Clinical trial NCT03064438
Conditions: Acne Rosacea
Sponsor: Accuitis, Inc.
Start date: 2017-11-28; Completion date: 2018-06-18
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study evaluated the safety, tolerability, and efficacy of ACCU-D1 when applied twice daily for 12 weeks in adult participants with moderate to severe acne rosacea. Two-third of the participants received ACCU-D1 while one-third of the participants received vehicle control.

Detailed description:

Arms: arm 1: Twice-daily application of ACU-D1 ointment to the face for 12 weeks. arm 2: Twice-daily application of ACU-D1 ointment vehicle to the face for 12 weeks.
Interventions: intervention 1: ACCU-D1 intervention 2: Vehicle
Intervention descriptions: intervention 1: ACCU-D1 intervention 2: Placebo Comparator

Protocol documents:
Prot_000.pdf: 
Accuitis, Inc. 
Protocol number: ACU-D1-201 
Page 1 of 49 
Date: 05-AUG-2017                                                                                                     Supersedes: 28-JUN-2017 
Protocol Number: ACU-D1-201 
 
A RANDOMIZED, DOUBLE-BLIND, VEHICLE CONTROLLED, PROOF-OF-
CONCEPT STUDY OF THE SAFETY AND EFFICACY OF ACU-D1 OINTMENT 
 
IN SUBJECTS WITH ACNE ROSACEA 
 
 
Sponsor 
Accuitis, Inc. 
1005 Alderman Drive 
Suite 104 
Alpharetta, GA 30005 
 
 
 
Study Contact 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Protocol Date 
28-JUN-2017 
 
 
 
 
 
 
 
 
 
 
 
 
This document is a privileged and confidential communication of Accuitis, Inc. Acceptance of this document 
constitutes an agreement by the recipient that no unpublished information contained herein will be used, published 
or disclosed without prior written approval from Accuitis, Inc. 




Accuitis, Inc. 
Protocol number: ACU-D1-201 
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Table of Contents 
INVESTIGATOR/SPONSOR AGREEMENT ...................................................................................... 2 
1. 
SYNOPSIS ........................................................................................................................................ 7 
2. 
INTRODUCTION ......................................................................................................................... 12 
2.1. 
Introduction and Background .................................................................................................. 12 
2.2. 
Study Rationale ........................................................................................................................... 12 
3. 
STUDY OBJECTIVES .................................................................................................................. 12 
4. 
SELECTION AND DISPOSITION OF STUDY POPULATION ......................................... 12 
4.1. 
Number of Subjects .................................................................................................................... 12 
4.2. 
Study Population Characteristics ............................................................................................ 12 
4.3. 
Inclusion Criteria ........................................................................................................................ 13 
4.4. 
Exclusion Criteria ....................................................................................................................... 13 
4.5. 
Previous and Concomitant Therapies ..................................................................................... 14 
4.5.1. 
Previous therapies .................................................................................................................... 14 
4.5.2. 
Concomitant therapies ............................................................................................................ 14 
4.5.3. 
Prohibited therapies ................................................................................................................ 15 
4.6. 
Subject Discontinuation from the Study ............................................................................... 15 
4.7. 
Subject Identifier (SI) ................................................................................................................ 16 
4.8. 
Replacement Subjects ................................................................................................................ 16 
5. 
INVESTIGATIONAL PLAN ...................................................................................................... 16 
5.1. 
Study Design ............................................................................................................................... 16 
5.2. 
Subject Instructions ................................................................................................................... 17 
5.3. 
Study Flow Chart ........................................................................................................................ 18 
5.4. 
Study Visits Description and Procedures .............................................................................. 19 
5.4.1. 
Visit 1 (Day -13 to 0); enrollment .......................................................................................... 19 
5.4.2. 
Visit 2 (Day 1); randomization and start of treatment period .......................................... 19 
5.4.3. 
Visit 3 (Day 15); treatment period follow-up ...................................................................... 21 
5.4.4. 
Visit 4 (Day 29); treatment period follow-up ...................................................................... 21 
5.4.5. 
Visit 5 (Day 57); treatment period follow-up ...................................................................... 22 
5.4.6. 
Visit 6 (Day 85); end of treatment period and start of no-treatment period ................. 22 
5.4.7. 
Visit 7 (Day 99); end of study ................................................................................................. 23 
5.5. 
Study Duration ............................................................................................................................ 23 
5.6. 
Study Medications ...................................................................................................................... 23 


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5.6.1. 
Study medication identity ...................................................................................................... 23 
5.6.2. 
Study medication packaging and labeling .......................................................................... 24 
5.6.3. 
Method of treatment assignment .......................................................................................... 25 
5.6.4. 
Subject randomization ............................................................................................................ 25 
5.6.5. 
Dispensing and collecting study medication ..................................................................... 26 
5.6.6. 
Study medication application ................................................................................................ 27 
5.6.7. 
Dose compliance record .......................................................................................................... 28 
5.6.8. 
Dose modification .................................................................................................................... 28 
5.7. 
Study Medication Management .............................................................................................. 29 
5.7.1. 
Accountability .......................................................................................................................... 29 
5.7.2. 
Return and disposition of study supplies ........................................................................... 29 
5.8. 
Blinding ........................................................................................................................................ 29 
5.8.1. 
Verification of blinding .......................................................................................................... 29 
5.8.2. 
Unblinding during the study ................................................................................................. 29 
6. 
STUDY ASSESSMENTS ............................................................................................................. 30 
6.1. 
Efficacy Evaluations ................................................................................................................... 30 
6.1.1. 
Lesion count .............................................................................................................................. 30 
6.1.2. 
Investigator’s global assessment (IGA) ............................................................................... 30 
6.2. 
Safety Evaluations ...................................................................................................................... 31 
6.2.1. 
Clinical laboratory sampling ................................................................................................. 32 
6.2.2. 
Local tolerability assessment (LTA) ..................................................................................... 33 
6.2.3. 
Vital signs .................................................................................................................................. 35 
6.2.4. 
Urine pregnancy tests .............................................................................................................. 36 
6.3. 
Other Evaluations ....................................................................................................................... 36 
6.3.1. 
Demographics ........................................................................................................................... 36 
6.3.2. 
Medical history ......................................................................................................................... 36 
6.3.3. 
Standardized photography ..................................................................................................... 36 
7. 
ADVERSE EVENTS ...................................................................................................................... 37 
7.1. 
Definitions ................................................................................................................................... 37 
7.1.1. 
Adverse events (AE)................................................................................................................. 37 
7.1.2. 
Serious adverse event (SAE) .................................................................................................. 38 
7.1.3. 
Unexpected adverse event ...................................................................................................... 38 
7.1.4. 
Adverse event reporting period ............................................................................................ 38 


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7.1.5. 
Severity ...................................................................................................................................... 39 
7.1.6. 
Relationship to study medication ......................................................................................... 39 
7.2. 
Reporting Procedures ................................................................................................................. 39 
7.2.1. 
Procedures for reporting adverse events ............................................................................. 39 
7.2.2. 
Procedure for reporting a serious adverse event ................................................................ 40 
8. 
PREGNANCY ................................................................................................................................ 41 
9. 
STATISTICAL ANALYSES ........................................................................................................ 42 
9.1. 
General Considerations ............................................................................................................. 42 
9.2. 
Types of Analyses (Intent-to-Treat, Per-Protocol) ................................................................ 42 
9.2.1. 
Modified intention-to-treat analysis (MITT) ...................................................................... 42 
9.2.2. 
Per-protocol analysis (PP) ....................................................................................................... 43 
9.3. 
Primary Efficacy Variable ......................................................................................................... 43 
9.3.1. 
Lesion count (papules, pustules and nodules) ................................................................... 43 
9.3.2. 
Statistical analysis of total lesion count ............................................................................... 43 
9.4. 
Secondary Efficacy Variables and Their Statistical Analyses ............................................ 44 
9.4.1. 
Investigator’s global assessment ........................................................................................... 44 
9.4.2. 
Treatment responders .............................................................................................................. 44 
9.4.3. 
Individual lesion counts ......................................................................................................... 45 
9.4.4. 
Subgroup analyses ................................................................................................................... 45 
9.5. 
Demographics and Baseline Characteristics ......................................................................... 45 
9.6. 
Interim Analysis ......................................................................................................................... 45 
9.7. 
Sample Size Determination ...................................................................................................... 46 
10. 
TRAINING, MONITORING, DATA MANGEMENT, AND QUALITY 
ASSURANCE ................................................................................................................................. 46 
10.1. 
Training ........................................................................................................................................ 46 
10.2. 
Monitoring ................................................................................................................................... 46 
10.3. 
Data Management....................................................................................................................... 46 
10.4. 
Quality Assurance ...................................................................................................................... 47 
10.5. 
Changes in Study Conduct and Protocol Amendments ...................................................... 47 
10.5.1. 
Study conduct and protocol amendments ........................................................................... 47 
11. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS ............................... 47 
11.1. 
Institutional Review Board (IRB) ............................................................................................ 47 
11.2. 
Ethical Conduct of the Study .................................................................................................... 47 
11.3. 
Subject Information and Consent ........................................................................................... 48 


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Protocol number: ACU-D1-201 
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11.4. 
Contractual Requirements ........................................................................................................ 48 
11.5. 
Data Collection and Archiving ................................................................................................ 48 
11.5.1. 
Data collection .......................................................................................................................... 48 
11.5.2. 
Source documentation ............................................................................................................. 48 
11.5.3. 
Archiving ................................................................................................................................... 48 
12. 
REFERENCES ................................................................................................................................ 49 
 
 
 


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Protocol number: ACU-D1-201 
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1. 
SYNOPSIS 
Title: 
A Randomized, Double-Blind, Vehicle Controlled, Proof of Concept Study of the Safety 
and Efficacy of ACU-D1-201 Ointment 
 in Subjects with Acne Rosacea. 
 
Objectives: 
The main objective of this study is to evaluate the safety, tolerability and efficacy of 
ACU-D1 Ointment 
 when applied twice daily for 12 weeks to papulopustular, 
Type-2, rosacea (acne rosacea) of the face. 
 
Methodology/Study Design: 
This study incorporates a randomized, double-blind, vehicle controlled, parallel-group 
design.  
 
During this study, the subjects will apply ACU-D1 Ointment 
 or ACU-D1 Ointment 
Vehicle to acne rosacea of the face twice daily during a 12-week treatment period.  
 
Approximately 36 subjects will be assigned to a study medication treatment group in a 
2:1 ratio (24 to ACU-D1 Ointment 
; 12 to ACU-D1 Ointment Vehicle) at multiple 
United States investigational centers. 
 
The duration of study participation is anticipated to be a maximum of 116 days per 
subject. The final study visit (Visit 7) has a maximum allowable visit window of 4 days.  
 
Study visits are: 
 Visit 1 (Day -13 to 0) enrollment and start of the screening period 
 Visit 2 (Day 1) randomization and start of the study medication treatment period 
 Visit 3 (Day 15) treatment period follow-up 
 Visit 4 (Day 29) treatment period follow-up 
 Visit 5 (Day 57) treatment period follow-up 
 Visit 6 (Day 85) end of the treatment period and start of the no treatment follow-
up period 
 Visit 7 (Day 99) no treatment follow-up, end of study. 
 
During Visit 1, the investigator determines eligibility of potential subjects for study 
enrollment and will, for eligible subjects, conduct the procedures to determine her/his 
eligibility for randomization.  
 
At Visit 2, eligible subjects will be randomized to a study medication treatment group, 
will initiate twice daily applications for the 12-week treatment period and will perform 
the first study medication while being observed by an investigational center staff 
member. 


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Protocol number: ACU-D1-201 
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At Visits 3-5, subjects will be seen for treatment period follow-up. 
 
At Visit 6, subjects will be seen for end of the treatment period follow-up and will start 
the 2-week no treatment follow-up period.  
 
At Visit 7, subjects will be seen for a no treatment follow-up and be discharged from the 
study. 
 
 
Number of Subjects: 
Approximately 36 subjects will be enrolled in this study at multiple United States 
investigational centers. Subjects will be randomized in a 2:1 ratio with the goal to have 
24 subjects randomized to treatment with ACU-D1 Ointment 
 and 12 subjects 
randomized to treatment with ACU-D1 Ointment Vehicle.  
 
Diagnosis and Main Criteria for Inclusion: 
Subjects will be adult males and females with a clinical diagnosis of papulopustular 
rosacea of the face that includes a total of ≥10 and ≤40 papules, pustules and nodules 
with ≤2 nodules. 
 
Study Medications, Application, and Mode of Administration: 
There are 2 study medications: 
 ACU-D1 Ointment 
 
 ACU-D1 Ointment Vehicle.  
 
There are 2 treatment groups: 
 ACU-D1 Ointment 
 applied twice daily for 12 weeks 
 ACU-D1 Ointment Vehicle applied twice daily for 12 weeks.  
 
Subjects will be assigned to one of the two treatment groups, in a blinded manner, in a 
2:1 ratio, 24 subjects will be assigned to receive ACU-D1 Ointment 
 and 12 subjects 
will be assigned to receive ACU-D1 Ointment Vehicle. 
 
Subjects will apply the assigned study medication twice daily during a 12-week 
treatment period. 
 
Duration of Study: 
The planned treatment and study durations are: 
 Enrollment period: approximately 84 days (12 weeks) 
 Subject participation period: up to 116 days 
 Study duration (first subject first visit, through last subject last visit): 
approximately 200 days.   
 
 
 


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Protocol number: ACU-D1-201 
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Evaluations – Efficacy: 
The investigator will perform a Lesion Count of papules, pustules and nodules and an 
Investigator’s Global Assessment (IGA), a static assessment of the average overall 
severity of papulopustular rosacea on the face, to evaluate the status of the rosacea 
throughout the study. 
Evaluations – Safety: 
Adverse events, local tolerability of signs and symptoms of irritation, clinical laboratory 
safety tests, vital sign readings and urine pregnancy tests will be monitored throughout 
the study. 
Evaluations – Other: 
Standardized color photographs of the subject’s face to document the status of the 
rosacea being treated will be taken throughout the study. 
Statistical Methods: 
The goal of the statistical analysis is to assess evidence of an overall effect of twice-daily 
ACU-D1 in the therapy of subjects with papulopustular rosacea. Next a set of planned 
pair-wise comparisons will be made evaluating the active dose against vehicle. Two 
types of study populations will be analyzed, namely, the Intention-To-Treat (ITT) and 
the Per-Protocol populations. The definitions of the populations for the different types 
of analyses follow those given in the ICH E9 guideline (1998). 
Safety analyses will include descriptive statistics calculated on the safety parameters 
using the ITT population. The proportion of subjects with treatment-emergent adverse 
events will be tabulated and presented by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class. Vital signs, Local Tolerability Assessment (LTA) scores 
and clinically relevant abnormal laboratory results will also be tabulated and presented. 
Where applicable data will be listed and summarized by visit. 
Safety summaries will include listings of adverse event incidences within each 
MedDRA System Organ Class, and changes from pre-application values in vital signs. 
Adverse event summaries will be presented showing the proportion of subjects 
experiencing adverse events, both overall and by MedDRA System Organ Class. 


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Protocol number: ACU-D1-201 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE  
Adverse Event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BUN  
Blood Urea Nitrogen 
C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CR 
Clinically Relevant 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
e.g.  
for example (Latin; exempla gratia) 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
i.e.  
that is 
Inc. 
Incorporated 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LTA 
Local Tolerability Assessment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat 
mL 
Milliliter 


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Abbreviation 
Term 
NCR 
Not Clinically Relevant 
OTC 
Over-the-counter 
SAE 
Serious Adverse Event 
SAS 
Statistical Analyses System 
SI 
Subject Identifier 
SOP 
Standard Operation Procedure 
US 
United States 
WOCBP 
Woman of childbearing potential 
 


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2. 
INTRODUCTION 
2.1. 
Introduction and Background 
Rosacea is one of the most commonly occurring dermatoses treated by dermatologists 
today. Rosacea is an inflammatory condition of the skin, classically presenting with 
flushing and/or blushing along with erythema, edema, telangiectasia, papules, pustules 
and nodules of the face.1 
 
ACU-D1 [pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate) 
(PTTC)] may be beneficial in the treatment of inflammatory lesions in patients with 
rosacea based on its anti-inflammatory properties. 
 
2.2. 
Study Rationale 
This study is designed to evaluate the safety and efficacy of ACU-D1 Ointment (PTTC) 
 and a matching ointment vehicle in the treatment of the inflammatory lesions of 
the face associated with Type-2 (papulopustular) rosacea. 
 
3. 
STUDY OBJECTIVES 
The main objective of this study is to evaluate the safety, tolerability and efficacy of 
ACU-D1 Ointment 
 when applied twice daily for 12 weeks to papulopustular 
(Type-2) rosacea (acne rosacea) of the face. 
 
4. 
SELECTION AND DISPOSITION OF STUDY POPULATION 
4.1. 
Number of Subjects 
Approximately 36 subjects will be enrolled in this study at multiple United States 
investigational centers. Subjects will be randomized in a 2:1 ratio with 24 subjects 
randomized to treatment with ACU-D1 Ointment 
 and 12 subjects randomized to 
treatment with ACU-D1 Ointment Vehicle. Subject enrollment will be competitive. 
 
4.2. 
Study Population Characteristics 
Male and female subjects, 18 years of age or older who meet all the inclusion criteria 
and none of the exclusion criteria will be allowed to enroll in this study. 
 
 
 


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4.3. 
Inclusion Criteria 
To be eligible for enrollment at Visit 1 the subject must fulfill all the following inclusion 
criteria: 
1. 
Subject is at least 18 years of age 
2. 
Subject has a clinical diagnosis of stable papulopustular rosacea (type-2) 
3. 
Subject has a total of ≥10 and ≤40 inflammatory lesions (papules, pustules 
and nodules) on the face 
4. 
Subject has a ≤2 nodules on the face 
5. 
Subject has an Investigator’s Global Assessment score of ≥3 
6. 
If the subject is a woman of childbearing potential, she has a negative 
urine pregnancy test and agrees to use an approved effective method of 
birth control for the duration of the study 
7. 
Subject is non-pregnant and non-lactating 
8. 
Subject is in good general health and free of any known disease state or 
physical condition which, in the investigator’s opinion, might impair 
evaluation of rosacea or which exposes the subject to an unacceptable risk 
by study participation 
9. 
Subject is willing and able to follow all study instructions and to attend all 
study visits 
10. 
Subject is able to comprehend and willing to sign an Informed Consent 
Form. 
 
4.4. 
Exclusion Criteria 
Any potential subject who meets one or more of the following criteria will not be 
included in this study: 
1. 
Subject is pregnant, nursing or planning to become pregnant during the 
duration of the study 
2. 
Subject has used systemic glucocorticosteroids within 42 days prior to 
Visit 1 (inhaled and ocular glucocorticosteroids are permitted) 
3. 
Subject has used systemic antibiotics within 28 days prior to Visit 1 
4. 
Subject has used any topical glucocorticosteroids on the face within 28 
days prior to Visit 1 
5. 
Subject has used any prescription or over-the-counter (OTC) product for 
the treatment of acne or rosacea within 14 days prior to Visit 1  
6. 
Subject is currently using any therapy that, in the investigator’s opinion, is 
a photosensitizer (e.g., phenothiazines, amiodarone, quinine, thiazides, 
sulphonamides, quinolones, etc.) 
7. 
Subject currently has any skin disease (e.g., psoriasis, atopic dermatitis, 
eczema), or condition (e.g., actinic keratosis, photo-damage, sunburn, 
excessive hair, open wounds) that, in the investigator’s opinion, might 
impair evaluation of rosacea or which exposes the subject to an 
unacceptable risk by study participation  


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8. 
Subject currently has, on the face, or has had on the face, any of the 
following within the specified period prior to Visit 1 that, in the 
investigator’s opinion, might impair evaluation of rosacea or which 
exposes the subject to an unacceptable risk by study participation: 
 A cutaneous malignancy; 180 days 
 Experienced a sunburn; 14 days 
9. 
Subject has facial hair, that in the investigator’s opinion, might impair 
evaluation of rosacea or proper study medication application 
10. 
Subject has a history of sensitivity to any of the ingredients in the study 
medications 
11. 
Subject has participated in an investigational drug trial in which 
administration of an investigational study medication occurred within 
30 days prior to Visit 1. 
 
4.5. 
Previous and Concomitant Therapies 
4.5.1. 
Previous therapies 
During Visit 1, subjects will be questioned to ensure they have not used any excluded 
therapies. 
 
4.5.2. 
Concomitant therapies 
Concomitant therapies are any new or existing therapy received by the subject after 
signing the ICF until discharge from the study.  
 
Concomitant therapies include drug (e.g., prescription and OTC) and non-drug (e.g., 
chiropractic, physical therapy, energy-based treatments) therapies. Subjects will refrain 
from receipt of any therapy in accord with the inclusion/exclusion criteria. Subjects will 
also refrain from changing the use of any concomitant therapies during the duration of 
the study.  
 
All new or modified concomitant therapy used during the study must be recorded. 
 
Any new or modified concomitant therapy must be considered to determine if it is 
related to an AE. An AE must be reported unless the therapy is added or modified for 
non-medical reasons (e.g., health insurance purposes) or it is for prophylaxis (e.g., 
vaccinations). 
 
A frequency of “as needed” (PRN) is not acceptable when reporting concomitant 
therapies. 
 


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4.5.3. 
Prohibited therapies 
During this study, subjects are prohibited from using therapies listed in the exclusion 
criteria.   
 
Starting with Visit 2 subjects are prohibited from applying any leave-on topical 
products, including but not limited to, lotions, creams, ointments, the investigator 
approved bland, non-medicated emollient/moisturizer and cosmetics to the treatment 
area within 8 hours prior to a study visit. The subject’s routine cleansers are allowed. 
 
The investigator should notify the Accuitis, Inc. Medical Monitor within 24 hours if any 
prohibited therapy is required to ensure subject safety. 
 
4.6. 
Subject Discontinuation from the Study 
Subjects will be informed that they are free to withdraw from the study at any time and 
for any reason.  
 
The investigator may remove a subject from the study if, in the investigator's opinion, it 
is not in the best interest of the subject to continue the study. Subjects may be 
discontinued due to occurrence of AEs, occurrence of pregnancy or use of a prohibited 
concomitant therapy. The investigator will notify the Accuitis, Inc. study monitor 
within 24 hours of any subject discontinuation.  
 
In case of premature discontinuation of study participation, efforts will be made to 
perform all the Visit 6 assessments for discontinuations during the treatment period and 
all the Visit 7 assessments for discontinuations during the no-treatment period. The date 
the subject is withdrawn from the study and the reason for discontinuation will be 
recorded on the subject’s case report forms (CRFs). All withdrawn subjects with 
ongoing AEs will be followed as appropriate. 
 
The study may be discontinued at the discretion of the investigator or Accuitis, Inc. 
Some examples of reasons for discontinuation are the occurrence of the following: 
 
Increased frequency, severity or duration of known AEs 
 
Medical, regulatory or ethical reasons affecting the continued 
performance of the study 
 
Difficulties in the recruitment of subjects 
 
Cancellation of the drug development program. 
 
 
 


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4.7. 
Subject Identifier (SI) 
The investigator will assign a unique four-digit Subject Identifier (SI) to each subject at 
Visit 1.  
 
The SI format will be NN-NN where the first two digits are the investigational center 
site number and the final two digits are the Subject Number (SN). The investigator 
center number will be provided by Accuitis and the SN must be assigned in ascending 
numerical order, without omitting or repeating any number, starting with 01 at each 
investigational center. For example, the SI for the second subject assigned at site 
number 2 would be 02-02.  
 
The subject will be identified using the SI in all study documentation for the duration of 
the study. 
 
4.8. 
Replacement Subjects 
Subject enrollment will continue until approximately 36 subjects have been 
randomized. Subjects who are randomized and do not complete the study will not be 
replaced. 
 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Study Design 
This is a randomized, double-blind, vehicle-controlled, parallel-group study of ACU-D1 
Ointment 
 and the ACU-D1 Ointment Vehicle in subjects with papulopustular 
rosacea on the face. 
 
The study will be conducted at multiple United States investigational centers. 
 
Study visits are: 
 Visit 1 (Day -13 to 0) enrollment and start of the screening period 
 Visit 2 (Day 1) randomization and start of the study medication treatment period 
 Visit 3 (Day 15) treatment period follow-up 
 Visit 4 (Day 29) treatment period follow-up 
 Visit 5 (Day 57) treatment period follow-up 
 Visit 6 (Day 85) end of the treatment period and start of the no treatment follow-
up period 
 Visit 7 (Day 99) no treatment follow-up, end of study. 
 
During Visit 1, the investigator determines eligibility of potential subjects for study 
enrollment and will, for eligible subjects, conduct the procedures to determine her/his 
eligibility for randomization.  


Accuitis, Inc. 
Protocol number: ACU-D1-201 
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At Visit 2 eligible subjects will be randomized to a study medication treatment group in 
a 2:1 ratio (ACU-D1 Ointment 
: ACU-D1 Ointment Vehicle). Subject’s will initiate 
twice daily applications for the 12-week treatment period and will perform the first 
study medication while being observed by an investigational center staff member. 
 
At Visits 3-5 subjects will be seen for treatment period follow-up. 
 
At Visit 6, subjects will be seen for end of the treatment period follow-up and will start 
the 2-week no treatment follow-up period.  
 
At Visit 7, subjects will be seen for a no treatment follow-up and be discharged from the 
study. 
 
5.2. 
Subject Instructions 
At Visit 1 a study staff member will dispense a Subject Instruction sheet to each subject. 
 
During the entire duration of the study subjects must:  
 Continue to use her/his routine facial cleansers and cosmetics except she/he 
many only use an investigator approved bland, non-medicated 
emollient/moisturizer (e.g., Cetaphil®) 
 Not apply any leave-on topical products including, but not limited to lotions, 
creams, ointments, investigator approved bland, non-medicated 
emollient/moisturizer and cosmetics, to the treatment area within 8 hours prior 
to a study visit (the subject’s routine cleansers are allowed) 
 Avoid exposing her/his face to excessive natural (e.g., sunlight) or artificial (e.g., 
tanning beds) ultraviolet radiation and use her/his routine sunscreen if excessive 
exposure cannot be avoided 
 Continue her/his routine cleansers and cosmetics 
 Bring the subject instruction sheet to every visit. 
 
During the 12-week treatment period, subjects must: 
 Apply the study medication to her/his entire face from the hairline down to the 
jaw line and from ear to ear as directed, twice daily, with at least 8 hours 
between each application 
 Not apply the study medication to the eyes, eyelids, any membrane of the inner 
nose, mouth, lips and open wounds 
 Not apply the study medication within 6 hours prior to any study visit 
 Not wash or submerge the treated area for at least 4 hours after a study 
medication application 
 Not apply any topical products to the treatment area for at least 20 minutes after 
a study medication application 


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 Not allow anyone else to use your study medication 
 Keep the study medication away from children 
 Keep the study medication refrigerated when it is not being used for an 
application and use the cooler provided by the investigational staff (or 
equivalent) to transport the study medication 
 Bring her/his study medication to every study visit. 
 
5.3. 
Study Flow Chart 
Visit 
1 
2 
3 
4 
5 
6 
7 
Protocol 
Section 
Day 
-13 to 0 
1 
15 
29 
57 
85 
99 
Informed consent 
X 
 
 
 
 
 
 
11.3 
Subject identifier 
X 
 
 
 
 
 
 
4.7 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
4.3/4.4 
Demographics 
X 
 
 
 
 
 
 
6.3.1 
Medical history 
X 
 
 
 
 
 
 
6.3.2 
Vital signs 
X 
X 
 
 
 
 
X 
6.2.3 
Urine pregnancy tests 
X 
 
 
 
 
 
X 
6.2.4 
Lesion count 
X 
X 
X 
X 
X 
X 
X 
6.1.1 
Investigator’s global 
assessment 
X 
X 
X 
X 
X 
X 
X 
6.1.2 
Local tolerability assessment 
 
X1 
X 
X 
X 
X 
X 
6.2.2 
Clinical laboratory samples 
X 
 
 
 
 
X 
 
6.2.1 
Identify investigator approved 
emollient/moisturizer 
X 
 
 
 
 
 
 
4.5.2 
Standardized photography 
 
X 
X 
X 
X 
X 
X 
6.3.3 
Randomization 
 
X 
 
 
 
 
 
5.6.4 
Dispense/collect study 
medication 
 
X 
X 
X 
X 
X 
 
5.6.5 
Study medication treatment  
 
 
 
5.6.6 
No treatment Follow-up 
 
 
 
 
 
 
 
5.6.6 
Subject instructions 
X 
X 
X 
X 
X 
X 
 
5.2 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
4.5.2 
Adverse events 
 
X 
X 
X 
X 
X 
X 
7 
1Local tolerability assessments will be performed before and after the first study 
medication application 
 
 


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5.4. 
Study Visits Description and Procedures 
A written, signed informed consent form (ICF) must be obtained from every subject 
prior to performing any study related procedure (i.e., vital signs, clinical laboratory 
sampling, urine pregnancy test or photography). 
 
5.4.1. 
Visit 1 (Day -13 to 0); enrollment 
The following procedures will be performed at Visit 1.  
 
At this visit, the investigator or designee will: 
1. Review and explain the nature of the study to the subject, particularly the 
prohibited activities and the time/logistical constraints, obtain the subject’s 
signature on the appropriate approved ICF and Health Insurance Portability and 
Accountability Act (HIPAA) authorization and provide a copy to the subject 
2. Assign a SI to each subject 
3. Confirm the subject meets all the inclusion criteria and none of the exclusion 
criteria 
4. Collect demographic information 
5. Collect medical history information 
6. Measure vital signs 
7. Perform a urine pregnancy test for women of childbearing potential (WOCBP); a 
negative result is required 
8. Report concomitant therapies information 
9. Perform a Lesion Count; a total of ≥10 and ≤40 inflammatory lesions (papules, 
pustules and nodules) with ≤2 nodules on the treatment area is required 
10. Perform an IGA; a score of ≥3 (moderate to severe) is required 
11. Collect blood samples for clinical laboratory evaluations 
12. Identify an investigator approved bland, non-medicated emollient/moisturizer 
13. Review the study instructions with the subject and dispense a Subject Instruction 
sheet 
14. Schedule Visit 2. 
 
5.4.2. 
Visit 2 (Day 1); randomization and start of treatment period 
This visit should occur within 14 days after Visit 1. Subsequent study visit dates must 
be scheduled based on the date of this visit.  
 
Prior to this visit the investigator/designee must confirm that all items necessary to 
determine the subject’s eligibility for randomization are available. 
 
 
 


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At this visit, the investigator or designee will perform the following procedures PRIOR 
TO RANDOMIZATION: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report any changes that are, in the investigator’s 
opinion, meaningful, as Medical History 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Measure vital signs 
5. Perform a Lesion Count; a total of ≥10 and ≤40 inflammatory lesions (papules, 
pustules and nodules) and ≤2 nodules on the treatment area is required 
6. Perform an IGA; a score of ≥3 (moderate to severe) is required 
7. Determine the subject’s eligibility for randomization 
8. Discharge from the study subjects who are not eligible for randomization.  
 
For subjects who are eligible for randomization the investigator or designee will 
perform the following procedures:  
1. Take standardized color photographs 
2. Have the subject perform a pre-treatment Local Tolerability Assessment (LTA) 
3. Perform a pre-treatment LTA 
4. Randomize eligible subjects 
5. Dispense study medication to the subject 
6. Instruct the subject on the proper study medication application technique 
7. Observe the subject’s first study medication application 
8. Monitor the subject for at least 20 minutes after the Application Completion Time 
to detect any adverse events 
9. Have the subject perform a post-treatment LTA 10 (±4) minutes after the 
Application Completion Time 
10. Perform a post-treatment LTA 20 (±4) minutes after the Application Completion 
Time 
11. Review the study instructions with the subject 
12. Schedule Visit 3. 
 
 
 


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5.4.3. 
Visit 3 (Day 15); treatment period follow-up 
This visit should occur 14 [±4] days after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report all AEs on the appropriate form 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Perform a Lesion Count 
5. Perform an IGA 
6. Have the subject perform an LTA 
7. Perform an LTA 
8. Take standardized color photographs 
9. Dispense and collect study medication as appropriate 
10. Review the study instructions with the subject 
11. Schedule Visit 4. 
 
5.4.4. 
Visit 4 (Day 29); treatment period follow-up 
This visit should occur 28 [±4] days after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report all AEs on the appropriate form 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Perform a Lesion Count 
5. Perform an IGA 
6. Have the subject perform an LTA 
7. Perform an LTA 
8. Take standardized color photographs 
9. Dispense and collect study medication as appropriate 
10. Review the study instructions with the subject 
11. Schedule Visit 5. 
 
 
 


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5.4.5. 
Visit 5 (Day 57); treatment period follow-up 
This visit should occur 56 [±4] days after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report all AEs on the appropriate form 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Perform a Lesion Count 
5. Perform an IGA 
6. Have the subject perform an LTA 
7. Perform an LTA 
8. Take standardized color photographs 
9. Dispense and collect study medication as appropriate 
10. Review the study instructions with the subject 
11. Schedule Visit 6. 
 
5.4.6. 
Visit 6 (Day 85); end of treatment period and start of no-treatment 
period 
This visit should occur 84 [±4] days after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report all AEs on the appropriate form 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Perform a Lesion Count 
5. Perform an IGA 
6. Have the subject perform an LTA 
7. Perform an LTA 
8. Collect blood samples for clinical laboratory evaluations 
9. Take standardized color photographs 
10. Collect all study medication 
11. Review the study instructions with the subject 
12. Schedule Visit 7. 
 
 
 


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5.4.7. 
Visit 7 (Day 99); end of study 
This visit should occur 98 [±4] days after Visit 2. 
 
The investigator must review the Visit 6 clinical laboratory test results prior to this visit.  
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health 
since the previous visit and report all AEs on the appropriate form 
2. Query the subject about any changes in her/his concomitant therapies since the 
previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions and has 
followed all study instructions 
4. Measure vital signs 
5. Perform a urine pregnancy test for WOCBP  
6. Perform a Lesion Count 
7. Perform an IGA 
8. Have the subject perform an LTA 
9. Perform an LTA 
10. Take standardized color photographs 
11. Discharge the subject from the study. 
 
5.5. 
Study Duration 
The duration of study participation for each subject is anticipated to be a maximum of 
116 days.   
 
The maximum total study duration (including allowable visit windows) is anticipated 
to be approximately 200 days from the first subject’s first visit to the last subject’s last 
visit.   
 
The study end date is the date of the last subject’s last visit.  
 
5.6. 
Study Medications 
5.6.1. 
Study medication identity 
The study medications are white to off-white colored ointments and are 
indistinguishable in physical appearance. The study medications must be maintained at 
the investigational center in a secure area with limited access under appropriately 
controlled and monitored storage conditions. Study medications must be stored in a 
refrigerator at the investigational center. 
 
 


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Date: 05-AUG-2017                                                                                                    Supersedes: 28-JUN-2017 
 
Study Medication Information 
Study medication name 
ACU-D1 Ointment 
 
ACU-D1 Ointment Vehicle 
Manufacturer 
 
Active ingredient 
PTTC 
None 
Active concentration 
 
0% 
Pharmaceutical Form 
Ointment 
Storage Conditions 
 
Dose regimen 
 
Route 
Topical 
Frequency 
Twice daily 
Duration of administration 
84 days (12 weeks) 
 
5.6.2. 
Study medication packaging and labeling 
The study medications will be packaged in identical appearing white plastic jars that 
each contain 2 ounces of study medication. 
 
One Subject Kit that contains 3 jars of study medication will be prepared for each 
subject.  
 
Subject Kits will be labeled with a two-part, three-panel, label. One part of the label 
remains attached to the Subject Kit, the other part (two-panel tear-off) is separated 
when the study medication is first dispensed to a subject. 
 
The affixed part and the first panel of the tear-off part show at least the following: 
 Subject Kit number (randomization number) 
 Protocol number 
 Storage conditions 
 Sponsor information 
 Space to enter SI 
 Space to enter the subject’s initials 
 Space to enter the date randomized. 
 
 
 
 


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The second panel of the tear-off part is a blinded label (e.g., sealed, tamper-evident 
envelope, scratch-off or equivalent) which when opened identifies the contents of the 
jars. The blinded label should only be opened in a medical emergency. 
 
Each study medication jar will be labeled with a one-part label that remains attached to 
the jar and shows at least the following: 
 Subject Kit number (randomization number) 
 Protocol number 
 Jar number 
 Directions for use 
 Investigational drug warning 
 Space to enter SI 
 Space to enter the subject’s initials 
 Space to enter date dispensed. 
 
5.6.3. 
Method of treatment assignment 
Prior to the start of the study, Accuitis Inc. or a designated third party will generate a 
list of randomization numbers that shall be transmitted to the assigned clinical 
packaging organization for study medication labeling. The randomization number is 
also the Subject Kit number. 
 
The randomization list will be stored with access limited to designated personnel for 
study medication labeling. The randomization list will be made available as appropriate 
to unblind the database. 
 
At Visit 2, eligible subjects will be assigned in a random manner to one of the 2 study 
medications in a 2:1 ratio (ACU-D1 Ointment 
: ACU-D1 Ointment Vehicle).  
 
5.6.4. 
Subject randomization 
This is a double-blind study. At Visit 2, the investigator or designee will assign study 
medication to eligible subjects by selecting Subject Kits in chronological sequence and in 
ascending numerical order starting with the lowest available Subject Kit number (the 
Subject Kit number is the randomization number). The investigator will not omit or 
reuse any Subject Kit numbers. 
 
The investigational center staff member randomizing the subject will enter the SI, 
subject initials and date randomized on both parts of the Subject Kit label, remove the 
tear-off part, attach it to the subject’s label page CRF, and record the Subject Kit number 
assigned in the subject’s CRF. 
 


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5.6.5. 
Dispensing and collecting study medication 
The study medication must be dispensed only to study subjects, only at investigational 
centers specified on the Form FDA 1572 (or its equivalent) and only by authorized 
personnel as required by applicable regulations and guidelines. 
 
At Visit 2, after the subject is randomized, locate study medication jar #1, enter the SI, 
subject initials and date dispensed on the jar label, and dispense the jar of study 
medication to the subject. Also dispense a cooler, provided by Accuitis, to each subject. 
 
The subject must bring dispensed study medication jars with them to all visits using use 
the cooler provided by the investigational staff (or equivalent) to transport the study 
medication. 
 
At Visits 3-5, examine the jar(s) of study medication dispensed to the subject, collect any 
jar that contains no useable study medication and dispense a new jar, if required, 
following the instructions above.  
 
At Visit 6, collect all study medication jars from the subject. 
 
The investigational center staff should make every effort to obtain all dispensed and 
unused study medication. Two documented telephone contacts followed by a 
registered letter to the subject are adequate follow-up efforts. If these efforts fail, the 
reason for the failure must be noted on the appropriate line of the study medication 
inventory CRF.  
 
All unused and un-dispensed study medication should be held for inspection by 
Accuitis, Inc.’s monitor. Upon completion of the study all study medication will be 
returned to Accuitis, Inc. or a designated third party by the monitor using a traceable 
method. 
 
 
 


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5.6.6. 
Study medication application 
The study medications are for external, topical use on the face only and on the 
appropriate study subject only.  
 
The treatment area is the subject’s entire face. For this study, the face is defined: 
 Vertically from the mandibular ridge to the hairline (for subjects with a receding 
hairline the maximum “hairline” is defined by the vertical line drawn over the 
top of the head from tragus to tragus; see below) 
 
Right Profile 
Left Profile 
 
 Horizontally from tragus to tragus, excluding the eyes, eyelids, any membrane 
of the inner nose, mouth, lips and open wounds.  
 
At Visit 2, an investigational center staff member will instruct the subject on the 
proposer study medication application technique, will observe the subject’s first 
application a will monitor the subject for adverse events for at least 20 minutes after the 
application is completed.  
 
 
 


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To perform a study medication application the subject should: 
 Wash her/his hands before starting the application 
 Avoid applying the study medication to the eyes and eyelids, any membrane of 
the inner nose, mouth, lips and open wounds  
 Apply an amount of the assigned study medication sufficient to cover the entire 
face with a thin layer of the medication 
 Gently rub in the study medication until no visible accumulation is evident 
 Wash her/his hands after completing the application. 
 
At Visit 2, a staff member must observe the subject’s study medication application to 
ensure proper application technique. A staff member must record the time the subject 
completes the application as the Application Completion Time. A staff member must 
monitor the subject for adverse events for at least 20 minutes after the Application 
Completion Time. 
  
The subjects are to continue twice-daily application of the assigned study medication to 
the face for 12 weeks with at least 8 hours between applications.  
 
After completing a study medication application subjects should not: 
 Wash the treated areas for at least 4 hours 
 Apply any topical products (e.g., cosmetics, investigator approved bland, non-
medicated emollient/moisturizer, sunscreens) to the treated area for at least 20 
minutes. 
 
Subjects should not apply the study medication within 6 hours prior to any study visit.  
 
5.6.7. 
Dose compliance record 
At Visits 3-6, an investigational center staff member must query each subject to 
determine compliance with the study medication application procedure and frequency. 
The staff member will document the study medication usage in the CRF. 
 
5.6.8. 
Dose modification 
Subjects should not modify the study medication application procedure or frequency. 
All application modifications must be reported on the appropriate CRF page. 
 
If any significant study medication intolerance or safety issue occurs, after consulting 
with the Accuitis, Inc. Medical Monitor (see Page 1), the investigator or designee may 
direct the subject to reduce the study medication application frequency. If the subject 
cannot perform twice daily applications to the entire treatment area for more than 4 
consecutive days, the subject must be removed from the study. 
 


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5.7. 
Study Medication Management 
5.7.1. 
Accountability 
The investigator or designee will maintain an accurate record of the receipt of the study 
medications as shipped by Accuitis, Inc. (or designee), including the date received and 
the condition of the study medications. One copy of this receipt will be returned to 
Accuitis, Inc. when the contents of the study medication shipment have been verified 
and one copy maintained in the study file. In addition, an accurate study medication 
disposition record will be kept, specifying the amount dispensed to each subject and the 
date of dispensing. This inventory record will be available for inspection at any time. At 
the completion of the study, the original inventory record will be available for review 
by Accuitis, Inc. upon request. 
 
5.7.2. 
Return and disposition of study supplies 
At the completion of the study, all unused study medication will be returned to 
Accuitis, Inc. (or designee) for disposal per Accuitis, Inc.’s (or designee’s) written 
instructions. 
 
5.8. 
Blinding 
5.8.1. 
Verification of blinding 
Blinding of the study medications is important for validity of this study. This study uses 
a double-blind design. The study medications are indistinguishable in appearance, 
packaging and labeling. 
 
5.8.2. 
Unblinding during the study 
Blinding is important for validity of this study. However, the blind may be broken in 
the event of a medical emergency in which knowledge of the study medication identity 
is critical to the management of the subject’s course of treatment. Before breaking the 
blind the investigator should determine that the information is necessary (i.e., that it 
will alter the subject’s immediate course of treatment). In many cases, particularly when 
the emergency is clearly not study medication-related, the problem may be effectively 
managed by assuming that the subject is receiving active study medication without the 
need for unblinding.  
 
If deemed necessary to break the blind for a study subject, attempt to contact the 
Accuitis, Inc. Medical Monitor (see Page 1) to obtain concurrence. If it is not possible to 
contact the Medical Monitor beforehand, contact her/him as soon as possible after 
breaking the blind for a subject. 
 


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To identify a subject’s study medication, locate the second panel of the Subject Kit tear-
off label attached to the subject’s CRF and follow the unblinding instructions on the 
label. Record the date of unblinding, the reason for unblinding and the initials of the 
investigational center staff member who performed the unblinding in the subject’s CRF. 
 
Any subject whose blind has been broken must be discharged from the study.  
 
6. 
STUDY ASSESSMENTS 
The study assessments will be performed according to the schedules noted below by the 
investigator or appropriately trained study staff member as noted for each assessment. 
The same staff member should perform the assessments for a given subject throughout 
the study. If this becomes impossible, an appropriate designee with overlapping 
experience with the subject and study should perform the assessments. 
 
6.1. 
Efficacy Evaluations 
6.1.1. 
Lesion count 
The Lesion Count is the total number of rosacea acne lesions (i.e., papules, pustules and 
nodules) on the subject’s face. 
 
At Visits 1-7, the investigator will report the total number for each of the following 
lesion types on the face: 
 Papules, defined as raised inflammatory lesions, <0.5cm in diameter with no 
visible purulent material 
 Pustules, defined as raised inflammatory lesions, <0.5cm in diameter with visible 
purulent material 
 Nodules, defined as any circumscribed, inflammatory mass ≥0.5cm in diameter. 
 
The investigator should count each lesion type separately papules first, then pustules 
then nodules. She/he should start counting at the middle of a subject’s forehead 
moving clockwise ending where she/he started, then count the number of lesions on 
the nose and report the total number of lesions.  
 
At Visit 1, to be enrolled and at Visit 2 to be randomized the subject must have a total of 
≥10 and ≤40 inflammatory lesions (papules, pustules and nodules) with ≤2 nodules, on 
the face. 
 
6.1.2. 
Investigator’s global assessment (IGA) 
The IGA is the investigator’s assessment of the average overall severity of rosacea on the 
subject’s face at a particular point in time. The investigator should NOT refer to any other 
assessments to assist with these assessments.  


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At Visits 1-7 the investigator will the assess the rosacea on each subject’s face and report 
the one integer that best describes the average overall severity using the scale below:  
 
Investigator’s Global Assessment 
Grade Descriptor 
0 
Clear: No papules or pustules, no nodules, none or barely perceptible erythema
1 
Near Clear: Very few (≤3) papules and/or pustules, no nodules, very mild 
erythema 
2 
Mild: Few papules and pustules present, no nodules, mild erythema 
3 
Moderate: Several papules and pustules are the predominant feature, ≤2 
nodules may be present, moderate erythema 
4 
Severe: Numerous papules and pustules, multiple nodules may be present, 
severe erythema 
 
At Visit 1, to be enrolled and at Visit 2, to be randomized, the subject must have an IGA 
grade of ≥3 (Moderate). 
 
At Visit 2 the IGA must be completed prior to the start of the first study medication 
application. 
 
6.2. 
Safety Evaluations 
In addition to routine AE monitoring the following safety assessments will be 
performed. 
 
 
 


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6.2.1. 
Clinical laboratory sampling 
At Visits 1 and 6 non-fasting blood samples for clinical laboratory analysis will be 
collected by a qualified staff member. At a minimum the following tests will be 
conducted: 
Chemistry Panel 
Complete Blood Count 
Albumin 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet count 
Aspartate aminotransferase (AST)
Red blood cell morphology 
Blood urea nitrogen (BUN) 
Red blood cell count 
Bicarbonate 
White blood cell count 
Calcium 
White blood cell differential 
Chloride 
    % & absolute 
Creatinine 
    Basophils 
Glucose 
    Eosinophils 
Lactate dehydrogenase (LDH) 
    Lymphocytes 
Phosphorus 
    Monocytes 
Potassium 
    Neutrophils 
Sodium 
 
Total bilirubin 
Complete Urinalysis 
Total protein 
 
Uric acid 
 
 
The investigator or physician subinvestigator must review the results of each subject’s 
Visit 1 clinical laboratory test results prior to Visit 2. The subject must be withdrawn 
from the study if any of the Visit 1 results are outside normal range for the laboratory 
AND, in the opinion of the reviewer, clinically relevant (CR).  
 
The results of the clinical laboratory tests will be reported on the laboratory’s standard 
reports. The investigator/subinvestigator must review all laboratory reports in a timely 
manner, noting NCR (not clinically relevant) or CR, or the equivalent, for any result that 
is outside the normal range for the laboratory then date and sign/initial the report.  
 
The investigator/subinvestigator must report all laboratory results that are BOTH 
outside the normal range for the laboratory AND, in the opinion of the 
investigator/subinvestigator CR as medical history if found in the results for samples 
collected prior to the start of the first study medication application and as adverse 
events if found in the results for samples collected after the start of the first study 
medication application. 


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6.2.2. 
Local tolerability assessment (LTA) 
The LTA is the investigator’s assessment of the average overall severity of signs and the 
subject’s assessment of the average overall severity of symptoms associated with irritation 
on the treated area. The investigator and subject must NOT refer to any other evaluation 
to assist with these assessments. This is not a comparison with the assessment at any other 
time point. 
 
LTA Signs (assessed by the investigator): 
 Erythema 
 Scaling/dryness. 
 
LTA symptoms (assessed by the subject): 
 Stinging 
 Burning 
 Pruritus (itch). 
 
At Visits 2-7, the investigator and the subject will evaluate the LTA signs and the LTA 
symptoms respectively.  
 
The investigator will assess the LTA signs as follows: 
 At Visit 2: 
o Prior to the first study medication application 
o 20 (±4) minutes after the Application Completion Time. 
 At Visits 3-7. 
 
The subject will assess the LTA symptoms as follows: 
 At Visit 2: 
o Prior to the first study medication application report the LTA for each 
symptom over the previous 24 hours 
o 10 (±4) minutes after the Application Completion Time, report the LTA for 
each symptom since the Application Completion Time. 
 At Visits 3-7: 
o Report the LTA for each symptom over the previous 24 hours. 
 
 
 


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The investigator, for the signs, should report the one integer that best describes the 
average overall severity on the face using the scales below: 
 
Local Tolerability Assessment – Erythema 
Grade Descriptor 
0 
Clear: No erythema present 
1 
Mild: Slight erythema 
2 
Moderate: Definite erythema 
3 
Severe: Marked, fiery erythema 
 
Local Tolerability Assessment – Dryness/Scaling 
Grade Descriptor 
0 
Clear: No signs of dryness or scaling 
1 
Mild: Slight roughness (may be more easily felt than seen), barely perceptible 
scaling 
2 
Moderate: Moderate roughness, definite scaling 
3 
Severe: Marked roughness, heavy scaling 
 
The subject, for the symptoms, should report the one integer that best describes the 
average overall severity on the face using the scales below: 
 
Local Tolerability Assessment – Stinging 
Grade Descriptor 
0 
Clear: No stinging 
1 
Mild: Slight tingling, not bothersome 
2 
Moderate: Definite tingling, slightly bothersome 
3 
Severe: Intense stinging, bothersome and/or uncomfortable 
 
Local Tolerability Assessment – Burning 
Grade Descriptor 
0 
Clear: No burning 
1 
Mild: Slight warmth, not bothersome 
2 
Moderate: Definite warmth, slightly bothersome 
3 
Severe: Intense feeling of heat, bothersome and/or uncomfortable 
 
 
 


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Local Tolerability Assessment – Pruritus (Itching) 
Grade Descriptor 
0 
Clear: No itching 
1 
Mild: Slight itching that is noticeable but is not bothersome 
2 
Moderate: Definite itching that is bothersome but does not disrupt activities or 
sleep 
3 
Severe: Intense itching this is bothersome and may disrupt activities or sleep 
 
Follow these steps to complete the LTA for each symptom by a subject: 
 An investigational center staff member, other than the evaluating investigator, 
will show the appropriate LTA symptom grading scale to the subject and instruct 
the subject on the time interval to be considered 
 The staff member should not give any opinion on the meaning of the LTA 
descriptors 
 The subject should verbally indicate the appropriate grade and the staff member 
will report the grade in the source document 
 Both the subject and the staff member must initial and date the source document 
to indicate the subject performed the LTA for symptoms as instructed 
 The staff member must not influence the subject’s assessment. 
 
6.2.3. 
Vital signs 
At Visits 1, 2 and 7, a qualified investigational center staff member will measure the 
following vital signs: 
 Body temperature 
 Pulse rate 
 Respiration rate 
 Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 
minutes 
 Height (at Visit 1 only) 
 Weight (at Visit 1 only). 
 
A systolic blood pressure >140mm Hg or a diastolic blood pressure >90mm Hg is 
considered abnormal and therefore the investigator must define the reading as CR or 
NCR. 
 
A weight of >300 pounds is considered abnormal and therefore the investigator must 
define the reading as CR or NCR. 
 
Any measure that is, in the opinion of the investigator, abnormal AND CR must be 
recorded as history if found prior to the start of the first study medication application or 
as an AE if found after the start of the first study medication application. 


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6.2.4. 
Urine pregnancy tests 
At Visits 1 and 7, the investigator or designee will perform a urine pregnancy test for 
subjects who are WOCBP. The urine pregnancy test kits used must have a minimum 
sensitivity of 25-mIU ß-HCG/milliliter (mL) of urine.  
 
Subjects who are WOCBP must have a negative pregnancy test result at Visit 1 to 
continue in the study. 
 
If the result of any post-treatment urine pregnancy test is positive, the subject will be 
withdrawn from the study and the subject’s pregnancy documented and followed. 
 
6.3. 
Other Evaluations 
6.3.1. 
Demographics 
At Visit 1, the investigator or designee will interview each subject to obtain 
demographic information including date of birth, sex at birth, race and ethnicity.  
 
6.3.2. 
Medical history 
At Visit 1, the investigator or designee will record medical history information 
including all medical conditions and disease states that: 
 Are ongoing 
 Require concomitant therapy 
 Are, in the opinion of the investigator, relevant to the subject’s study 
participation.  
 
For women who are not of childbearing potential the reason they are not of 
childbearing potential must be reported as medical history. 
 
6.3.3. 
Standardized photography 
At Visits 2-7, an appropriately trained investigational center staff member other than 
the evaluating investigator will take standardized photographs to document the status 
of rosacea on the subject’s face. The study images are intended to be used for scientific, 
training and promotional purposes. 
 
Care must be taken to ensure similar lighting, background, subject positioning relative 
to the camera and camera settings are used for each photograph.  
 
Equipment, supplies, training and detailed instructions for obtaining and managing the 
photographs will be provided to the investigational center prior to the initiation of 
subject enrollment.  
 


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Study photographs are to document the status of the subjects’ clinical condition.  
7. 
ADVERSE EVENTS 
Adverse events will be monitored throughout the study and reported to Accuitis, Inc. 
on the appropriate AE CRF.   
 
7.1. 
Definitions 
7.1.1. 
Adverse events (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign or symptom associated with the use of an investigational product 
(including an abnormal laboratory finding), whether or not related to the 
investigational product.  
 
Thus any new, clinically relevant worsening of an existing sign, symptom or disease, 
should be considered an AE.  
 
Worsening of the Lesion Count, IGA or LTA should be reported as an AE only if the 
use of the study medication is interrupted or discontinued or other therapy is 
required to manage the event. 
 
Every new episode or clinically relevant worsening of a chronic condition (e.g., 
headaches, allergies, depression, and hypertension) should be reported as a separate 
AE, even if the condition is reported in the subject’s medical history. 
 
The investigator should, when certain, report a diagnosis rather than the signs, 
symptoms or clinically relevant abnormal laboratory values associated with the AE. 
Otherwise, signs, symptoms or abnormal laboratory values may be used to describe the 
AE. 
 
An abnormality discovered (e.g., clinically relevant laboratory abnormalities), prior to 
the first study medication application, should be reported as medical history, not as an 
AE. 


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7.1.2. 
Serious adverse event (SAE) 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect 
 Is an important medical event. 
 
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of event; it does not refer to an event that hypothetically might have caused 
death if it was more severe. 
 
Inpatient hospitalization is considered to have occurred if the subject is admitted to the 
hospital on an in-patient basis even if released the same day. Prolongation of 
hospitalization is defined as an additional night stay in the hospital. Hospitalization for 
a diagnostic test (even if related to an AE) or elective hospitalization that was planned 
before study enrollment are not themselves reasons for an event to be defined as a SAE. 
 
Important medical events are those that may not be immediately life threatening, result 
in death, hospitalization but are clearly of major clinical significance and may 
jeopardize the subject or require intervention to prevent one of the outcomes listed in 
the definition above. These should also usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasia or convulsions that do not result in hospitalization. 
 
7.1.3. 
Unexpected adverse event 
An unexpected AE is any AE that the investigator defines as related to a study 
medication, the nature of which is not consistent with the Investigator’s Brochure or 
package insert. 
 
7.1.4. 
Adverse event reporting period 
AEs (serious and non-serious) must be reported starting with the subject’s first study 
medication until the end of the subject’s last study visit OR until 30 days after the 
subject’s last study medication application, whichever is longer. 
 


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7.1.5. 
Severity 
The investigator is to define the severity each AE using the following definitions as a 
guideline. The investigator will consider the range of the possible severity of the event 
and identify the severity that is the most appropriate according her/his medical 
judgment. 
 
Mild – Awareness of signs or symptom, but easily tolerated 
Moderate – Discomfort, enough to cause interference with usual activity 
Severe – Incapacitating with inability to perform usual activity. 
 
7.1.6. 
Relationship to study medication 
The investigator will determine if there is a reasonable causal relationship between the 
study medication and an AE or not. The investigator will use her/his best medical 
judgment and consider all relevant factors (e.g., temporal relationship, location of the 
event, the subject’s relevant medical history, concomitant therapies and concurrent 
conditions) to determine the relationship of the AE to the study medication. The 
investigator will define the relationship of an AE to the study medication by selecting 
one of the following categories: 
 
Related – There is a reasonable possibility that there is a causal relationship 
between the study medication and the AE. 
 
Not Related – There is not a reasonable possibility that there is a causal 
relationship between the study medication and the AE. 
 
The term “reasonable causal relationship” means there are facts or arguments to 
suggest a causal relationship (International Conference on Harmonization (ICH) E2A). 
 
7.2. 
Reporting Procedures 
7.2.1. 
Procedures for reporting adverse events 
At each post enrollment visit, the investigator will question the subject to elicit AEs 
using a non-directive question such as “Has there been any change in your health since 
the previous study visit?”  
 


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Any AE noted during the reporting period must be reported in the source documents 
and on the appropriate AE CRF. AEs that are defined as “Not Related” to the study 
medications will be followed until they are resolved or until the subject’s last visit. AEs 
that are defined as “Related” to the study medications will be followed until they are 
resolved or, if not resolved after the subject’s last study visit, until in the opinion of the 
investigator, the AE reaches a clinically stable outcome with or without sequelae. 
 
7.2.2. 
Procedure for reporting a serious adverse event 
Upon becoming aware of a SAE occurring during the AE reporting period, whether or 
not related to the study medications, the investigator must: 
 
1. 
Take the appropriate medical action to ensure the subject’s safety 
2. 
Immediately inform the Medical Monitor of the SAE by telephone: 
 
 
Accuitis, Inc. 
Medical Monitor 
 
 
 
3. 
Within 24-hours complete, as fully as possible, an AE CRF and an SAE form; fax or 
e-mail the forms and any other relevant information (e.g., concomitant medication 
CRF, medical history CRF, laboratory test results) to the Accuitis, Inc. Medical 
Monitor. 
4. 
Monitor and document the progress of the SAE until it resolves or, if not resolved 
after the subject’s last study visit, until in the opinion of the investigator the AE 
reaches a clinically stable outcome with or without sequelae AND the investigator 
and Accuitis, Inc. Medical Monitor agree that the SAE is satisfactorily resolved. 
5. 
Inform the Accuitis, Inc. Medical Monitor of SAE updates by telephone followed 
by an SAE form update sent by fax or by e-mail. 
6. 
Comply with the appropriate regulatory requirements and Accuitis, Inc. 
instructions regarding reporting of the SAE to the responsible IRB. 
 


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8. 
PREGNANCY 
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 
consecutive months). Even women who are using oral, implanted or injected 
contraceptive hormones, an intrauterine device, barrier methods (e.g., diaphragm, 
condoms, spermicides) to prevent pregnancy, practicing abstinence or where the 
partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential. 
 
All WOCBP must use an effective method of birth control during the course of the 
study, in a manner such that risk of failure is minimized. Effective methods of birth 
control approved for this study are: 
 Implants (e.g., Norplant® system); when used continuously for at least 90 days 
 Injectables (e.g., Depo-Provera®); when used continuously for at least 90 days 
 Transdermal patch 
 Combined oral contraceptives 
 Barrier methods (e.g., diaphragm, condoms with spermicides 
 Intrauterine devices (e.g., ParaGard® and Mirena®).  
 
Abstinence or having a sterile partner is not considered an effective method of birth 
control. 
 
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this 
discussion.  During the trial, all WOCBP will be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period). 
 
If a subject becomes pregnant during the study, or within 30 days of discontinuing the 
study medication, whichever is longer, the investigator should report the pregnancy to 
the Accuitis Inc. Medical Monitor within 24 hours of becoming aware of the pregnancy. 
 
If a subject or investigator suspects that the subject may be pregnant prior to study 
medication administration, the study medication must be withheld until the results of a 
pregnancy test are available.  If pregnancy is confirmed, the subject must not receive 
study medication and must be discharged from the study.  
 


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If, following study medication administration, it is determined that the subject may 
have been or was pregnant at the time of study medication exposure the investigator 
must immediately notify the Accuitis Inc. Medical Monitor and record the event on a 
pregnancy surveillance form. All pregnancies must be reported using a pregnancy 
surveillance form and following the procedures for SAE reporting. 
Protocol-required procedures for trial discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated. 
In addition, the investigator must report to the Accuitis, Inc. Medical Monitor on the 
pregnancy surveillance form, follow-up information regarding the course of the 
pregnancy, including perinatal and neonatal outcome. Infants should be followed for a 
minimum of six weeks. 
  
9. 
STATISTICAL ANALYSES 
9.1. 
General Considerations 
The statistical plan describes the statistical analysis as it is foreseen at the time of 
planning the trial.  Any deviation from the statistical plan, the reasons for such 
deviations, and any additional statistical analyses that may be performed will be 
submitted as amendments prior to the unblinding of the randomization code.   
 
All subject protocol deviations will be summarized in the clinical study report. All 
exclusions from the per-protocol population will be reviewed in a blind data review 
meeting before breaking the blind. 
 
9.2. 
Types of Analyses (Intent-to-Treat, Per-Protocol) 
The definitions of the populations for the different types of analyses follow those given 
in the ICH E9 guideline (1998). 
 
9.2.1. 
Modified intention-to-treat analysis (MITT) 
The modified intention-to-treat (MITT) population will include all randomized subjects 
who were dispensed study medication and provided any post-baseline efficacy data.  
The general analysis procedure for any post-baseline visit with missing efficacy data 
will be to impute data values from the most recent non-missing post-baseline visit. For 
analysis purposes, the endpoint analysis will use the last non-missing post-baseline 
data for each efficacy variable. 
 
The safety population will include all randomized subjects. The analysis of safety will 
include variables such as clinical laboratory evaluations, vital signs, and adverse drug 
experiences. It is not necessary that measurements of any efficacy variable post 
randomization be available. 


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The MITT analysis provides estimates of treatment effects that may be more likely to 
mirror those effects observed in subsequent practice.  Consequently, this analysis will 
be considered the primary efficacy analysis. 
 
9.2.2. 
Per-protocol analysis (PP) 
The per-protocol (PP) population is a subset of the MITT population and includes 
subjects who have no violations of the inclusion/exclusion criterion and who are 
compliant with treatment medication, defined as greater than or equal to 80% of 
specified medication.  Before breaking the blind the precise reasons for excluding 
subjects from the PP population will be fully documented in a blinded data review 
meeting.   
 
The last non-missing observation (post randomization) of these subjects will be carried 
forward to any subsequent missing visits and to endpoint.   
 
9.3. 
Primary Efficacy Variable 
9.3.1. 
Lesion count (papules, pustules and nodules) 
Total lesion count is the sum of the papule count, the pustule count, and the nodule 
count. The total lesion count obtained at endpoint is the variable that will be used for 
the primary efficacy evaluation.   
 
9.3.2. 
Statistical analysis of total lesion count 
Total lesion count will be summarized for each treatment group and at each visit using 
mean, standard deviation, median, minimum, and maximum.  The comparison between 
the two treatments will be based on the difference for each subject between each visit 
and Visit 2. 
 
In accordance with ICH E9 guideline on Statistical Consideration in the Design of 
Clinical Trials (1998), the type 1 error rate of the test will be 5%. 
 
At each post-baseline visit, an analysis of covariance (ANCOVA) will be performed to 
test the null hypothesis of no treatment effect.  The dependent variable will be the 
difference between the value at each post-baseline visit, including endpoint, and the 
baseline value.  The change from baseline to the endpoint (Visit 6) will be the primary 
efficacy analysis.  The baseline value will be the covariate. Treatment group and study 
center will be the main effects in the model.  This analysis will be performed on the 
MITT and PP populations.  Efficacy will be declared if the treatment effect p-value for 
the MITT population is no greater than 0.05 and is favorable to ACU-D1 Ointment 
. 
 


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A second ANCOVA, which includes a treatment-by-center interaction, will be 
performed in order to test the significance of the interaction term in an exploratory 
manner.  If the interaction term is significant at the 0.10 level, summary data will be 
presented for each study center in an appendix to the study report.  In addition, if the 
interaction term is significant at the 0.10 level, the interaction term may be included in 
the final ANCOVA model to examine treatment effects if inclusion of this term 
increases the sensitivity of the analysis. 
The residuals from the primary ANCOVA model will be analyzed for deviations from 
normality.  If the test for normality fails at the 0.05 level of significance then the 
ANCOVA analysis will be supplemented by a Van Elteren test, stratified by study 
center.  
 
Subgroup analyses including but not limited to race, age and gender will be performed 
for exploratory purposes, provided adequate sample sizes are available in potential 
subgroups. An exploratory mixed-model repeated-measures analysis of change from 
baseline across all post-baseline visits may be performed to explore changes in 
treatment effect over time and to potentially increase overall and by-visit sensitivity.  
Similar ANCOVA analyses to those described above will be performed on the PP 
population and will be considered exploratory analyses. 
 
9.4. 
Secondary Efficacy Variables and Their Statistical Analyses 
9.4.1. 
Investigator’s global assessment  
The Investigator’s Global Assessment score is an ordered categorical value ranging 
from 0 (Clear) to 4 (Severe).  The assessment is obtained at each visit.  
 
Investigator’s Global Assessment score will be summarized for each treatment group 
and at each visit using the median, minimum, maximum and frequency distributions.  
The comparison between the two treatments will be based on the difference for each 
subject between each visit, including the endpoint visit, and the baseline visit. 
 
The van Elteren test, stratified by study center, as defined for the primary efficacy 
variable will be used for the analysis of IGA.  Ordinal logistic regression models of the 
IGA, parameterized in the same manner as the ANCOVA models for the primary 
efficacy variable, will be used in an exploratory analysis of the impact of treatment on 
IGA scores.   
 
9.4.2. 
Treatment responders 
Treatment responders will be defined at each visit and at endpoint as subjects who have 
either (1) two ordinal or more reductions in the Investigator’s Global Assessment (IGA) 
or (2) an IGA score of 0 or 1.   
 


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Treatment response (yes/no) is a dichotomous binomial variable.  Treatment response 
will be summarized for each treatment group and at each visit using frequency 
distributions.  At each visit, these scores will be analyzed using a Fisher’s exact test 
supplemented by a Mantel-Haenszel analysis stratified by Investigator. The Breslow-
Day test will be used to test the homogeneity of the treatment responder effect among 
investigators. The analysis of treatment success at endpoint visit is the primary 
responder analysis. 
 
9.4.3. 
Individual lesion counts 
As ancillary efficacy parameters, papules, pustule, and nodule counts will be 
summarized for each treatment group and at each visit using mean, standard deviation, 
median, minimum, and maximum.  Change from baseline for papule, pustule, nodule, 
and papule plus pustule counts will be analyzed at each post randomization visit using 
the same parametric or non-parametric analysis as was used in the primary efficacy 
variable (total inflammatory lesions). 
 
9.4.4. 
Subgroup analyses 
Subgroup analyses including but not limited to race, age and sex will be performed for 
exploratory purposes on all secondary efficacy variables for the ITT population, 
provided adequate sample sizes are available in potential subgroups.  In addition, the 
analyses performed on the PP population are considered exploratory. 
 
9.5. 
Demographics and Baseline Characteristics 
Demographic variables are race, age and sex.  Age will be summarized for each 
treatment group using mean, standard deviation, median, minimum, and maximum.  
Gender and race will be summarized for each treatment group using frequency 
distributions.   
 
Baseline characteristics are a complete medical history, lesion score (total number of 
facial lesions and number of papules, pustules, and nodules) and Investigator’s Global 
Assessment score.  Medical histories will be listed for each subject.  Investigator’s 
Global Assessment score will be summarized using frequency distributions and will be 
tested for baseline comparability of treatment groups using the Mantel-Haenszel Chi-
Square test.  Total number of facial lesions and numbers of papules, pustules, and 
nodules will be summarized for each treatment group using mean, standard deviation, 
median, minimum, and maximum and will be tested for baseline comparability of 
treatment groups using a two-sample Student’s t-test. 
 
9.6. 
Interim Analysis 
No interim analyses will be conducted for this study. 


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9.7. 
Sample Size Determination 
This is a pilot study for which no previous data are available to make a power 
calculation.  This will be the seminal study. 
10. 
TRAINING, MONITORING, DATA MANGEMENT, AND QUALITY 
ASSURANCE 
10.1. 
Training 
For each investigational center, there will be an initiation visit prior to enrolling any 
study subjects. 
 
It is strongly recommended that all investigators, other evaluators, study nurses, study 
coordinators or other applicable personnel attend this visit.  During this visit, 
participants will be trained to the protocol, study specific procedures, and the CRFs.  
Those unable to attend the initiation visit must receive on-site training prior to 
participating in any of the procedures and evaluations in this study.  
 
Clinical Research Associates (CRAs) and other applicable personnel will be trained 
prior to study initiation to familiarize CRAs with the disease, the Standard Operating 
Procedures (SOPs), the protocol and other study specific items.  Team organization, 
communication and operational issues will also be discussed. 
 
Accuitis, Inc. will provide an investigational center file to each center. 
 
10.2. 
Monitoring 
The conduct of the study will be closely monitored by representatives of Accuitis, Inc. 
to verify adherence to ICH Good Clinical Practice (GCP) guidelines and applicable 
SOPs.  Reports of these verifications will be archived with the study report.  The 
investigator will allow the Accuitis, Inc. representatives designee and/or and any 
regulatory agency to have direct access to all study records, CRFs, corresponding 
subject medical records, study medication dispensing records and study medication 
storage area, and any other documents considered source documentation.  The 
investigator also agrees to assist the representative, if required. 
 
10.3. 
Data Management 
Data-management activities of this study will be sub-contracted. 
 


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Edit checks and review processes will be performed by the sub-contractor until all data 
clarifications are resolved. The data will be exported to be stored in SAS datasets by the 
sub-contractor. After all data clarifications are resolved and subject’s evaluability is 
determined, the database will be locked. 
 
10.4. 
Quality Assurance 
The study is conducted under the sponsorship of Accuitis, Inc. in compliance with the 
applicable regulatory requirements as well as applicable ICH guidelines, Helsinki 
Declaration and in respect of the Accuitis, Inc. and/or sub-contractor SOPs for study 
conduct and monitoring. 
 
Audits may be carried out by the Accuitis, Inc. or the Accuitis, Inc. representatives and 
inspections may be performed by regulatory authorities or IRBs before, during or after 
the study.  The investigator will provide the auditing/inspecting group direct access to 
all study records (e.g., CRFs, subject medical records, study medication dispensing 
records) and the investigational center study facilities. The investigator and study staff 
will be available and will assist the auditing/inspecting groups as appropriate.  
 
10.5. 
Changes in Study Conduct and Protocol Amendments 
10.5.1. 
Study conduct and protocol amendments 
With the exception of eliminating an immediate hazard to a subject, the investigator 
should not deviate from the protocol or implement any changes without prior written 
approval from Accuitis, Inc. and prior review and documented approval from the IRB. 
 
Changes that involve only logistical or administrative changes are allowed.  The 
investigator should document and explain any deviation from the protocol. 
 
11. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS 
11.1. 
Institutional Review Board (IRB) 
This protocol and all amendments, ICF and subject recruitment advertisements (if 
applicable) will be approved by an IRB. 
 
11.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles originating from 
the Declaration of Helsinki, the ICH GCP guidelines, local regulatory requirements and, 
at US investigational centers, in compliance with the HIPAA. 
 


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11.3. 
Subject Information and Consent 
All subjects who participate in this study must be fully informed about the study in 
accordance with the GCPs, federal regulations local regulations and, at US 
investigational centers, with HIPAA.  The ICF, approved by an IRB, will be fully 
explained to the subject.  Prior to any study related procedures, including washout from 
therapies, the subject will sign and date the ICF.  The investigator must maintain each 
subject’s ICF in the investigational center’s study file and must provide each subject 
with a copy of the signed and dated ICF. 
 
11.4. 
Contractual Requirements 
A contractual agreement will be signed between Accuitis, Inc. and each investigator.  
This document will contain supplemental information, including financial terms, 
confidentiality, study schedule, third party responsibility, and publication rights. 
 
11.5. 
Data Collection and Archiving 
11.5.1. 
Data collection  
The Investigator must maintain required records for all study subjects.  Data for this 
study will be recorded in the subject's source document and on the CRFs.  All data on 
these CRFs should be recorded completely and promptly.  A copy of the completed 
CRFs for each subject will be retained by the investigational center. 
 
11.5.2. 
Source documentation 
Investigators must keep accurate separate records (other than the CRFs) of all subjects' 
visits that include all pertinent study related information.  A statement should be made 
indicating that the subjects have been enrolled in this clinical study, and have provided 
written informed consent.  Any AEs must be completely documented. 
 
Source documentation includes results of any diagnostic tests conducted during the 
study.   
 
11.5.3. 
Archiving 
All pertinent data, samples, photographs, correspondence, original or amended 
protocol, reports and all other material relating to the study will be maintained securely 
by Accuitis, Inc./Contract Research Organization (CRO)/investigator archives for the 
legally required duration for archiving. 
 
The investigator should maintain the essential study documents as specified in ICH 
GCP, and in compliance with all regulatory requirements. The investigator should 
ensure these documents are protected from accidental destruction or disposal. 


Accuitis, Inc. 
Protocol number: ACU-D1-201 
Page 49 of 49 
Date: 05-AUG-2017                                                                                                    Supersedes: 28-JUN-2017 
 
If the Investigator needs to re-assign responsibility for maintaining these documents 
(e.g., due to retirement) it must be transferred to a person willing to accept this 
responsibility.  The investigator must notify Accuitis, Inc., in writing, of the name and 
address of the new individual. 
 
12. 
REFERENCES 
1 
Wilkin JK.  Rosacea:  pathology and treatment. Arch Dermatol. 1994;130:359-362. 
 

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