................................................. 12 
8.5 
Methods for Handling Missing Data ..................................................................... 13 
8.6 
Screening and Baseline Assessments .................................................................... 13 
8.6.1 
Demographic and Baseline Characteristics ................................................... 13 
8.6.2 
Medical History and Dermatologic Exam ..................................................... 13 
8.6.3 
Vital Signs ....................................................................................................... 13 
8.6.4 
Prior Medications and Therapies/Procedures Identified in the Exclusion 
Criteria 13 
8.6.5 
Concomitant Medications and Concurrent Therapies/Procedures ............... 14 
8.6.6 
Dosing Compliance ......................................................................................... 14 
8.7 
Efficacy Analyses ................................................................................................... 14 
8.7.1 
Primary Efficacy Analyses ............................................................................. 14 
8.8 
Safety Analyses ....................................................................................................... 15 
8.8.1 
Adverse Events ................................................................................................ 15 
8.8.2 
LSRs ................................................................................................................. 15 
8.8.3 
Urine Pregnancy Tests .................................................................................... 15 
8.9 
Sample Size ............................................................................................................. 15 
8.10 
Protocol Deviations ............................................................................................. 16 
8.11 
Interim Analysis .................................................................................................. 16 
8.12 
Subgroup Analyses ............................................................................................. 16 
094-3153-301- SAP- 08APR2014- vl. 0 
Page 3 of 16 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
Statistical Analysis Plan 
GLOSSARY OF TERMS 
 
ADR 
AE 
AK 
ATC 
BSA 
CRF 
CSR 
EOS 
ITT 
LOCF 
LSR 
MedDRA 
pp 
PT 
SAE 
SAP 
SAR 
soc 
 
UPT 
WHO 
WOCBP 
 
Adverse Drug Reaction 
Adverse Event 
Actinic Keratosis 
Anatomical Therapeutic Classification 
Body Surface Area 
Case Report Form 
Clinical Study Report 
End of Study 
Intent-to-Treat 
Last Observation Carried Forward 
Local Skin Reaction 
Medical Dictionary for Regulatory Activities 
Per-Protocol 
Preferred Term 
Serious Adverse Event 
Statistical Analysis Plan 
Suspected Adverse Reaction 
System Organ Class 
 
Urine Pregnancy Test 
World Health Organization 
Women of Childbearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
094-3153-301- SAP- 08APR2014- vl. 0 
Page 4 of 16 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
1 
INTRODUCTION 
Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be 
performed for data from Protocol 094-3153-301, "A Multicenter, Randomized, Double­ 
blind, Vehicle-controlled, Parallel Group Comparison Study to Determine the 
Therapeutic Equivalence of Generic Imiquimod Cream, 2.5% and Zyclara™ (Imiquimod) 
Cream 2.5% in Subjects with Actinic Keratoses." 
 
This SAP was created using Clinical Protocol 094-3153-301 Version 1.0 dated 30 July 
2013 and the Case Report Forms for Protocol 094-3153-301 Version 1.0 dated 04 
October 2013. 
2 
PURPOSE OF THE ANALYSES 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
Clinical Study Report (CSR) for Protocol 094-3153-301. Any post-hoc or unplanned 
analyses not identified in this SAP will be clearly identified in the CSR. 
3 
STUDY OBJECTIVES 
The objective is to evaluate the safety and therapeutic equivalence1 of generic imiquimod 
cream, 2.5% to Zyclara™ (imiquimod) Cream, 2.5% and to establish the superiority of 
the efficacy of these two products over the vehicle cream in the treatment of actinic 
keratoses (AK). 
4 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel group 
comparison study of a generic imiquimod cream, 2.5% and Zyclara™ (imiquimod) 
cream, 2.5% in subjects with AK on the full face or balding scalp. Approximately 435 
subjects with at least 5 but no more than 20 clinically typical, visible or palpable AK 
lesions at least 4 mm in diameter on either the face (excluding the ears) or the balding 
scalp who fulfill the eligibility criteria as defined in the protocol (including 
inclusion/exclusion criteria) will be enrolled at approximately 25 US study sites. 
 
Subjects will be randomized to one of three treatment groups on a 
 basis as follows: 
• 
Imiquimod cream, 2.5% (Actavis) 
• 
Zyclara™ (imiquimod) cream, 2.5% (Medicis) 
• 
Vehicle cream (Actavis) 
 
Subjects who are eligible for enrollment into the study will be randomized by assigning 
the lowest subject kit number available at the site. All subjects will apply the assigned 
test article to the designated treatment area (full face or balding scalp) identified by the 
investigator at Visit 1. The assigned test article will be applied once daily for two, 2- 
week treatment cycles separated by a 2-week no treatment interval. Subjects will also 
return for an End of Study (EOS) Visit, 8 weeks post-treatment. At the end of the study, 
 
1 "Therapeutic equivalence" is synonymous with the term "bioequivalence with clinical  endpoint" as used 
in Draft Guidance on Imiquimod, Feb 2011. 
 
094-3153-301- SAP- 08APR2014- vl. 0 
Page 5 of 16 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
Statistical Analysis Plan 
safety and efficacy outcome measures will be compared to a) determine if dosing with 
generic imiquimod cream, 2.5% is clinically equivalent to the currently marketed Zyclara 
(imiquimod) cream, 2.5% and b) both imiquimod 2.5% creams are superior in 
comparison to the vehicle cream. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
094-3153-301_SAP_08APR2014_vl. 0 
Page 6 of 16 


Generic Imiquimod Cream, 2.5% 
Protocol 094-3153-301 
 
Actavis Elizabeth LLC 
5 
STUDY SCHEDULE AND PROCEDURES 
5.1 
Study Schedule 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
Treatment Period 
Treatment Cycle= Test Article Application Once Daily for 14 Consecutive Days 
Treatment Cycle I-Visit 1 to Visit 3 Treatment Cycle 2-Visit 4 to Visit 6 
Informed Consent2 
X 
Medical History, Demographics 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
Brief Physical Exam including 
Dermatologic Exam and Vital 
Sign Assessment 
X 
Inclusion/Exclusion Criteria 
X 
Treatment Area (Face or Balding 
Scalp) ID • Location & Size 
X 
AK Lesion Count 
X 
X 
X 
Local Skin Reaction (LSR) 
Assessment 
X 
X 
X 
X 
X 
Confirm Next Visit Appointment, 
Review Dosing Instructions and 
Query About AEs. 
X 
X 
Pregnancy Testing3for WOCBP 4 
X 
X 
Issue Subject Diary 
X 
X 
Review/ Collect Subject Diary for 
Compliance 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Dispense/Return Test Article 
(Perform Drug Accountability) 
X 
X 
X 
X 
5.2 
Procedures at Study Assessment Time Points 
The study consists of five protocol-specified visits and two follow-up phone contacts as 
follows: 
 
 
2 Informed consent may be obtained within 30 days prior to the Baseline Visit. 
3 Urine pregnancy tests must have a minimum sensitivity of 25 mIU 13-hCG/mL of urine and must be performed within 
24 hours prior to the start of test article at baseline. 
4 See Protocol Section 14.4 for definition of woman of childbearing potential (WOCBP). 
 
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• 
Visit 1 /Screening/ Baseline/ Day -30 to 1 
Statistical Analysis Plan 
Study subjects may be consented up to 30 days before Visit 1. If no washout from 
prohibited medications or treatments is required, the Screening and Baseline Visits 
may occur the same day. Procedures to be performed include: 
Informed consent 
Identify Treatment Area 
Inclusion/exclusion criteria review 
%BSA of the Treatment Area 
UPT for WOCBP 
AK lesion count 
Medical history 
Demographics 
Prior and/or concomitant therapies 
Brief dermatologic exam 
Vital signs assessment 
Diameter of each AK lesion 
LSR assessment 
Randomize the subject 
Dispense test article 
Issue subject diary 
 
• 
Visit 2 - Phone Call (Week 1/Day 8 ± 2) 
The subject will be queried regarding changes in health status or any adverse events 
since the last visit. The application instructions will be reviewed and the next visit 
confirmed. 
 
• 
Visit 3 (Week 2 I Day 15 + 3) 
Procedures to be performed include: 
LSR assessment 
Collect and review subject diary 
 
 
• 
Visit 4 (Week 4 / Day 29 ± 2) 
Procedures to be performed include: 
LSR assessment 
Issue subject diary 
Dispense test article pumps 
Collect used and unused test article pumps 
Adverse events 
Concomitant therapies 
 
 
 
Adverse events 
Concomitant therapies 
 
• 
Visit 5 - Phone Call (Week 5/Day 36 ± 2) 
The subject will be queried regarding changes in health status or any adverse events 
since the last visit. The application instructions will be reviewed and the next visit 
confirmed. 
 
• 
Visit 6 (14-17 Days after Visit 4) 
Procedures to be performed include: 
AK lesion count 
LSR assessment 
Collect and review subject diary 
 
 
 
 
 
 
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Collect used and unused test article pumps 
Adverse events 
Concomitant therapies 
 
 
 
 
 
 
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• 
Visit 7 (Week 14 / Day 99 ± 4) 
Procedures to be performed include: 
AK lesion count 
LSR assessment 
Collect and review subject diary 
UPT for WOCBP 
Adverse events 
Concomitant therapies 
Statistical Analysis Plan 
 
 
End of Study Form 
 
• 
Unscheduled Visits 
Unscheduled visits occur at the investigator's discretion with the following 
procedures to be performed: 
LSR assessment 
Review subject diary 
Adverse events 
Concomitant therapies 
6 
EFFICACY AND SAFETY MEASUREMENTS 
6.1 
Efficacy Measurements 
6.1.1 AK Lesion Counts 
AK lesion counts within the Treatment Area (full face or balding scalp) will be 
performed at Visits 1, 6 and 7 by the investigator or qualified designee. All AK lesions 
(baseline AKs and new AKs), independent of size, in the Treatment Area will be 
identified, counted, and recorded. The number of AK lesions in the Treatment Area that 
are 
4 mm in diameter and the diameter of each AK lesion in the treatment area will be 
documented at the Baseline Visit. The Treatment Area at Baseline must include 5 to 20 
clinically typical, visible or palpable AKs each at least 4 mm in diameter, in an area 
greater than 25 cm2on either the face (excluding ears) or the balding scalp, but not both. 
At Visits 6 and 7, the number of total AK lesions in the treatment area will be counted 
and the number of new AKs will be identified. A new AK is defined as a lesion that was 
not present at the Baseline Visit. 
If the AK count cannot be performed due to a LSR this will be documented on the CRF. 
The AK clearance rate for a subject will be calculated as follows: 
{1 - [ (#AKs at follow-up)/ (#AKs at Baseline)]}* 100. 
 
Therefore, if the AK count at follow-up is 0, the clearance rate will be 100%, i.e., 
complete clearance of AK lesions. 
6.2 
Safety Measurements 
6.2.1 Laboratory 
UPTs must be performed on all WOCBP at Baseline prior to randomization and at the 
EOS visit. 
 
 
 
 
 
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6.2.2 
Local Skin Reactions (LSR) Assessments 
Statistical Analysis Plan 
The Treatment Area will be assessed for the following LSRs at Visits 1, 3, 4, 6, 7, and 
Unscheduled Visits: erythema, edema, erosion/ulceration, scabbing/crusting, 
weeping/exudate, flaking/scaling/dryness, pain (within the last 24 hours) and pruritus 
(within the last 24 hours). Each LSR will be rated according to the following 4-point 
scale: 0 = None, 1 = Mild, 2 = Moderate, and 3 = Severe. 
 
LSRs will be collected independently of adverse events. Any LSR that occurs within the 
treatment area (full face [excluding the ears] or balding scalp) and extends to adjacent 
surrounding skin (defined to be up to a 5 cm border around the treatment area) will be 
considered LSRs. LSRs that require medical intervention (prescription medication) or 
extend beyond the 5 cm of skin surrounding the Treatment Area will be documented as 
an adverse event. 
6.2.3 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a test 
article, whether or not considered related to the test article. 
 
Any AE caused by a drug is an adverse drug reaction (ADR). ADRs are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. Any AE for which there is a reasonable possibility that the drug caused the event 
is a suspected adverse reaction (SAR). Serious adverse events (SAE) are defined as any 
untoward medical occurrence that at any dose in the view of either the Investigator or 
Sponsor results in death, is life-threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or is a congenital 
anomaly/birth defect. 
 
The AE and SAE reporting period starts following the subject's written consent to 
participate in the clinical trial with the first trial related procedure and ends after the last 
treatment dose. Throughout the clinical trial the subject will be questioned in a non­ 
directive way as to the occurrence of adverse events. All adverse events which were not 
present at Screening will be recorded. Adverse events will be followed through the last 
day of the study, until the investigator determines outcome, stabilization, and/or 
resolution of the event, or not-relatedness to study medication, or up to 30 days after the 
last dose of study drug. 
 
The severity of an AE will be recorded as mild, moderate or severe. The relationship 
between an AE and the test article will be classified as certain, probable, possible or not 
related. The AE outcome will be specified as not recovered/resolved, recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving, fatal, or unknown. 
 
 
 
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Statistical Analysis Plan 
6.2.4 Concomitant Medications and Concurrent Therapies/Procedures 
Details of concomitant medication use and concurrent therapies/procedures will be 
collected for each subject. 
7 
DATA SETS ANALYZED 
The Safety population will include all randomized subjects who received the test article. 
Subjects who were randomized and applied at least one dose oftest article and returned 
for at least one post-Baseline evaluation will be included in the intent-to-treat (ITT) 
population. Subjects who complete the two, 2-week cycles of treatment and all of the 
Visit 7 follow-up evaluations at Week 14 will be considered to have completed the study. 
 
The per-protocol (PP) population is a subset of the ITT population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
Efficacy summaries and analyses will be carried out in the ITT and PP populations. All 
summaries of safety will be carried out in the Safety population. 
8 
STATISTICAL METHODS 
8.1 
General Considerations 
All statistical processing will be performed using SAS Version 9.4, unless otherwise 
noted. Continuous data will have the following summary statistics reported: number of 
subjects, mean, standard deviation, minimum and maximum. For categorical data, the 
number and percentage of subjects within each category will be reported. 
 
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Statistical Analysis Plan 
 
All data will be listed in subject data listings sorted by treatment group, site and subject 
number unless otherwise noted. Data tabulations will be prepared as described in the 
sections below. 
8.2 
Efficacy Endpoints 
8.2.1 Primary Endpoint 
Complete clearance rate (treatment success) is defined as the proportion of subjects in a 
treatment group with a 100% clearance of all AK lesions within the Treatment Area. The 
primary endpoint is the proportion of subjects in the PP population with treatment 
success at Visit 7 (Week 14/ End of Study). All AKs (Baseline and new lesions), 
independent of size, within the Treatment Area will be included in the AK lesion count 
for each visit. 
8.3 
Safety Endpoints 
8.3.1 Dosing Compliance 
Measures of test article compliance will include the total number of days of test article 
applications recorded in the case report forms and verified from the data in the subject 
diaries. Compliant subjects are defined as those who apply at least 75% and no more 
than 125% of the test article applications and no other evidence of material dosing 
noncompliance. 
8.3.2 Adverse Events and LSRs 
The severity and frequency of adverse events and local skin reactions (LSRs) will be 
assessed in the three treatment groups. 
8.4 
Subject Disposition 
All subjects enrolled into the study that are issued a subject number will be accounted for 
in Subject Disposition. Subjects who complete the two, 2-week cycles of treatment and 
all of the Visit 7 follow-up evaluations at Week 14 will be considered to have completed 
the study. Data will be tabulated by treatment group and the number and percentages of 
subjects in each treatment group who are enrolled, randomized and treated, who comprise 
the ITT population, who comprise the PP population, and who complete the study or 
withdraw prematurely along with the reason for discontinuation will be presented. The 
number of subjects who were seen at each assessment time point will also be tabulated. 
 
The number of subjects who were screen failures will be tabulated by site and reason for 
screen failure. 
 
All patients who drop out of the study will be listed. The listing will include, site 
number, subject number, reason for dropout, treatment group, last visit, and whether the 
subject was replaced. 
 
 
 
 
 
 
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8.5 
Methods for Handling Missing Data 
Statistical Analysis Plan 
 
 
 
 
 
 
8.6 
Screening and Baseline Assessments 
8.6.1 Demographic and Baseline Characteristics 
Gender, age (derived), race and ethnicity will be summarized by treatment group for the 
ITT and PP populations. The number in each of the following age groups will also be 
summarized by treatment group for the ITT and PP populations: 18-40, 41-64, 65-75, and 
>75. Age will be calculated as floor[(screening date - date ofbirth)/365.25]. 
 
The size of the Treatment Area (in centimeters) at Baseline will be determined from an 
estimate of the %BSA treated, the subject's height and weight using the Mosteller 
formula. Characteristics of the AK lesions in the Treatment Area at Baseline will be 
summarized including the total number of AK lesions and the number of AK lesions at 
least 4 mm in diameter. 
 
Informed consent information and subject eligibility status will be provided in a listing. 
8.6.2 Medical History and Dermatologic Exam 
Medical history, including onset of actinic keratoses, will be presented in a subject data 
listing. Verbatim terms on the CRFs will be mapped into system organ class and 
preferred term using MedDRA Coding Dictionary version 16.0. Tabulations of the 
number of subjects reporting medical history events will be presented by System Organ 
Class (SOC), Preferred Term (PT), and treatment group. Abnormalities noted during the 
dermatologic exam, excluding AKs, will be provided in a listing. 
8.6.3 
Vital Signs 
Systolic and diastolic blood pressures (mm Hg), pulse rate (beats/minute), temperature 
(°F), and respiration rate (breaths/minute), as well as, height (in) and weight (lbs) will be 
summarized by treatment group for the ITT population. 
8.6.4 Prior Medications and Therapies/Procedures Identified in the Exclusion 
Criteria 
Listings will be provided for the prior medications and therapies/procedures that needed a 
washout period prior to the subjects' enrollment. 
 
 
 
 
 
 
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Statistical Analysis Plan 
8.6.5 
Concomitant Medications and Concurrent Therapies/Procedures 
Concomitant medications and concurrent therapies/procedures will be provided in 
separate subject listings. Concomitant medications will be coded using the WHO Drug 
dictionary (version effective 01 September 2012). The medications will be tabulated by 
treatment group, Drug Class (pharmacological level, ATC3) and Drug Name (chemical 
substance level, ATC5). 
8.6.6 
Dosing Compliance 
Study medication dosing will be recorded daily during each of the two-week treatment 
cycles including the number of pump actuations applied per day with indications of 
whether or not the dose was missed or held. The number of applications, missed doses, 
held doses and percent of expected doses will be summarized by descriptive statistics for 
the ITT and PP populations. The percent of expected doses will be calculated using 28 
(once daily dosing for two 14 day treatment cycles) as the expected number of doses. 
Compliant subjects are defined as those who apply at least 75% and no more than 125% 
of the expected test article applications. 
 
8.7 
Efficacy Analyses 
8.7.1 
Primary Efficacy Analyses 
The primary efficacy endpoint is the complete clearance rate (treatment success), defined 
as the proportion of subjects in the PP population at the EOS visit with 100% clearance of 
AK lesions in the Treatment Area. All AKs (baseline and new lesions) independent of 
size within the treatment area will be included in the efficacy lesion count for each visit. 
 
The 90% Wald's confidence interval with Yate's continuity correction will be 
constructed on the difference (generic imiquimod minus Zyclara) in the proportions of 
subjects with complete lesion clearance to evaluate the therapeutic comparability of the 
two active treatments. 
 
Two-sided, continuity-corrected Z-tests will be used to evaluate the superiority of each 
active treatment's complete clearance rate over that of the Vehicle treatment. 
 
If the 90% confidence interval on the difference between the Test and Reference lesion 
complete clearance rates at EOS in the PP population is contained within the interval 
-0.20 to +0.20, and each of these proportions in the ITT population is greater than, and 
statistically different (p<0.05) from, the Vehicle proportion in the ITT population at EOS, 
then the Test and Reference products will be considered to be therapeutically equivalent. 
 
The therapeutic comparability evaluations in the PP population will be considered 
primary while those in the ITT will be considered supportive. The superiority 
comparisons in the ITT population will be considered primary while those in the PP 
population will be considered supportive. 
 
 
 
 
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8.8 
Safety Analyses 
8.8.1 Adverse Events 
Statistical Analysis Plan 
Verbatim terms on the CRFs will be mapped into system organ class and preferred terms 
using MedDRA Coding Dictionary version 16.0. Tabulations of the number of subjects 
experiencing adverse events will be presented by System Organ Class (SOC) and 
Preferred Term (PT) and treatment group for (a) adverse events, (b) adverse events by 
maximum severity and (c) adverse events by closest relationship to study drug. Adverse 
events will be counted only once for a subject within each Preferred Term and System 
Organ Class; thus, since a subject may have more than one Preferred Term within an 
SOC, percentages of PT may not sum to the percentage in the SOC. If a subject reports a 
PT multiple times with differing severities, only the most severe is counted. If a subject 
reports a PT multiple times with differing relationships to study medication, only the one 
most related to study medication is counted based on the following order: certain, 
probable, possible, and not related. 
 
Fisher's Exact tests will be performed on adverse events with a 2% or greater frequency 
to facilitate evaluation of potential safety differences among treatments. 
 
Serious adverse events will be listed separately for systemic AEs, if applicable. 
8.8.2 LSRs 
LSRs within the Treatment Area will be summarized by treatment group by the most 
intense score for each LSR and by the sum score at each visit and over the course of the 
study. The frequency of the individual LSRs will be tabulated by severity and treatment 
group at each visit. 
 
8.8.3 
Urine Pregnancy Tests 
Results of UPT tests will be provided in a subject data listing. 
8.9 
Sample Size 
 
. Bioequivalence was concluded if the 90% continuity-corrected 
confidence interval on the difference in active treatment complete clearance rates was 
between -0.20 and +0.20 in the per protocol (PP) population, and each active treatment 
was found to be statistically superior to the vehicle by independent continuity-corrected 
Z-tests in the intent-to-treat (ITT) population. The probability of study success was 
estimated as the percent of the simulated trials that met both these confidence interval and 
superiority criteria. A total of 435 ITT subjects 
 
 for demonstrating bioequivalence between the active 
treatments and showing that each active treatment is superior to vehicle treatment. 
 
 
 
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8.10 Protocol Deviations 
All protocol deviations will be listed. 
8.11 Interim Analysis 
No interim analyses are planned. 
8.12 Subgroup Analyses 
No subgroup analyses are planned. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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