Clinical trial NCT02959970
Conditions: Acne Vulgaris
Sponsor: Almirall, S.A.
Start date: 2016-10-31; Completion date: 2018-03-09
Enrollment: 100 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of ACZONE Gel, 7.5% administered topically once-daily for 12 weeks in 9 to 11 year-olds with acne vulgaris.

Detailed description:

Arms: arm 1: Participants applied ACZONE 7.5 % gel topically, once-daily to the entire face, neck, upper chest, upper back and shoulders starting from Day 1 under maximal use conditions (2 grams per day) for Day 8 consecutive days, followed by a thin layer to their face and acne-affected areas on the upper chest, upper back, and shoulders for next 11 weeks. arm 2: Participants applied ACZONE 7.5% gel topically, once-daily in a thin layer to their face and acne-affected areas on upper chest, upper back, and shoulders for 12 weeks.
Interventions: intervention 1: dapsone gel
Intervention descriptions: intervention 1: Dapsone (ACZONE) 7.5% gel topically once daily.

Protocol documents:
Prot_000.pdf: 
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
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Approval Date: 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 3 
Protocol Summary .................................................................................................................... 7 
1. 
Background and Clinical Rationale ................................................................................. 13 
1.1 
Introduction ............................................................................................................ 13 
1.2 
Clinical Pharmacokinetics of Dapsone .................................................................. 14 
1.3 
Rationale for the Study ........................................................................................... 15 
1.4 
Rationale for the Study Design .............................................................................. 15 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 16 
2.1 
Study Objectives .................................................................................................... 16 
2.2 
Clinical Hypotheses ............................................................................................... 16 
3. 
Study Design .................................................................................................................... 16 
4. 
Study Population and Entry Criteria ................................................................................ 17 
4.1 
Number of Patients ................................................................................................. 17 
4.2 
Study Population Characteristics ........................................................................... 18 
4.3 
Inclusion Criteria .................................................................................................... 18 
4.4 
Exclusion Criteria................................................................................................... 19 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 21 
4.5.1  Permissible Medications/Treatments ......................................................... 21 
4.5.2  Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .............................................................................. 21 
4.5.3  Prohibited Medications/Treatments ........................................................... 21 
4.5.4  Special Diet or Activities ........................................................................... 22 
5. 
Study Treatments ............................................................................................................. 23 
5.1 
Study Treatments and Formulations ....................................................................... 23 
5.2 
Methods for Masking/Blinding .............................................................................. 23 
5.3 
Method for Assignment to Treatment Groups/Randomization .............................. 23 
5.4 
Treatment Regimen and Dosing ............................................................................. 23 
5.4.1  Conduct of the Study .................................................................................. 23 
5.4.2  Stopping Rules ........................................................................................... 24 
5.5 
Storage of Study Medications/Treatments ............................................................. 25 
5.6 
Treatment Administration ...................................................................................... 25 
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Approval Date: 
 
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Protocol 1679-401-006
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6. 
Response Measures and Summary of Data Collection Methods ..................................... 26 
6.1 
Pharmacokinetics ................................................................................................... 26 
6.1.1  Pharmacokinetic Sampling Timepoints...................................................... 26 
6.1.2  Pharmacokinetic Sample Collection and Processing ................................. 26 
6.1.3  Pharmacokinetic Sample Bioanalysis ........................................................ 26 
6.2 
Efficacy Measures .................................................................................................. 27 
6.2.1  Investigator’s Global Assessment .............................................................. 27 
6.2.2  Lesion Count .............................................................................................. 28 
6.2.3  Other Measures .......................................................................................... 29 
6.3 
Safety Measures ..................................................................................................... 29 
6.3.1  Adverse Events .......................................................................................... 29 
6.3.2  Suspected Sensitization .............................................................................. 30 
6.3.3  Unscheduled Visits ..................................................................................... 30 
6.3.4  Local Tolerability ....................................................................................... 30 
6.4 
Other Study Supplies .............................................................................................. 31 
6.5 
Summary of Methods of Data Collection .............................................................. 32 
7. 
Statistical Procedures ....................................................................................................... 33 
7.1 
Analyses Populations ............................................................................................. 33 
7.2 
Pharmacokinetic Analysis ...................................................................................... 33 
7.3 
Efficacy Analysis ................................................................................................... 33 
7.3.1  Safety Analyses .......................................................................................... 34 
7.4 
Other Analysis ........................................................................................................ 35 
7.5 
Subgroup Analyses ................................................................................................. 35 
7.6 
Sample Size Calculation ........................................................................................ 35 
7.7 
Interim Analyses..................................................................................................... 35 
8. 
Study Visit Schedule and Procedures .............................................................................. 35 
8.1 
Patient Entry Procedures ........................................................................................ 35 
8.1.1  Overview of Entry Procedures ................................................................... 35 
8.1.2  Informed Consent and Patient Privacy ....................................................... 35 
8.2 
Washout Intervals ................................................................................................... 36 
8.3 
Procedures for Final Study Entry ........................................................................... 36 
8.4 
Visits and Associated Procedures ........................................................................... 36 
8.4.1  Screening Visit (Days -30 to -1) ................................................................. 36 
8.4.2  Baseline/Day 1 (Visit 2) ............................................................................. 37 
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Approval Date: 
 
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Protocol 1679-401-006
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GDD-TA-T-004 v2015.10 
 
8.4.3  Week 1/Visit 3 [Day 8 (+ 2 days)] and Week 2/Visit 4 (Day 15 ± 3 days) 38 
8.4.4  Week 4/Visit 5 (Day 29 ± 7 days)) and Week 8/Visit 6 (Day 57 ± 7 days))
 
38 
8.4.5  Week 12/Early Exit/Visit 7 (Day 85 ± 7 days) ........................................... 39 
8.5 
Instructions for the Patients .................................................................................... 39 
8.6 
Unscheduled Visits ................................................................................................. 40 
8.7 
Compliance With Protocol ..................................................................................... 40 
8.8 
Early Discontinuation of Patients .......................................................................... 40 
8.9 
Withdrawal Criteria ................................................................................................ 40 
8.10  Study Termination .................................................................................................. 40 
9. 
Adverse Events ................................................................................................................ 41 
9.1 
Definitions .............................................................................................................. 41 
9.1.1  Adverse Event ............................................................................................ 41 
9.1.2  Serious Adverse Event ............................................................................... 41 
9.1.3  Severity ...................................................................................................... 42 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 42 
9.2 
Procedures for Reporting Adverse Events ............................................................. 42 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 43 
9.4 
Procedures for Unmasking of Study Medication ................................................... 44 
10.  Administrative Items ....................................................................................................... 44 
10.1  Protection of Human Patients ................................................................................ 44 
10.1.1  Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 44 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 44 
10.1.3  Compliance With Good Clinical Practice .................................................. 44 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21CFR Part 11) ................................................................................... 45 
10.2  Changes to the Protocol ......................................................................................... 45 
10.3  Patient Confidentiality ........................................................................................... 45 
10.3.1  Patient Privacy ........................................................................................... 45 
10.4  Documentation ....................................................................................................... 46 
10.4.1  Source Documents ..................................................................................... 46 
10.4.2  Case Report Form Completion................................................................... 47 
10.4.3  Study Summary .......................................................................................... 48 
10.4.4  Retention of Documentation ...................................................................... 48 
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Approval Date: 
 
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GDD-TA-T-004 v2015.10 
 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 48 
10.5.1  Labeling/Packaging .................................................................................... 48 
10.5.2  Clinical Supply Inventory .......................................................................... 49 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 49 
10.6  Monitoring by the Sponsor .................................................................................... 49 
10.7  Handling of Biological Specimens......................................................................... 49 
10.8  Publications ............................................................................................................ 50 
11.  References ........................................................................................................................ 51 
12.  Attachments ..................................................................................................................... 53 
12.1  Examination Procedures, Tests, Equipment, and Techniques ................................ 53 
12.2  Handling of Biological Specimens......................................................................... 57 
12.3  Glossary of Abbreviations ...................................................................................... 58 
 
List of Tables 
Table 1 
Schedule of Visits and Procedures .................................................................. 13 
Table 2 
Investigator’s Global Assessment ................................................................... 30 
 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
Protocol Summary 
Study Compound:  ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Phase:  4 
Study Objectives:  
To evaluate the safety and tolerability of ACZONE Gel, 7.5% (hereafter referred to as ACZONE 7.5%) 
administered topically once-daily for 12 weeks in 9 to 11 year-olds with acne vulgaris 
To evaluate the peak and trough plasma drug concentrations in 9 to 11 year-olds with acne vulgaris following 
once-daily dosing of ACZONE 7.5% under maximal use conditions for the first 8 days (+ 2 days) 
To explore the efficacy of ACZONE 7.5% administered topically once-daily in 9 to 11 year-olds with acne 
vulgaris 
Study Design 
Structure:  Multicenter, open-label, non-comparative trial 
Duration:  Patient participation is up to approximately 16 weeks from screening to trial exit; treatment duration 
is up to 12 weeks 
Study Treatment Groups:  ACZONE 7.5%  
Controls:  No control group 
Dosage/Dose Regimen:  All patients will receive treatment with ACZONE 7.5% once-daily 
Pharmacokinetic (PK) Cohort (at least 16 evaluable PK patients): For the first 8 days (+ 2 days), study drug will 
be administered once-daily under maximal use condition (~2 grams/day) to the entire face, neck, upper chest, 
upper back and shoulders as instructed by the study site. The study drug should be rubbed in gently and 
completely. On Day 1, the study drug will be administered on site. From Day 2 through Day 7, the study drug 
will be administered in the morning at home by the patient’s legally authorized representative.  At the 
Week 1/Visit 3 [Day 8 (+2 days)], the study drug will be administered on site in the morning.  After the 
Week 1/Visit 3, patients or the patient’s legally authorized representative will apply a pea-sized amount of study 
drug in a thin layer to the patient’s face, once-daily, at home for the remaining 11 weeks, the same as the dose 
regimen for the Non-PK Cohort.  Acne-affected areas on the upper chest, upper back, and shoulders should also 
be treated with a thin layer during the final 11 weeks.  Evaluable PK patients are defined as those that are 
administered at least 8 days of study drug under maximal use conditions, and provided PK samples for analysis 
without any major protocol deviations.  
Non-PK Cohort (approximately 84 patients): Patients or the patient’s legally authorized representative will 
apply a pea-sized amount of study drug in a thin layer to the patient’s face once-daily for 12 weeks as instructed 
by the study site. Acne-affected areas on the upper chest, upper back, and shoulders should also be treated with 
a thin layer. 
Randomization/Stratification: No randomization; all patients will receive ACZONE 7.5%.  Assignment to PK 
or Non-PK Cohort will be based on patient/legally authorized representative choice and investigator’s 
judgment. 
Visit Schedule includes up to 7 scheduled study visits (see Table 1 for further details): 
• 
Visit 1:  Screening (-30 to day -1) 
• 
Visit 2:  Day 1 (Baseline)a 
• 
Visit 3:  Week 1 (Day 8 + 2 days) 
• 
Visit 4:  Week 2 (±3 days) 
• 
Visits 5 and 6: Weeks 4 and 8 (±7 days) 
• 
Visit 7:  Week 12 / Early Exit (±7 days) 
a Can be combined with the screening visit if no washout period is required. 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
 
Study Population Characteristics 
Number of Patients:   
For the PK Cohort, at least 16 subjects will be enrolled to ensure 16 evaluable PK subjects at the Week 1 visit.  
For the Non-PK Cohort, approximately 84 patients will be enrolled. 
Condition/Disease:  Patients with mild, moderate, or severe facial acne vulgaris who are otherwise in good 
health. 
Key Inclusion Criteria:  Male or female, 9 to 11 years of age, with a score of 2 (mild), 3 (moderate), or 4 
(severe) on the Investigator’s Global Assessment (IGA) scale and 20-100 total lesions (noninflammatory and/or 
inflammatory) on the face, including the nose. 
Key Exclusion Criteria:  Patients with uncontrolled systemic disease(s); patients with severe cystic acne, acne 
conglobata, acne fulminans, or secondary acne (chloracne, drug-induced acne, etc); patients who have used 
topical dapsone within 1 month prior to the screening visit, oral dapsone within 2 months prior to the screening 
visit, or have any allergy or sensitivity to the study drugs or their components. 
Response Measures 
Safety:  
Adverse events; physical examination; vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature); urine pregnancy tests for female patients.   
Tolerability:  
• 
Investigator’s or trained designee’s assessment: dryness, scaling, and erythema 
• 
Patient’s assessment: stinging/burning 
Pharmacokinetics:  
For patients in the PK Cohort who will be dosed under maximal use conditions for the first 8 days (+ 2 days), 
blood samples will be collected at the Week 1/Visit 3 30 min prior to dosing at the site in the morning and at 
approximately 10 hours post dose (± 3 hour) to determine the peak and trough plasma concentrations of 
dapsone, N-acetyl dapsone (NAD), dapsone hydroxylamine (DHA), and other metabolites or analytes (if 
warranted).  
Efficacy:  
Lesion counts (face only); IGA (face only) 
General Statistical Methods and Types of Analyses:   
Three analysis populations will be utilized as follows: 
1. The safety population includes all patients who are treated with at least 1 application of study drug. 
2. The modified intent-to-treat (mITT) population includes all enrolled patients who have a baseline 
assessment and at least 1 postbaseline assessment.  
3. The PK population will be defined as all patients who received applications of study drug for at least 
8 days under maximal use conditions and have evaluable blood samples for PK analyses.  This 
population will be used for pharmacokinetic analyses.  
 
Safety analyses will be based on the safety population.  Efficacy analyses will be based on the mITT population.  
No imputation for missing data will be performed for safety or efficacy analyses. 
Safety Analyses: Safety variables are treatment-emergent adverse events (TEAEs), including new findings from 
physical examinations, local (dermal) tolerability, and vital signs. 
For TEAEs, the number and percentage of patients reporting each TEAE at least once will be tabulated in 
descending order of incidence rate by primary system organ class (SOC) and preferred term (PT), and by 
primary SOC, PT, and severity. Treatment-related TEAEs will be analyzed in the same manner. Local (dermal) 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
tolerability data will be summarized using descriptive statistics, and frequency distributions.  Positive 
pregnancy test results will be listed. 
Efficacy Analyses: The frequency distribution of patients with a Grade 0 or Grade 1 on the IGA will be 
summarized by visit. Descriptive statistics will be used to summarize change from baseline in each of the 
following by visit: inflammatory lesion counts, non-inflammatory lesion counts, and total lesion counts.    
Pharmacokinetic Data Analysis: For patients in the PK Cohort who will be dosed under maximal use conditions 
for the first 8 days (+ 2 days), the peak and trough plasma concentrations of dapsone, NAD, DHA, and other 
metabolites or analytes (if warranted) at Week 1/Visit 3 will be summarized using descriptive statistics, if 
applicable. 
Sample Size Calculation: The sample size for this trial was determined empirically, and is consistent with that 
requested by the FDA in the postmarketing requirement for ACZONE 7.5%.   
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
Table 1 
Schedule of Visits and Procedures 
Study Period 
Screeninga 
Baseline/Day 1a 
Week 1 
Week 2 
Weeks 4 and 8 
Week 12/ 
Early Exit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 and 
Visit 6 
Visit 7 
Visit Windows  
Day -30 to 
Day -1  
N/A 
Day 8 (+ 2 
days) 
Day 15 (± 3 
days) 
Day 29 (± 7 
days) and Day 
57 (± 7 days) 
Day 85 (± 7 
days) 
Informed consent/authorization and minor assentb 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Skin phototype assessment 
X 
 
 
 
 
 
Physical examination includes vital signs, height and 
weightc 
X 
 
 
 
 
X 
Pregnancy test (urine)d 
X 
X 
 
 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
Lesion count 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
PK Cohort: Dispense study drug, training on 
application/returne 
 
D 
R/D 
 
R/D 
R 
Non-PK Cohort: Dispense study drug, training on 
application/returnf 
 
D 
 
 
R/D 
R 
Standardized photographsg 
 
X 
 
 
 
X 
Local tolerabilityh 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
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Protocol 1679-401-006
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GDD-TA-T-004 v2015.10 
 
Study Period 
Screeninga 
Baseline/Day 1a 
Week 1 
Week 2 
Weeks 4 and 8 
Week 12/ 
Early Exit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 and 
Visit 6 
Visit 7 
Visit Windows  
Day -30 to 
Day -1  
N/A 
Day 8 (+ 2 
days) 
Day 15 (± 3 
days) 
Day 29 (± 7 
days) and Day 
57 (± 7 days) 
Day 85 (± 7 
days) 
Concomitant procedures 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
PK samplingi 
 
 
X 
 
 
 
D = dispense; IGA = Investigator’s Global Assessment; N/A = not applicable; R = return; PK= pharmacokinetic 
a 
If a washout period is not required, then screening and baseline visits can occur on the same day, and the procedures required to be repeated at both visits should 
be performed once. 
b 
Consent for photography is included in the informed consent process at select centers. 
c 
Physical examination and vital signs are to be performed if inclusion/exclusion criteria are met at screening; not required for screen failures.  Vital signs include 
heart rate, blood pressure, respiratory rate, and body temperature. 
d 
Female patients only.  The urine pregnancy test can also be performed at any timepoint during the course of the trial at the investigator’s discretion. If a patient 
misses a menstrual cycle, a urine pregnancy test must be performed. 
e 
Patients in the PK cohort will be dispensed 1 kit with 14 tubes on Baseline/Day 1 (Visit 2). All patients in the PK cohort will start dosing on Day 1 using the 
2.0 gram tubes dispensed for individual application.PK Cohort patients will return used study drug at Week 1/Visit 3. At Week 1/Visit 3, Week 4 (Visit 5) and 
Week 8 (Visit 6) the patients in the PK Cohort are dispensed 60-gram pumps. Dispensed and returned study drug will be weighed at the study center. 
f 
All patients will start dosing on day 1. The patients in the Non-PK Cohort are dispensed 60-gram pumps on Baseline/Day 1 (Visit 2), Week 4 (Visit 5) and Week 
8 (Visit 6).  Dispensed and returned study drug will be weighed at the study center.   
g 
At select centers, patients may have photographs taken of their face for illustration or presentation purposes. Patients who consent to being photographed will be 
required to remove any make-up at least 20 minutes prior to having photographs taken. 
h 
Local tolerability will be assessed prior to drug administration on day 1, as well as postdose on the face only. 
i 
Only applies to patients in the PK Cohort at the Week 1/Visit 3. Blood samples will be collected within 30 minutes prior to dosing in clinic in the morning and 
at approximately 10 hours post dose (± 3 hour) (patients are allowed to leave and come back if needed) under maximal use conditions to determine the peak and 
trough plasma drug concentrations. 
 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
Table 2 
Detailed Schedule of Procedures Specific to the PK Cohort 
Study Period 
Screening 
Baseline/Day 1 
Day 2 
Day 3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 8 (+ 2 Days) 
Week 1 
Visit Number 
Visit 1 
Visit 2 
NA 
NA 
NA 
NA 
NA 
NA 
Visit 3 
PK Sampling 
 
 
 
 
 
 
 
 
Xa 
On-Site dose 
administration 
 
X 
 
 
 
 
 
 
Xb 
At home dose 
administrationb 
 
 
X 
X 
X 
X 
X 
X 
 
NA= not applicable; PK= pharmacokinetic. 
a Two PK samples will be collected. Samples will be collected within 30 minutes prior to dosing in clinic in the morning and at approximately 10 hours post dose 
(± 3 hour). 
b Dosing for the PK cohort should always occur at approximately the same time in the morning. 
 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
1. Background and Clinical Rationale  
1.1 Introduction 
Acne vulgaris is a complex skin disorder involving multiple abnormalities of the 
pilosebaceous unit, including hyperkeratinization (leading to obstruction of the follicle), 
increased sebum production (stimulated by androgens), bacterial proliferation 
(Propionibacterium acnes, an anaerobic diphtheroid bacterium), and inflammation (Fleischer 
et al, 2010, Longshore and Hollandsworth, 2003).  The disease is characterized by papules, 
pustules, comedones, nodules, and cysts.  The face, upper chest, and upper back are most 
commonly affected related to a greater concentration of sebaceous glands in these areas.   
Acne vulgaris is estimated to affect approximately 40 to 50 million people in the United 
States alone (Bhate and Williams, 2013).  It affects 80% of adolescents, but may also be 
observed in 54% of adult women and 40% of adult men (Ramos-e-Silva and Carneiro, 2009).  
For many patients, acne poses a significant psychosocial burden, negatively affecting mood, 
self-esteem, body image, and perceived levels of social isolation (Bhate and Williams, 2013).  
Successful treatment of acne significantly reduces symptoms of anxiety and depression and 
improves acne patients’ quality of life (Klassen et al, 2000, Rubinow et al, 1987).  
Pharmacological treatment options for acne vulgaris may be directed at reducing comedone 
formation, inflammation, P. acnes levels, or sebum production.  Dapsone is a sulfone that has 
anti-inflammatory properties including inhibition of neutrophil myeloperoxidase and 
eosinophil peroxidase and suppression of hypochlorous acid production (Bozeman et al, 
1990).  Dapsone scavenges reactive oxygen species and minimizes associated inflammation, 
suppresses neutrophil recruitment and local production of toxic respiratory and secretory 
products, and inhibits chemoattractant-induced signal transduction (Debol et al, 1997).   
Oral dapsone has been available for over 60 years and used for the treatment of leprosy and 
skin disorders such as dermatitis herpetiformis and nodulocystic acne.  However, its clinical 
use is limited by hematologic reactions, including hemolysis, methemoglobinemia, and 
agranulocytosis.  In patients treated with oral dapsone, hemolysis and Heinz body formation 
may be exaggerated in individuals with glucose-6-phosphate dehydrogenase (G6PD) 
(Dapsone Tablets Package Insert, 2011).  The hemolytic process is most likely related to 
metabolites of dapsone (particularly the N-hydroxylamine product) rather than the parent 
compound.  These hematologic reactions are much less likely with topical treatment due to 
considerably lower systemic exposure.  
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ACZONE® (dapsone) Gel, 5% (hereafter referred to as ACZONE 5%), administered 
twice-daily, and ACZONE® (dapsone) Gel, 7.5% (hereafter referred to as ACZONE 7.5%), 
administered once-daily, are both approved by the FDA for topical treatment of acne vulgaris 
in patients 12 years of age and older (ACZONE [dapsone] Gel, 5% package insert, 2015, 
ACZONE [dapsone] Gel, 7.5% package insert, 2016).  ACZONE 7.5% simplifies the dosage 
regimen from the twice-daily dosing of ACZONE 5% to once-daily and thereby potentially 
enhances patient adherence to therapy.  In vehicle-controlled, phase 3, pivotal trials, 
ACZONE 7.5% was safe and well tolerated, and was statistically superior to its vehicle for 
the percent of Global Acne Assessment Score (GAAS) successes and the reduction in all 
lesion counts for the protocol-defined primary analysis as well as all supportive and 
sensitivity analyses at the end of the treatment period.  In clinical trials with either ACZONE 
5% and ACZONE 7.5%, there was no evidence of clinically relevant hemolysis or anemia in 
patients treated with dapsone gel including patients who were G6PD-deficient. 
1.2 Clinical Pharmacokinetics of Dapsone 
Dapsone absorption after once-daily ACZONE 7.5% administration in patients with acne 
vulgaris results in low systemic exposure to dapsone and its metabolites.  Systemic exposure 
to dapsone from ACZONE 7.5% is expected to be about 1% of that from a typical oral dose 
of dapsone 100 mg.  Mean maximum plasma concentration (Cmax) and area under the plasma-
concentration time curve from time 0 to 24 hours postdose of dapsone at steady-state after 
once-daily dosing of dapsone 7.5% were approximately 28.6% and 28.7% lower than those 
following twice-daily dosing of ACZONE 5%, respectively (NDA 21-794).  The volume of 
distribution of dapsone is about 1.5 to 2.5 L/kg.  It is distributed throughout total body water 
and present in all tissues, especially liver, muscle, kidney, and skin.  Its protein binding is 
70% to 90%, and the acetylated dapsone metabolite has a protein binding of ~99%.  Dapsone 
is acetylated by N-acetyl transferase in the liver to its major metabolite, N-acetyl dapsone 
(NAD).  The acetylation of dapsone is reversible, resulting in a relatively constant ratio of 
NAD to dapsone in plasma during the elimination phase.  Dapsone is also N-hydroxylated 
via cytochrome (CYP) P4502E1 and CYP3A4 to dapsone hydroxylamine (DHA) in the liver, 
which appears to be responsible for the drug’s hematologic toxicity.  The Cmax and area under 
the concentration-time curve for DHA are approximately 5% of those of the parent 
compound.  The relationship between oral and topical exposure for DHA is expected to be 
similar to the relationship observed for the dapsone parent compound.  The apparent terminal 
half-life (T1/2) values of dapsone and NAD are estimated to be similar and the mean/median 
values are in the range of 30 to 44 hours after multiple doses of dapsone.  The DHA is 
primarily excreted in urine (~85%), with a small percentage excreted in feces.  Consistent 
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with lower systemic exposures, urinary excretion of DHA after topical dapsone is about 1% 
of that obtained with the oral formulation. 
1.3 Rationale for the Study 
The FDA approval of ACZONE 7.5% included a post-marketing requirement (PMR 3017-1) 
to assess the product in patients 9 to 11 years of age, including pharmacokinetic (PK) 
evaluation in a subset of patients (FDA Letter, 2016).  
Preadolesecent acne tends to be uncommon, mild, and predominantly noninflammatory 
(Lucky et al, 1991, Lucky et al, 1994, Friedlander et al, 2011).  Compared to the more 
substantial acne typical of older patients, preadolescent acne tends to be less likely to 
precipitate patients to seek medical care and is more frequently be left untreated (Eichenfield 
et al, 2012).  Nevertheless, there have been recent suggestions that preadolescent acne may 
become more common and/or recognized (Eichenfield et al, 2013-Pediatrics, Eichenfield et 
al, 2013-J Drugs of Dermatol, Eichenfield et al, 2012, Goldberg et al, 2011, Friedlander et al, 
2010).   
1.4 Rationale for the Study Design 
This 12-week phase 4 trial will enroll a total of approximately 100 patients aged 9 to 11 years 
with mild, moderate, or severe acne, including a subset of at least 16 evaluable PK patients 
who are to be treated once-daily with 2 grams of the ACZONE 7.5% under maximal use 
conditions during the first 8 days in order to obtain blood samples for PK assessment.  
Evaluable PK patients are defined as those who are administered at least 8 days of study drug 
under maximal use conditions, and provided PK samples for analysis without any major 
protocol deviations. 
Several elements of the trial design were included because of the predominantly 
noninflammatory nature of the preadolescent acne and the challenging nature of recruiting 
this population into a clinical trial, particularly the subset receiving PK assessment: 
• Given that preadolescence acne tends to be predominately noninflammatory, the trial 
will (1) enroll patients with 20 to 100 total lesions on the face, and (2) use a modified 
global assessment corresponding to the more noninflammatory nature of 
preadolescence acne, consistent with a recent trial in this population (Eichenfield et 
al, 2012). 
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Protocol 1679-401-006
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• For the subset of patients with PK assessments (PK Cohort; at least 16 evaluable PK 
patients), study drug will be administered once-daily for the first 8 days under 
maximal use condition (~2 grams/day) to the entire face, neck, upper chest, upper 
back and shoulders.  On Day 1, the study drug will be administered on site.  From 
Day 2 through Day 7, the study drug will be administered in the morning at home by 
the patient’s legally authorized representative.  At the Week 1/Visit 3 [Day 8 (+2 
days)], the study drug will be administered on site in the morning.  After the Week 
1/Visit 3, patients or the patient’s legally authorized representative will apply a pea-
sized amount of study drug in a thin layer to the patient’s face, once-daily, at home 
for the remaining 11 weeks, the same as the dose regimen for the Non-PK Cohort.  In 
order to minimize the number of blood draws, blood samples will be collected at 2 
timepoints corresponding to the peak and trough steady-state concentrations at 
Week 1/Visit 3 for steady-state pharmacokinetic assessment.  
2. Study Objectives and Clinical Hypotheses  
2.1 Study Objectives 
To evaluate the safety and tolerability of ACZONE 7.5% administered topically once-daily 
for 12 weeks in 9 to 11 year-olds with acne vulgaris.   
To evaluate the peak and trough plasma drug concentrations in 9 to 11 year-olds with acne 
vulgaris following once-daily dosing of ACZONE 7.5% under maximal use conditions for 
the first 8 days (+ 2 days).  
To explore the efficacy of ACZONE 7.5% administered topically once-daily in 9 to 11 year-
olds with acne vulgaris. 
2.2 Clinical Hypotheses 
ACZONE 7.5% is safe and well tolerated when administered topically once-daily for 
12 weeks to 9 to 11 year-old patients with acne vulgaris.  
3. Study Design  
This study is a multicenter, open label, non-comparative, 12-week trial to evaluate the safety, 
tolerability, pharmacokinetics, and efficacy of ACZONE 7.5% in 9 to 11 year-old patients 
with mild, moderate, or severe acne vulgaris. 
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Patient participation is up to approximately 16 weeks.  Patients will attend up to the 
following 7 visits: Screening, Baseline/Day 1 (Screening and Baseline/Day 1 may be 
combined if no washout is needed), and Weeks 1, 2, 4, 8, and 12/early exit.  The total 
treatment duration of trial participation for each patient is up to 12 weeks.  Safety measures 
include adverse events, physical examination, and vital signs.  Efficacy measures include the 
Investigator’s Global Assessment (IGA) and lesion counts in the face. 
The 2 cohorts will enroll concurrently; the PK cohort and the non-PK Cohort. 
The PK Cohort will include at least 16 evaluable PK patients. Evaluable PK patients are 
defined as those that are administered at least 8 applications of study drug under maximal use 
conditions, and provided PK samples for analysis without any major protocol deviations. For 
the first 8 days, study drug will be administered once-daily under maximal use condition (~2 
grams/day) to the entire face, neck, upper chest, upper back and shoulders as instructed by 
the study site. The study drug should be rubbed in gently and completely. On Day 1, the 
study drug will be administered on site. From Day 2 through Day 7, the study drug will be 
administered in the morning at home by the patient’s legally authorized representative.  At 
the Week 1/Visit 3 [Day 8 (+2 days)], the study drug will be administered on site in the 
morning.  After the Week 1/Visit 3, patients or the patient’s legally authorized representative 
will apply a pea-sized amount of study drug in a thin layer to the patient’s face, once-daily, at 
home for the remaining 11 weeks, the same as the dose regimen for the Non-PK Cohort.  
Acne-affected areas on the upper chest, upper back, and shoulders should also be treated with 
a thin layer during the final 11 weeks. 
For the Non-PK Cohort (approximately 84 patients), patients or the patient’s legally 
authorized representative will apply a pea-sized amount of study drug in a thin layer to the 
patient’s face once-daily at home for 12 weeks as instructed by the study site.  Acne-affected 
areas on the upper chest, upper back, and shoulders should also be treated with a thin layer. 
4. Study Population and Entry Criteria 
4.1 Number of Patients  
For the PK Cohort, at least 16 subjects will be enrolled to ensure 16 evaluable PK subjects at 
the Week 1 visit.  For the Non-PK Cohort, approximately 84 additional patients will be 
enrolled in the study for a total of approximately 100 patients.  PK Cohort patients who 
discontinue from the trial prior to either of the PK blood draws scheduled at Week 1/Visit 3 
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GDD-TA-T-004 v2015.10 
 
(or who otherwise do not have evaluable PK samples) will be replaced.  Assuming an 
attrition rate of 15%, approximately 85 patients are expected to complete the 12-week trial.  
4.2 Study Population Characteristics 
Study participants will be 9 to 11 year-old male and female patients with mild, moderate, or 
severe acne vulgaris who are otherwise in good health.  For the PK Cohort, mild, moderate, 
or severe acne vulgaris patients will be enrolled for PK characterization until at least 
16 evaluable PK patients are enrolled.  After 16 evaluable PK patients are enrolled, additional 
patients with moderate or severe acne vulgaris may continue to be enrolled in the PK Cohort. 
4.3 Inclusion Criteria 
The following are requirements for entry into the trial: 
1. Written informed consent has been obtained from the patient’s legally authorized 
representative prior to any trial related procedure 
2. Written assent has been obtained from the patient (a minor) in accordance with local 
laws and IRB/IEC requirements 
3. Written documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable (eg, Written Authorization for Use and 
Release of Health and Research Study Information for US centers) 
4. Male or female patients, 9 to 11 years of age 
5. Patients with acne vulgaris who have minimum of 20 but not more than 100 total 
inflammatory (papules, pustules, cysts, nodules) or noninflammatory (open or closed 
comedones) lesions on the face (including the nose) at screening and baseline 
6. Patients with an acne grade of 2 (mild), 3 (moderate), or 4 (severe) using the IGA as 
assessed by the investigator at screening and baseline.  For the PK Cohort only: 
after at least 16 PK patients are enrolled, additional patients with acne grades of 
3 (moderate) or 4 (severe) using the IGA as assessed by the investigator at screening 
and baseline may continue to be enrolled in the PK Cohort unless specified by the 
Sponsor to refrain 
7. Negative urine pregnancy test result for females at the Screening and Day 1 visits 
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8. Patient is in good health as determined by medical history, physical examination, and 
vital signs 
9. Patient is willing to follow study instructions, complete study assessments without 
any assistance, and likely to complete all required visits 
4.4 Exclusion Criteria 
The following are criteria for exclusion from participating in the trial: 
1. Uncontrolled systemic disease(s) 
2. Patients with severe cystic acne, acne conglobata, acne fulminans, or secondary acne 
(chloracne, drug-induced acne, etc) 
3. Patients using systemic immunosuppressive drugs within 4 weeks prior to screening 
or anticipated use of any systemic therapy with the potential to affect acne during the 
trial 
4. Any of the following topical procedures or treatments on the face occurring in the 
specified period prior to baseline (day 1): 
o 1 week:  antibacterials (eg, clindamycin), salicylic acid, sulfur, sodium 
sulfacetamide, phototherapy devices (eg, ClearLight™), energy-based devices, 
adhesive cleansing strips (eg, Pond’s®, Biore®), or cosmetic procedures (eg, 
facials, peeling, comedo extraction) 
o 2 weeks:  anti-inflammatory drugs, corticosteroids, benzoyl peroxide-containing 
products (eg, benzamycin), retinoids, other topical acne treatments 
(eg, photodynamic therapy) 
note:  No washout is required for alpha hydroxy acid products, astringents, 
antiseptics, devices used for cleansing and/or exfoliating the skin (eg, scrubs, 
pads, brushes), or preparations with alcohol for astringent effects, but they are not 
permitted at any time during the trial. 
5. Any of the following systemic medications in the specified period prior to baseline 
(day 1): 
o 4 weeks:  antibacterials (except penicillins used for 2 weeks or less) 
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o 6 months:  other acne treatments (eg, isotretinoin, anti-androgens such as 
spironolactone) 
6. Patients who are using or have used hormonal contraceptives and therapies 
7. Patients who have used topical dapsone within 1 month prior to the screening visit or 
oral dapsone within 2 months prior to the screening visit 
8. Patients who have any allergy or sensitivity to the study drug or its components 
9. Patients with underlying diseases or other dermatologic conditions such as, but not 
limited to, atopic dermatitis, perioral dermatitis or rosacea, which require the use of 
topical or systemic therapy that may interfere with the study assessments in the 
opinion of the investigator 
10. Skin abnormalities (other than acne vulgaris), excessive hair, or other physical 
characteristics in or around the test sites that could confound the trial results based on 
the investigator’s judgment 
11. Patients who anticipate the need for surgery or hospitalization during the trial 
12. Females who are pregnant, nursing, or think they may be pregnant at the start of the 
trial 
13. Current enrollment in an investigational drug or device study, or participation in such 
a study within 30 days prior to screening for this trial 
14. Patients who have a clinically significant finding or condition, or are in a situation 
which, in the investigator's opinion, may put the patients at significant risk, may 
confound the trial results, or may interfere significantly with patient’s participation in 
the trial 
15. Patients who have a medical history of hepatitis B, hepatitis C or human immune 
deficiency virus (HIV) infection 
16. Patients with a history of liver or kidney disease 
17. Patient who is an immediate family member (eg, partner, offspring, parents, siblings, 
or sibling’s offspring) of an employee (eg, of sites, the Sponsor, or vendors) involved 
in the trial 
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Approval Date: 
 
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Allergan Confidential 
Protocol 1679-401-006
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GDD-TA-T-004 v2015.10 
 
4.5 Permissible and Prohibited Medications/Treatments 
4.5.1 Permissible Medications/Treatments 
Therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator.  If concomitant medications may have an effect on trial outcomes, those 
medications should be administered in dosages that remain constant throughout the course of 
the trial.  If the permissibility of a specific medication/treatment is in question, please contact 
the Sponsor.   
Patients should maintain their usual skin care regimen, eg, non-medicated soaps, throughout 
the trial (with the exception of prohibited products). 
4.5.2 Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
For purposes of this study, all females will be considered of childbearing potential.  If a 
patient misses a menstrual cycle, a urine pregnancy test must be performed.   
If a female becomes pregnant during the study, the investigator will notify the sponsor 
immediately after the pregnancy is confirmed and the study treatment should be 
discontinued.  The patient will be exited from the study after appropriate safety follow-up.  
The investigator will (1) notify the patient’s physician that the patient was being treated with 
ACZONE 7.5%, and (2) follow the progress of the pregnancy.  The investigator must 
document the outcome of the pregnancy and provide a copy of the documentation to the 
Sponsor. 
4.5.3 Prohibited Medications/Treatments  
The decision to administer a prohibited medication/treatment is done with the safety of the 
patient as the primary consideration.  When possible, the Sponsor should be notified before 
the prohibited medication/treatment is administered.  
Medications requiring washout (Section 4.4) must not be used during the study.  Patients 
must not use topical drugs or treatments on acne affected areas.  Patients must not use 
hormonal therapies or contraceptives. 
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Approval Date: 
 
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Protocol 1679-401-006
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GDD-TA-T-004 v2015.10 
 
For patients in the PK Cohort, use of any concomitant systemic medications that could affect 
PK outcomes is not permitted from 2 weeks prior to Day 1 through the Week 1/Visit 3 [Day 8 
(+ 2 days)]. 
All patients are not permitted to use phototherapy devices, cosmetic procedures, or other 
topical acne treatments (eg, photodynamic therapy, laser therapy, or medicated soap).  
Certain systemic medications (such as rifampin, anticonvulsants, St. John’s Wort, and 
trimethoprim-sulfamethoxazole) may increase the formation of DHA, a metabolite of 
dapsone associated with hemolysis.  With oral dapsone treatment, folic acid antagonists such 
as pyrimethamine have been noted to possibly increase the likelihood of hematologic 
reactions.  Concomitant use of ACZONE 7.5% with drugs that induce methemoglobinemia 
such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, 
dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, 
pamaquine, para‐aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and 
quinine may increase the risk for developing methemoglobinemia. 
4.5.4 Special Diet or Activities 
All patients, and their legally authorized representative(s), will be instructed that throughout 
the trial they must refrain from: 
• Intensively scratching their body at any areas of treatment  
• Swimming or bathing up to 8 hours following drug application 
• Tattooing their skin or body piercings to the areas of study drug application 
Patients will be instructed to maintain their regular skin care regimen (with the exception of 
prohibited products) during the trial and must not use new products on treated areas while in 
the trial. 
For patients in the PK Cohort, from Day 1 through the Week 1/Visit 3 [Day 8 
(+ 2 days)], patients should not bathe, shower, swim, or wash face for at least 8 hours 
following administration of study drug. 
13SEP2018 CSR 1679-401-006
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5. Study Treatments 
5.1 Study Treatments and Formulations 
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5.2 Methods for Masking/Blinding 
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5.3 Method for Assignment to Treatment Groups/Randomization 
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5.4 Treatment Regimen and Dosing 
5.4.1 Conduct of the Study 
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CCI


 
 
Approval Date: 
 
23-Jun-2016
Allergan Confidential 
Protocol 1679-401-006
22 Jun 2016 
 
 
 
GDD-TA-T-004 v2015.10 
 
To ensure maximal use conditions for the PK Cohort for the first 8 days, study drug will be 
provided in individual usage tubes containing approximately 2 grams each.  One individual 
usage tube will be used each day for the first 8 days. The patients will be dispensed 1 kit with 
14 tubes on Baseline/Day 1 (Visit 2).  PK Cohort patients will return used study drug on 
Week 1/Visit 3.   
For the first 8 days, study drug will be administered once-daily under maximal use condition 
(~2 grams/day) to the entire face, neck, upper chest, upper back and shoulders as instructed 
by the study site. The study drug should be rubbed in gently and completely. On Day 1, the 
study drug will be administered on site. From Day 2 through Day 7, the study drug will be 
administered in the morning at home by the patient’s legally authorized representative.  At 
the Week 1/Visit 3 [Day 8 (+2 days)], the study drug will be administered on site in the 
morning.  After the Week 1/Visit 3, patients or the patient’s legally authorized representative 
will apply a pea-sized amount of study drug in a thin layer to the patient’s face, once-daily, at 
home for the remaining 11 weeks, the same as the dose regimen for the Non-PK Cohort.  
Acne-affected areas on the upper chest, upper back, and shoulders should also be treated with 
a thin layer during the final 11 weeks.  Evaluable PK patients are defined as those that are 
administered at least 8 days of study drug under maximal use conditions, and provided PK 
samples for analysis without any major protocol deviations. 
For the non-PK Cohort, patients or the patient’s legally authorized representativewill apply 
the study drug to the patient’s entire face once-daily at home for the entire trial.  The patients 
in the non-PK Cohort will be dispensed 60-gram pumps on Baseline/Day 1 (Visit 2), Week 4 
(Visit 5) and Week 8 (Visit 6).  Acne-affected areas on the neck, upper chest, upper back, and 
shoulders (where the patient can reach) should also be treated. 
5.4.2 Stopping Rules 
The safety and tolerability data for each patient will be monitored throughout the trial by the 
investigator and the Sponsor’s Medical Safety Physician.  In the event that a patient 
experiences unacceptable safety and/or dermal tolerability as designated by either the patient, 
the patient’s legally authorized representative, or investigator, treatment should be 
discontinued. 
13SEP2018 CSR 1679-401-006
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Approval Date: 
 
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Allergan Confidential 
Protocol 1679-401-006
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5.5 Storage of Study Medications/Treatments 
The study drug must be stored in a secure area and administered only to patients entered into 
the clinical trial, at no cost to the patient, in accordance with the conditions specified in this 
protocol.  
The study drug must be stored at controlled room temperature, 20°to 25°C (68°to 77°F). 
Sites must report any temperature excursions as described in the Study Reference Manual or 
contact the Sponsor or its designee for further instructions. 
5.6 Treatment Administration 
For the PK Cohort, at the Day 1 visit, patients and their legally authorized representative(s) 
will be instructed how to administer the study drug, and the study drug will be administered 
on site.  For Days 2 thorugh 7, study drug should be applied at approximately the same time 
in the morning (ie, before noon) at home by the patient’s legally authorized representative.  
On Day 8 of the trial, study drug will be administered on site and in the morning. 
After the skin on the face is gently washed and patted dry, legally authorized 
representative(s) of the patients will apply the contents of an individual usage tube containing 
2 grams of study drug.  The study drug will be applied to the patient’s face, neck, upper 
chest, upper back, and shoulders.  Wearing gloves, legally authorized representative(s) will 
spread the product on the patient’s face, on the area between the mandibular line, and the 
hairline edge, taking care to avoid the areas around the eyes and the lips.  The legally 
authorized representative(s) will also spread the study drug on the patient’s neck, shoulders, 
upper chest, and upper back.  New gloves will need to be used each day when applying the 
study drug.  The product should be applied evenly to the entire face, neck, upper chest, upper 
back, and shoulders of the patient, and rubbed in gently and completely.  All study drug 
should be rubbed in until no visible mass of the gel is observed on the surface of the skin.  
All patients and their legally authorized representatives will be provided with written 
instructions on the application of the study drug.  Adherence to these instructions will be 
assessed at subsequent visits, with retraining performed as needed for noncompliant patients.  
Documentation of patient and legally authorized representative(s) training by site staff will 
be noted.  See the non-PK Cohort section for information on PK Cohort patient dosing from 
the Week 1/Visit 3 until the end of study visit.  
For the Non-PK Cohort at the Day 1 visit, patients and their legally authorized 
representative(s) will be instructed regarding how to administer the study drug for the 
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remainder of the trial.  If dosing of the patient is performed by the patient’s legally authorized 
reppersentative, they should wear gloves, and new gloves should be used each day.  If dosing 
is performed by the patient, the patient must wash his/her hands before and after each 
application.  After the patient’s skin on the face is gently washed and patted dry, the patient 
or the patient’s legally authorized representativewill apply an approximately pea-sized 
amount of study drug in a thin layer to the patient’s entire face.  The product should be 
rubbed in gently and completely.  Acne-affected areas on the neck, upper chest, upper back, 
and shoulders (where the patient can reach) should also be treated by applying enough to 
cover the affected areas, then rubbing in gently and completely.  All study drug should be 
rubbed in until no visible mass of the gel is observed on the surface of the skin.  All patients 
and their legally authorized representatives will be provided with written instructions on the 
application of the study drug.  Adherence to these instructions will be assessed at subsequent 
visits, with retraining performed as needed for noncompliant patients.  Documentation of 
patient and legally authorized representative(s) training by site staff will be noted. 
6. Response Measures and Summary of Data Collection Methods 
6.1 Pharmacokinetics 
6.1.1 Pharmacokinetic Sampling Timepoints 
For patients in the PK Cohort who will be dosed under maximal use conditions for the first 
8 days, blood samples will be collected prior to dosing and at approximately 10 hours post 
dose (± 3 hours) (patient can leave the site in between blood samples) at Week 1/Visit 3 [Day 
8 (+ 2 days)] to determine the peak and trough plasma concentrations of dapsone, NAD, 
DHA, and other metabolites or analytes (if warranted). 
6.1.2 Pharmacokinetic Sample Collection and Processing 
Detailed instructions on sample collection, processing, and storage of plasma samples for 
drug assay are given in the Procedure Manual.   
6.1.3 Pharmacokinetic Sample Bioanalysis 
Plasma concentrations of dapsone, NAD, DHA, and other metabolites or analytes (if 
warranted) will be determined using a validated liquid chromatography-tandem mass 
spectrometry method. 
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6.2 Efficacy Measures 
Each patient’s overall severity of acne vulgaris will be evaluated by a 5-point IGA.  The IGA 
assessment must be performed by an investigator. 
The lesion counts will be conducted on the face only.  Lesion counts may be performed by an 
investigator or trained designated study personnel. 
Assessments should be performed in a well-lit room under consistent lighting at each study 
visit.  When possible, the evaluator(s) performing the IGA and/or lesion counts at an 
individual study center should perform these evaluations for all patients throughout the trial.  
If the same evaluator performs both IGA and lesion counts, the IGA assessment should be 
performed prior to lesion count assessment.  In the rare event there is a change in the 
assigned evaluator for a given patient, the reason for change must be documented.  If it is not 
possible to use the same evaluator to follow a given patient, the Sponsor recommends that 
evaluations between the primary and subsequent evaluator overlap (both evaluators should 
examine the patient together and discuss findings) for at least one visit; this should be 
documented.   
6.2.1 Investigator’s Global Assessment 
The IGA will be evaluated at screening, baseline, and on weeks 1, 2, 4, 8 and 12/early exit.  
Patients’ acne severity will be evaluated by the investigator using a 5-point IGA scale as 
shown in Table 3.  This assessment must be performed by an investigator, ie, the principal 
investigator or subinvestigator.  Only the face of the patient will be evaluated using the IGA.   
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Table 3 
Investigator’s Global Assessment 
Grade 
Description 
0 
Clear 
• 
No comedones, papules or pustules 
• 
Residual hyperpigmentation and erythema may be present 
1 
Almost Clear 
• 
Rare comedones 
• 
No more than a few small papules and pustules 
2 
Mild 
• 
Easily recognizable comedones in limited numbers 
• 
+/- Presence of small papules and pustules 
3 
Moderate 
• 
Many comedones 
• 
+/- Easily recognizable small and medium-sized papules 
• 
No nodules or cysts. 
4 
Severe 
• 
Widespread and numerous comedones 
• 
Many small, medium-sized and large papules and pustules 
• 
Nodules or cysts may or may not be present. 
(Eichenfield et al, 2013, J of Dermatol) 
6.2.2 Lesion Count 
The lesion counts will be performed at screening, baseline, and at weeks 1, 2, 4, 8, and 
12/early exit.  The lesion counts will be performed by the investigator or an appropriately 
trained designee. 
For each area, the following lesion types will be evaluated: 
• Inflammatory Lesions 
Papule – a small, red, solid elevation less than 1.0 cm in diameter 
Pustule – a small, circumscribed elevation of the skin that contains yellow-white 
exudate 
Nodule – a circumscribed, elevated, solid lesion generally more than 1.0 cm in 
diameter with palpable depth 
Cyst – a smooth, dome-shaped, elevated, freely moveable, skin colored, round to 
ovoid lesion greater than 0.7 cm in diameter 
• Noninflammatory Lesions 
Open Comedone – a pigmented dilated pilosebaceous orifice (blackhead) 
Closed Comedone – a tiny white papule (whitehead) 
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Total lesions will be the sum of inflammatory lesion counts and noninflammatory lesion 
counts.  In addition, the presence of truncal acne will be documented.   
6.2.3 Other Measures 
6.2.3.1 Skin Phototype 
At screening, Fitzpatrick skin phototype will be rated (FDA Federal Register, 1999): 
I:  Always burns easily; never tans (sensitive) 
II:  Always burns easily; tans minimally (sensitive) 
III:  Burns moderately; tans gradually (light brown) (normal) 
IV:  Burns minimally; always tans well (moderate brown) (normal) 
V:  Rarely burns; tans profusely (dark brown) (insensitive) 
VI:  Never burns; deeply pigmented (insensitive) 
6.3 Safety Measures 
The following safety measures will be collected: 
• Adverse events 
• Physical examination 
• Height 
• Weight 
• Vital signs (heart rate, blood pressure, respiratory rate, and body temperature) 
• Urine pregnancy tests for females 
• Local dermal tolerability assessments (stinging/burning rated by the patient; dryness, 
scaling, and erythema rated by an investigator or appropriately trained designee) 
6.3.1 Adverse Events 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
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The investigator will question the patient to ascertain whether any adverse events were 
experienced since the previous visit.  All pertinent information regarding adverse events (ie, 
date and time of onset and stop, duration, outcome, severity, relation to study drug, action or 
treatment required) will be obtained and recorded in the source documents and appropriately 
transcribed on the electronic case report form (eCRF) page. 
6.3.2 Suspected Sensitization 
If the patient experiences a skin reaction of such nature or severity that a contact allergy is 
suspected, the patient should discontinue the study drug.  The event should be documented as 
an adverse event.  The patient should be re-challenged using the assigned study drug to 
confirm or rule out contact dermatitis.  If the diagnosis of allergic contact dermatitis is 
confirmed the patient may have an additional patch test with the study drug and the 
individual study drug ingredients.  The patch test will be performed at least 2 weeks after 
discontinuation of the study drug.  Patches will be applied to untreated areas on the back for 
48 hours.  Readings will be performed approximately 15 to 30 minutes and 48 hours 
following the removal of the patches.  At the investigator’s discretion, a facultative additional 
reading might be performed at 96 or 120 hours after removal of the patches if an equivocal 
reaction is observed at the previous reading.   
6.3.3 Unscheduled Visits 
If a patient is seen for an unscheduled visit, an assessment and record of adverse events 
should be completed.  Additional evaluations should be performed as necessary, and the 
appropriate eCRFs should be completed. 
6.3.4 Local Tolerability 
Local (dermal) tolerability examination will be performed at timepoints given in Table 1 and 
will include assessments of stinging/burning (rated by the patient), dryness, scaling, and 
erythema (rated by an investigator, or appropriately trained designee).  Dryness, scaling, and 
erythema must be assessed by the same person throughout the trial whenever possible.  Local 
tolerability will be assessed on the face and will be rated as none, mild, moderate, or severe 
based on the detailed descriptions that follow.   
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Patient-rated 
Stinging/Burning:  prickling pain sensation after dosing (also performed predose on Day 1). 
None (0) = No stinging/burning 
Mild (1) = Slight warm, tingling/stinging sensation; not really bothersome 
Moderate (2) = Definite warm, tingling/stinging sensation that is somewhat bothersome  
Severe (3) = Hot, tingling/stinging sensation that has caused definite discomfort 
Investigator-rated 
Dryness:  brittle and/or tight sensation 
None (0) = No dryness 
Mild (1) = Slight but definite roughness 
Moderate (2) = Moderate roughness 
Severe (3) = Marked roughness 
Scaling:  abnormal shedding of the stratum corneum 
None (0) = No scaling 
Mild (1) = Barely perceptible shedding, noticeable only on light scratching or rubbing 
Moderate (2) = Obvious but not profuse shedding 
Severe (3) = Heavy scale production 
Erythema:  abnormal redness of the skin 
None (0) = No erythema 
Mild (1) = Slight pinkness present 
Moderate (2) = Definite redness, easily recognized 
Severe (3) = Intense redness 
If any sign or symptom is judged to be an adverse event in the opinion of the investigator, it 
will be captured on the patient’s adverse event source document and eCRF. 
6.4 Other Study Supplies 
The following will be provided by the Sponsor: 
• The central laboratory will provide vacutainer tubes and polypropylene tubes for 
plasma collection for pharmacokinetic analysis if not already present at the site 
• At selected sites, standardized cameras and photographic equipment which will be 
supplied by a qualified third party vendor 
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The following will be provided by the Investigator: 
• Urine pregnancy test kits with a sensitivity of at least 25 mIU/mL for human 
chorionic gonadotropin  
• Patch test supplies 
• Gloves for legally authorized representative(s) performing dosing 
• Scale with a readability of 0.1 gram or lower to weigh study drug 
• Equipment for collection of vital signs 
• Freezer set to maintain -20ºC for storage of PK samples 
6.5 Summary of Methods of Data Collection 
This trial will use eCRFs using remote electronic data capture.  The data will be entered on 
the eCRFs in a timely manner on an ongoing basis.  The investigator is responsible for 
ensuring that data are properly recorded on each patient’s eCRFs and related documents.  An 
investigator who has signed the protocol signature page should personally electronically sign 
for the case report forms (CRFs; as indicated in the eCRFs) to ensure that observations and 
findings are recorded on the eCRFs correctly and completely.  A certified electronic copy of 
the eCRFs including data corrections will be provided to the site for archiving at the end of 
the trial. 
A qualified central laboratory will be used to store samples drawn for PK analysis and 
samples will be stored until shipment to a qualified bioanalytical laboratory. 
A qualified bioanalytical laboratory will be used to determine the plasma concentrations of 
dapsone, DHA, NAD, and other metabolites or analytes (if warranted).  Pharmacokinetic data 
will be transferred to the Sponsor by the end of the trial. 
At selected sites, for patients who consent to photographs, facial photographs will be taken 
by study personnel for illustration or presentation purposes using standardized cameras and 
photographic equipment which will be supplied by a qualified third party vendor. Each 
selected site will receive documented training and instructions on taking photographs. The 
photographs will be uploaded to a secure server via the internet. All photographs will be 
transferred to the Sponsor at the end of the study. The sponsor will process the photographs 
and shall have full ownership rights to any photographs derived from the study.  
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7. Statistical Procedures 
A detailed analysis plan will be approved prior to database lock.  Database lock will follow 
completion of data entry, verification and validation, database audit, and data clarification 
resolution. 
7.1 Analyses Populations 
The following 3 analysis populations will be utilized: 
1. The safety population includes all patients who are treated with at least one application of 
study drug. 
2. The modified intent-to-treat (mITT) population includes all enrolled patients who have a 
baseline assessment and at least one post-baseline assessment.  
3. The PK population will be defined as all patients who received applications of study drug 
for at least 8 days under maximal use conditions and have evaluable blood samples for PK 
analysis.  This population will be used for PK analyses. 
Safety analyses will be based on the safety population.  Efficacy analyses will be based on 
the mITT population.  No imputation for missing data will be performed for safety or 
efficacy analyses. 
7.2 Pharmacokinetic Analysis 
For patients in the PK Cohort who will be dosed under maximal use condition for the first 
8 days, the peak and trough plasma concentrations of dapsone, NAD, DHA, and other 
metabolites or analytes (if warranted) at Week 1/Visit 3 will be summarized using descriptive 
statistics, if applicable. 
No formal inferential statistics will be performed with the PK data.  However, if warranted, 
graphical methods may be used to examine the relationships between systemic drug 
concentrations and the changes in lesion counts and safety parameters.  Details of these 
analyses will be described in the PK data analysis plan. 
7.3 Efficacy Analysis 
All efficacy analyses are considered exploratory and will be performed using the 
mITT population.  All efficacy summaries will use data from both study cohorts combined.  
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For lesion counts, change and percent change from baseline in inflammatory lesion counts 
will be summarized using descriptive statistics.  Baseline is the predose measurement on 
Day 1.  Inflammatory lesion counts include papules, pustules, nodules and cysts.  The same 
summarizations will be done for noninflammatory lesion counts and total lesion counts.  
Noninflammatory lesion counts include open and closed comedones, and total lesion counts 
include inflammatory and noninflammatory lesion counts. 
If a number of patients have fewer than 5 inflammatory or noninflammatory lesions at 
baseline, an additional analysis may be conducted for that lesion type including only those 
patients with at least 5 lesions of that type at baseline.   
A frequency distribution will be used to summarize the proportion of patients with none (0) 
or minimal (1) score on the IGA at each visit.  In addition, a frequency distribution will be 
used to summarize the proportion of patients with none (0) or minimal (1) score plus at least 
a 2-grade improvement on the IGA at each visit.  
7.3.1 Safety Analyses 
Safety variables are treatment-emergent adverse events (TEAEs), inlcuding new findings 
from physical examinations, local (dermal) tolerability, and vital signs.  
All adverse events will be coded from the verbatim text to the lower level term and mapped 
to preferred term (PT) and primary system organ class (SOC) using the Medical Dictionary 
for Regulatory Activities (MedDRA). 
All TEAEs will be listed by patient.  For TEAEs regardless of causality, and for treatment-
related TEAEs, the number and percentage of patients reporting the TEAEs at least once will 
be tabulated by descending order of incidence rate by PT within primary SOC, and by 
primary SOC, PT, and severity. 
Local (dermal) tolerability data will be summarized using descriptive statistics and frequency 
distributions.  Vital signs will be summarized using descriptive statistics. Positive pregnancy 
test results will be listed. 
More detailed analyses for the safety measures will be described in the analysis plan. 
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7.4 Other Analysis 
Skin phototype will be summarized by frequency distributions.  Further details will be 
provided in the analysis plan. 
7.5 Subgroup Analyses 
Key safety analyses and summaries will be performed as described in the detailed analysis 
plan.  
7.6 Sample Size Calculation 
The sample size for the trial was determined empirically, and is consistent with that requested 
by the FDA in the postmarketing requirement for ACZONE 7.5%. 
7.7 Interim Analyses 
There is no planned interim analysis. 
8. Study Visit Schedule and Procedures 
Please see Table 1 for a schematic of the schedule of visits and procedures. 
8.1 Patient Entry Procedures 
8.1.1 Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3, and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 Informed Consent and Patient Privacy 
The study will be discussed with the patient’s legally authorized representative(s) and they 
must give informed consent and the patients must give written assent prior to any study-
related procedures.  Additionally, for those patients in the PK Cohort, the legally authorized 
representatives will provide a written informed consent prior to the patient participating in 
PK sampling procedures.  See also Section 10.1. 
Each patient enrolled in to the study will be assigned a patient number that will be used on 
patient documentation throughout the study. 
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8.2 Washout Intervals 
Drugs requiring a washout period (Section 4.4) should not be used during the study.  Please 
see Section 4.5.3 for prohibited medications. 
8.3 Procedures for Final Study Entry 
See Section 5.3 for the method for assignment to treatment groups. 
8.4 Visits and Associated Procedures 
This study consists of visits at screening (days -30 to -1), day 1 (baseline), and weeks 1, 2, 4, 
8, and 12/early exit. 
After obtaining informed consent and authorization the patient’s legally authorized 
representative and assent from the patient, patients will undergo a series of screening 
procedures to assess qualification for the study.  Final eligibility for the study will be 
determined at the day 1 (baseline) visit.  The following is a description of the procedures to 
be performed at each visit from screening to week 12/early exit.  To the extent possible, 
procedures should occur in the order presented below.   
8.4.1 Screening Visit (Days -30 to -1) 
• Informed consent/authorization and minor assent obtained 
• Inclusion/exclusion eligibility criteria reviewed – ongoing throughout visit 
• Demographics obtained 
• IGA performed (should be performed before lesion count) 
• Lesion count performed 
• Medical/surgical history status obtained 
• Skin phototype assessed 
• Urine pregnancy test administered for females 
• Physical examination completed and vital sign measurements obtained, including 
height and weight (not required for screen failures) 
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• Adverse events recorded 
• Concomitant medications and concomitant procedures recorded 
8.4.2 Baseline/Day 1 (Visit 2) 
Procedures (May be combined with the Screening Visit if no washout period is required) 
• IGA performed (should be performed before lesion count)* 
• Lesion count performed* 
• Inclusion/exclusion eligibility criteria re-evaluated* 
• Urine pregnancy test administered for females prior to administration of study drug* 
• Local tolerability assessed on the face prior to study drug administration on day 1 
• Standardized photography performed at selected centers (make up must be removed 
at least 20 minutes prior to photography) 
• Training on study drug application 
• Study drug weighed 
• Study drug administered on site and dispensed for at-home use for the PK Cohort.  
Patients will receive 2.0 gram tubes for daily application from Baseline to Day 8 
(+ 2 days) and then 60-gram pumps will be dispensed from Week 1/Visit 3 onwards. 
• Study drug administered on site and dispensed for at-home use for the 
non-PK Cohort.  Patients will receive 60-gram pumps starting on Baseline/Day 1. 
• Local tolerability performed on the face, postdose 
• Adverse events recorded 
• Concomitant medications and concomitant procedures recorded* 
* These may not need to be repeated if the baseline and screening visits occur on the same 
day. 
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8.4.3 Week 1/Visit 3 [Day 8 (+ 2 days)] and Week 2/Visit 4 (Day 15 ± 
3 days) 
• IGA performed (should be performed before lesion count) 
• Lesion count performed 
• Local tolerability assessed on the face only 
• Adverse events recorded 
• Concomitant medications and concomitant procedures recorded 
• Study drug is dispensed for the PK Cohort 
• Study drug returned will be assessed for the PK Cohort only at Week 1/ Visit 3 
[Day 8 (+ 2 days)]-sites need to verify dosing compliance, retraining to be completed 
if needed 
• At Week 1/Visit 3 [Day 8 (+ 2 days)] only, PK samples will be collected for the PK 
Cohort patients (see below) 
At Week 1/Visit 3 [Day 8 (+ 2 days)] Procedures for the PK Cohort only 
Blood samples will be collected within 30 minutes prior to dosing in clinic in the morning 
and at approximately 10 hours post dose (± 3 hour) under maximal use conditions at the 
Week 1/Visit 3 [Day 8 (+ 2 days)] to determine the peak and trough plasma drug 
concentrations.  Dosing of the study drug will occur on site in the morning on Week 1/Visit 3. 
8.4.4 Week 4/Visit 5 (Day 29 ± 7 days)) and Week 8/Visit 6 (Day 57 ± 
7 days)) 
• IGA performed (should be performed before lesion count) 
• Lesion count performed 
• Local tolerability assessed on the face only 
• Urine pregnancy test administered for females 
• Adverse events recorded 
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• Concomitant medications and concomitant procedures recorded 
• Study drug dispensed 
• Study drug returned will be assessed 
8.4.5 Week 12/Early Exit/Visit 7 (Day 85 ± 7 days) 
• IGA performed (should be performed before lesion count) 
• Lesion count performed 
• Local tolerability assessed on the face only 
• Adverse events are recorded 
• Urine pregnancy test administered for females 
• Physical examination completed and vital sign measurements obtained 
• Standardized photography performed at selected centers 
• Concomitant medications and concomitant procedures recorded 
• Study drug returned will be assessed 
8.5 Instructions for the Patients 
Patients will be instructed to maintain their regular skin care regimen (with the exception of 
prohibited products) during the trial and must not use new products on treated areas while in 
the trial. 
For patients in the PK Cohort, from Day 1 through Week 1/Visit 3, patients should not 
bathe, shower, swim, or wash face for at least 8 hours following administration of study drug. 
Patients (or their legally authorized representative, if applicable) will be instructed to avoid 
all prohibited medications, treatments, and activities, as described in Section 4.5.4.  In 
addition, patients (and their legally authorized representative, if applicable) should be 
instructed to arrive at the research unit approximately 30 minutes before any scheduled 
procedures. 
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8.6 Unscheduled Visits 
Additional examinations may be conducted as necessary to ensure the safety and wellbeing 
of patients during the study period.  Case report forms should be completed for each 
unscheduled visit.   
8.7 Compliance With Protocol 
Dispensed and returned study drug will be weighed at the study center.  Patients will be 
asked questions to evaluate compliance with the medication regimen.  At each visit, patients 
will be asked by site staff if they have complied with their instructions, dietary restrictions, 
and activity restrictions for a given visit. 
8.8 Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time.  Notification of early patient 
discontinuation from the study and the reason for discontinuation will be made to the sponsor 
and will be clearly documented on the appropriate eCRFs. 
8.9 Withdrawal Criteria 
Patients should be discontinued from the study if any of the following criteria are met: 
• Patient develops (or has an exacerbation of) any medical condition that, in the 
opinion of the investigator, would put the patient at an unacceptable medical risk 
or compromises the patient’s ability to participate in the study. 
• Patient is unable/unwilling to comply with study procedures. 
Where possible, the decision to withdraw a patient from the study should be discussed with 
the Sponsor. 
8.10 Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  The 
Sponsor may stop the study (and/or the study site) for any reason with appropriate 
notification. 
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9. Adverse Events 
Adverse events occurring during the study will be recorded on an adverse event CRF page.  
If adverse events occur, the first concern will be the safety of the study participants. 
9.1 Definitions 
9.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this  treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product. 
Note:  Adverse events must be collected once informed consent/assent has been obtained, 
regardless of whether or not the patient has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the CRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate CRF. 
9.1.2 Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
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life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
The Sponsor considers all cancer adverse events as serious adverse events.  In addition, the 
Sponsor considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to the Sponsor. 
9.1.3 Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
 
9.1.4 Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the study drug or study procedure. 
9.2 Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate CRF. 
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All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities. 
Adverse events which are ongoing at exit and require follow-up include serious adverse 
events and any non-serious adverse events of special interest suggestive of 
methemoglobinemia, anemia, hemolysis, peripheral neuropathy, severe skin reactions, 
suicide attempt, tonic clonic movements, severe vomiting, pancreatitis, or severe pharyngitis. 
9.3 Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study drug must be immediately 
reported but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events  must be reported to the Sponsor(or Agent of the Sponsor) as listed on the Sponsor’s 
Study Contacts Page and recorded on the serious adverse event form.  All patients with a  
serious adverse event must be followed up and the outcomes reported.  The investigator must 
supply the sponsor and the IRB/IEC with any additional requested information (eg, autopsy 
reports and discharge summaries). 
In the event of a serious adverse event, the investigator must: 
1. Notify the Sponsor immediately by fax or email using the  serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Sponsor personnel contacts are also on the front page of 
protocol and Study Contacts Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide the Sponsor with a complete, written description of the adverse event(s) on 
the serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
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4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 Procedures for Unmasking of Study Medication 
This is an open-label study. 
10. Administrative Items 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines, eg, the ICH Guideline on GCP. 
10.1 Protection of Human Patients 
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 
50) and Relevant Country Regulations 
Written informed consent is to be obtained from the patient's legally authorized 
representative.  the consent form must be signed by the legally authorized representative in 
accordance with the relevant country and local regulatory requirements. 
A separate written minor assent (in accordance with any applicable state and local 
laws/regulations) are required prior to study enrollment or any study-related procedures. 
10.1.2 Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
The Sponsor is to be notified immediately if the responsible IRB/IEC has been disqualified 
or if proceedings leading to disqualification have begun.  Copies of all IRB/IEC 
correspondence with the investigator should be provided to the Sponsor. 
10.1.3 Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
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10.1.4 Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 Changes to the Protocol 
The investigator must not implement any deviation from or changes to the protocol without 
approval by the Sponsor and prior review and documented approval/favorable opinion from 
the IRB/IEC of a protocol amendment, except where necessary to eliminate immediate 
hazards to study patients, or when the changes involve only logistical or administrative 
aspects of the study (eg, change in monitors, change of telephone numbers). 
10.3 Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the Sponsor of the study, the Sponsor, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 Patient Privacy 
Written authorization (United States [US] sites only), and Personal Information Protection 
and Electronic Documents Act (PIPEDA; Canadian sites only), and other documentation in 
accordance with the relevant country and local privacy requirements (where applicable) were 
obtained from each patient prior to enrollment into the study, and/or from thepatient’s legally 
authorized representative in accordance with the applicable privacy requirements (eg, 
HIPAA). 
Samples of ICF and privacy documentation forms are on file in the sponsor’s trial master file 
and are available upon request.  
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10.4 Documentation 
10.4.1 Source Documents 
Source documents may include a patient's medical records, hospital charts, clinic charts, the 
investigator's patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms. The investigator's copy of the CRFs serves as part 
of the investigator's record of a patient's study-related data. 
The following information should be entered into the patient's medical record: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and patient drug kit 
number dispensed and returned 
• The study title and/or the protocol number of the study and the name of the Sponsor 
• A statement that informed consent and assent was obtained (including the date).  A 
statement that written authorization (US sites only), or other country and local patient 
privacy required documentation for this study has been obtained (including the date) 
• Documentation that a patient met all of the inclusion and exclusion criteria for study 
entry, and the date when eligibility was confirmed 
• Patient’s demographics, skin phototyping, and medical history, as collected at 
screening 
• Documentation that females had a negative pregnancy test result at screening, 
baseline/Day 1 (Visit 2), Week 4/Visit 5, Week 8/Visit 6, and Week 12/early exit 
(Visit 7). 
• Dates of all patient visits 
• Occurrence and status of any adverse events 
• The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation 
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• Documentation of PK sample collection, processing, storage, and shipping for the 
patients in the PK Cohort 
• Training on study drug administration, dispensing and weighing/confirming dosing 
compliance 
• The results of laboratory tests performed by the site for an adverse event 
• Key study variables such as: 
o Documentation of the patient’s compliance with study restrictions, including 
activity restrictions 
o All concomitant medications (List all prescription and non-prescription 
medications being taken at the time of enrollment.  At each subsequent visit, 
changes to the list of medications should be recorded.) 
o Concomitant procedures 
o Results of vital sign, body weight, and height measurements 
o Results of local tolerability assessments 
o IGA assessment 
o Lesion count results, including information on who the assessor is 
o Documentation confirming standardized photography has been completed at 
the selected sites 
Source documentation practices must follow Section 4.0 of ICH E6,GCP: Consolidated 
Guidance and ALCOA; ie, records must be Attributable, Legible, Contemporaneous, Original 
and Accurate. 
10.4.2 Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient's 
case report forms and related documents.  An investigator who has signed the protocol 
signature page should personally sign for the case report forms (as indicated in the case 
report forms) to ensure that the observations and findings are recorded on the case report 
forms correctly and completely.  The case report forms are to be submitted to the Sponsor in 
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a timely manner at the completion of the study, or as otherwise specified by the Sponsor and 
will be maintained in a central data repository. 
10.4.3 Study Summary 
An investigator's summary will be provided to the Sponsor within a short time after the 
completion of the study, or as designated by the Sponsor.  A summary is also to be provided 
to the responsible IRB/IEC. 
10.4.4 Retention of Documentation 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of case report forms should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
The Sponsor requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 Labeling/Packaging 
All study drug will be packaged, labeled, and supplied by the Sponsor.  To ensure maximal 
use conditions for the PK Cohort for the first 8 days, study drug will be provided in 
individual usage tubes containing approximately 2 grams each.  Each weekly kit will contain 
14 x 2-gram tubes.  After Week 1/Visit 3 the maximal use condition portion of the trial for the 
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PK Cohort, study drug will be supplied in 60-gram pumps as it has been for the non-PK 
Cohort from the start of the study.  The study drug will be identified as an investigational 
compound. The kit number will be identified on the unit label.  
10.5.2 Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from the Sponsor, dispensed or administered to the patients, the number of units 
returned to the investigator by the patient (if applicable), and the number of units returned to 
the Sponsor during and at the completion of the study.  A detailed inventory must be 
completed for the study drug.  The study drug must be dispensed or administered only by an 
appropriately qualified person to patients in the study.  The drug is to be used in accordance 
with the protocol for patients who are under the direct supervision of an investigator.   
10.5.3 Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study drugs/treatments and/or supplies will be returned to the Sponsor or the 
Sponsor’s designee for destruction. 
10.6 Monitoring by the Sponsor 
A representative of the sponsor will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of the Sponsor or regulatory authority representatives will 
conduct on-site visits to review, audit and copy study-related documents.  These 
representatives will meet with the investigator(s) and appropriate staff at mutually convenient 
times to discuss study-related data and questions. 
10.7 Handling of Biological Specimens 
Blood samples obtained at selected sites will be analyzed for dapsone, NAD, DHA, and other 
metabolites or analytes (if warranted) by a bioanalytical laboratory. 
All samples will be returned to the Sponsor or the Sponsor’s designee for destruction.  The 
Sponsor shall have full ownership rights to any biological specimens/samples derived from 
the study. 
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10.8 Publications 
The Sponsor has proprietary interest in this study.  Authorship and manuscript composition 
will reflect joint cooperation between multiple investigators and sites and the Sponsor’s 
personnel.  Authorship will be established prior to the writing of the manuscript.  As this 
study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with the Sponsor. 
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11. References 
ACZONE [dapsone 5% gel] package insert.  Irvine CA:  Allergan, Inc; 2015. 
ACZONE [dapsone 7.5% gel] package insert.  Irvine CA:  Allergan, Inc; 2016. 
Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol. 2013;168(3):474-485. 
Bozeman PM, Learn DB, Thomas EL. Assay of the human leukocyte enzymes 
myeloperoxidase and eosinophil peroxidase. J Immunol Methods. 1990;126(1):125-133. 
Dapsone Tablets, USP, 25 mg and 100 mg [package insert]. Princeton, NJ: Jacobus 
Pharmaceutical Company, Inc; July 2011. 
Debol SM, Herron MJ, Nelson RD. Anti-inflammatory action of dapsone: inhibition of 
neutrophil adherence is associated with inhibition of chemoattractant-induced signal 
transduction. J Leukoc Biol. 1997;62(6):827-836. 
Eichenfield LF, Hebert AA, Schachner L, Paller AS, Rossi AB, Lucky AW. Tretinoin 
microsphere gel 0.04% pump for treating acne vulgaris in preadolescents: a randomized, 
controlled study. Pediatr Dermatol. 2012;29:598-604. 
Eichenfield LF, Krakowski AC, Piggott C, Del Rosso J, Baldwin H, Friedlander SF,et al.  
Evidence-based recommendations for the diagnosis and treatment of pediatric acne. 
Pediatrics.  2013;131(Suppl 3):S163-S186. 
Eichenfield LF, Draelos Z, Lucky AW, Hebert AA, Sugarman J, Stein Gold L, et al.  
Preadolescent moderate acne vulgaris: a randomized trial of the efficacy and safety of topical 
adapalene-benzoyl peroxides. J Drugs Dermatol. 2013;12(6):611-8. 
FDA Letter 2016:  
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/207154Orig1s000ltr.pdf. 
Fleischer AB, Shalita A, Eichenfield LF, Abramovits W, Lucky A, Garrett S, et al.  Dapsone 
gel 5% in combination with adapalene gel 0.1%, benzoyl peroxide gel 4% or moisturizer for 
the treatment of acne vulgaris: a 12-week, randomized, double-blind study.  J Drugs 
Dermatol.  2010;9(1):33-40. 
Friedlander SF, Eichenfield LF, Fowler JF Jr, Fried RG, Levy ML, Webster GF. Acne 
epidemiology and pathophysiology. Semin Cutan Med Surg. 2010;29(2 Suppl 1):2-4. 
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Friedlander SF, Baldwin HE, Mancini AJ, Yan AC, Eichenfield LF. The acne continuum: an 
age-based approach to therapy. Semin Cutan Med Surg. 2011;30(3 Suppl):S6-11. 
Goldberg JL, Dabade TS, Davis SA, Feldman SR, Krowchuk DP, Fleischer AB. Changing 
age of acne vulgaris visits: another sign of earlier puberty? Pediatr Dermatol. 
2011;28(6):645-648. 
Klassen AF, Newton JN, Mallon E.  Measuring quality of life in people referred for specialist 
care of acne: comparing generic and disease-specific measures.  J Am Acad Dermatol.  
2000;43:229-233. 
Longshore SJ, Hollandsworth K.  Acne vulgaris: One treatment does not fit all.  Cleve Clin J 
Med. 2003;70(8):670, 672-674, 677-678 passim. 
Lucky AW, Biro FM, Huster GA, Morrison JA, Elder N. Acne vulgaris in early adolescent 
boys. Correlations with pubertal maturation and age. Arch Dermatol.  1991;127(2):210-216. 
Lucky AW, Biro FM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris in 
premenarchal girls. An early sign of puberty associated with rising levels of 
dehydroepiandrosterone. Arch Dermatol.  1994;130(3):308-314. 
Ramos-e-Silva M, Carneiro SC. Acne vulgaris: review and guidelines. Dermatol Nurs. 
2009;21:63-68. 
Rubinow DR, Peck GL, Squillace KM, Gantt GG.  Reduced anxiety and depression in cystic 
acne patients after successful treatment with oral isotretinoin.  J Am Acad Dermatol.  
1987;17:25-32. 
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12. Attachments  
12.1 Examination Procedures, Tests, Equipment, and Techniques 
Pharmacokinetic Measures 
• Plasma concentrations of dapsone, its metabolites (NAD, DHA), and other metabolites or 
analytes (if warranted) 
Detailed instructions on the collection, processing, and storage of pharmacokinetic samples 
are provided in the Procedure Manual. 
Safety Measures 
• Adverse events 
The investigator will question the patient in order to ascertain whether any adverse events 
were experienced since the previous visit.  All pertinent information regarding adverse 
events (ie, date of onset and stop, duration, outcome, severity, relationship to study drug, 
action or treatment required) will be obtained and recorded in the source documents and 
appropriately transcribed on the eCRF page. 
• Urine pregnancy test 
All females will be asked to provide a urine sample for pregnancy testing.  Sample testing 
will be performed in accordance with the instructions provided in the pregnancy test kit. 
• Vital signs 
Heart rate (beats per minute) and respiratory rate:  patients should be seated for at 
least 10 minutes, and heart rate and respiratory rate will be counted over 60 seconds, and 
recorded in the source document and eCRF. 
Blood pressure (millimeters of mercury):  patients should be seated for at least 
10 minutes, and systolic/diastolic blood pressure will be measured with a 
sphygmomanometer. 
Body temperature (°C):  patients should have had no oral intake for 5 minutes before 
the body temperature is taken orally. 
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• Physical examination (PE) 
The body systems listed below will be checked.  The date of PE will be recorded, and any 
new PE findings will be recorded on the AE CRF. 
1. General Appearance 
2. HEENT (head, eyes, ears, nose, and throat) 
3. Heart/Cardiovascular 
4. Lungs 
5. Abdomen 
6. Neurologic 
7. Extremities 
8. Back 
9. Musculoskeletal 
10. Lymphatic 
11. Skin 
12. Other: ___________________________ 
• Body weight and height 
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Efficacy Measures: 
• 
IGA 
 
Grade 
Description 
0 
Clear 
• 
No comedones, papules or pustules 
• 
Residual hyperpigmentation and erythema may be present 
1 
Almost Clear 
• 
Rare comedones 
• 
No more than a few small papules and pustules 
2 
Mild 
• 
Easily recognizable comedones in limited numbers 
• 
+/- Presence of small papules and pustules 
3 
Moderate 
• 
Many comedones 
• 
+/- Easily recognizable small and medium-sized papules 
• 
No nodules or cysts. 
4 
Severe 
• 
Widespread and numerous comedones 
• 
Many small, medium-sized and large papules and pustules 
• 
Nodules or cysts may or may not be present. 
(Eichenfield et al, 2013, J of Dermatol) 
• Local dermal tolerability assessment 
The local tolerability examination of the face is to be performed by the investigator (or 
appropriately trained designee), who will assess dryness, scaling, and erythema, and the 
patient will assess stinging/burning.  The assessor will examine the skin area where study 
drug is applied in comparison to the surrounding skin from day 1 to week 12.  The same 
assessor will rate dryness, scaling, and erythema at each visit, where possible.  Local 
tolerability signs and symptoms will be rated using a severity scoring of 0 (none), 1 
(mild), 2 (moderate), or 3 (severe), as further defined below. 
Based on the assessor’s medical judgment, if a sign or symptom is clinically significant, 
it must be recorded on the adverse event eCRF.  Other dermatological findings of clinical 
significance in the patient’s treated area must also be reported as adverse events on the 
eCRF. 
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Patient-rated: 
Stinging/Burning:  prickling pain sensation immediately after (within 5 minutes of 
dosing, except baseline) 
None (0) = No stinging/burning 
Mild (1) = Slight warm, tingling/stinging sensation; not really bothersome 
Moderate (2) = Definite warm, tingling/stinging sensation that is somewhat 
bothersome 
Severe (3) = Hot, tingling/stinging sensation that has caused definite 
discomfort 
Investigator- (or designee) rated: 
Dryness:  brittle and/or tight sensation 
None (0) = No Dryness 
Mild (1) = Slight but definite roughness 
Moderate (2) = Moderate roughness 
Severe (3) = Marked roughness 
Scaling:  abnormal shedding of the stratum corneum 
None (0) = No Scaling 
Mild (1) = Barely perceptible shedding, noticeable only on light scratching or 
rubbing 
Moderate (2) = Obvious but not profuse shedding 
Severe (3) = Heavy scale production 
Erythema:  abnormal redness of the skin 
None (0) = No Erythema 
Mild (1) = Slight pinkness present 
Moderate (2) = Definite redness, easily recognized 
Severe (3) = Intense redness 
 
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• Fitzpatrick skin phototype (FDA Federal Register, 1999): 
I:  Always burns easily; never tans (sensitive) 
II:  Always burns easily; tans minimally (sensitive) 
III:  Burns moderately; tans gradually (light brown) (normal) 
IV:  Burns minimally; always tans well (moderate brown) (normal) 
V:  Rarely burns; tans profusely (dark brown) (insensitive) 
VI:  Never burns; deeply pigmented (insensitive) 
 
• Photographs will be taken by a subset of study sites.  Photographs will be transferred 
to the Sponsor on a periodic basis. 
12.2 Handling of Biological Specimens 
Details relating to the handling of biological samples are provided in the Procedure Manual. 
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12.3 Glossary of Abbreviations 
Term/Abbreviation 
Definition 
CRF 
case report form 
Cmax 
maximum plasma concentration  
DHA 
dapsone hydroxylamine 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
G6PD 
glucose-6-phosphate dehydrogenase  
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IETD 
investigator emergency treatment disclosure 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NAD 
N-acetyl dapsone 
NSAID 
nonsteroidal anti-inflammatory drug 
PK 
Pharmacokinetics 
PT 
preferred term 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
US 
United States 
 
13SEP2018 CSR 1679-401-006
58


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Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
2. 
Table of Contents 
1. 
Title Page ................................................................................................................................. 1 
2. 
Table of Contents ..................................................................................................................... 2 
2.1 
List of Tables .................................................................................................................. 3 
2.2 
List of Figures ................................................................................................................ 4 
3. 
List of Abbreviations and Definition of Terms ........................................................................ 5 
4. 
Introduction .............................................................................................................................. 6 
4.1 
Study Design Summary ................................................................................................. 6 
4.2 
Study Objectives and Endpoints .................................................................................... 7 
4.3 
Schedule of Activities .................................................................................................... 9 
5. 
Statistical Methodology and Study Endpoints ....................................................................... 11 
5.1 
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 11 
5.1.1  Statistical and Analytical Plans ........................................................................ 11 
5.1.1.1  Common Conventions ....................................................................... 11 
5.1.1.2  Demographics .................................................................................... 12 
5.1.1.3  Efficacy Analyses .............................................................................. 15 
5.1.1.4  Pharmacokinetic Analyses ................................................................. 17 
5.1.1.5  Safety Analyses ................................................................................. 17 
5.1.1.6  Subgroup Analyses ............................................................................ 20 
5.1.1.7  Interim Analyses ................................................................................ 20 
5.1.2  Determination of Sample Size ......................................................................... 20 
5.2 
Changes in the Conduct of the Study or Planned Analyses ......................................... 20 
5.2.1  Changes in the Conduct of the Study ............................................................... 20 
5.2.2  Changes to Analyses Prior to Database Lock .................................................. 20 
6. 
Data Handling and Analysis Conventions ............................................................................. 21 
6.1 
Study Treatment Conventions ...................................................................................... 21 
6.1.1  Analysis Days .................................................................................................. 21 
6.2 
Analysis Visit Windows ............................................................................................... 21 
6.2.1  Efficacy ............................................................................................................ 21 
6.2.2  Safety ............................................................................................................... 21 
6.3 
Missing/Incomplete Date Conventions ........................................................................ 22 
6.3.1  Missing/Incomplete AE Start Date .................................................................. 22 
6.3.2  Missing/Incomplete Medication Start Date ..................................................... 23 
6.3.3  Missing/Incomplete AE/Medication End Date ................................................ 23 
13SEP2018 CSR 1679-401-006
2


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
6.4 
Safety Endpoint Conventions ....................................................................................... 23 
6.4.1  Adverse Events ................................................................................................ 23 
6.4.1.1  Missing Intensity or Relationship ...................................................... 23 
6.4.2  Vital Signs ........................................................................................................ 23 
6.4.2.1  Continuous Descriptives Parameters ................................................. 23 
6.4.3  Local Dermal Tolerability ................................................................................ 23 
6.5 
Imputed Value Listing Conventions ............................................................................. 24 
7. 
References .............................................................................................................................. 24 
8. 
Amendment(s) ....................................................................................................................... 24 
 
2.1 
List of Tables 
Table 3-1 
Abbreviations and Definitions of Terms ................................................................. 5 
Table 5-1 
Analysis Populations ............................................................................................. 11 
Table 5-2 
Statistical Methodology ........................................................................................ 11 
Table 5-3 
Participant Disposition Summaries ....................................................................... 12 
Table 5-4 
Protocol Deviations ............................................................................................... 13 
Table 5-5 
Demographic Summaries ...................................................................................... 13 
Table 5-6 
Baseline Characteristics Summaries ..................................................................... 14 
Table 5-7 
Medical History Summary .................................................................................... 14 
Table 5-8 
Medication Summaries ......................................................................................... 15 
Table 5-9 
Efficacy Assessments ............................................................................................ 16 
Table 5-10 
Efficacy Analyses .................................................................................................. 16 
Table 5-11 
Study Treatment Summaries ................................................................................. 17 
Table 5-12 
AE Terms .............................................................................................................. 18 
Table 5-13 
AE Summaries ...................................................................................................... 18 
Table 5-14 
Vital Signs Summaries .......................................................................................... 19 
Table 5-15 
Local Dermal Tolerability Summaries .................................................................. 20 
Table 6-1 
Analysis Day Definitions ...................................................................................... 21 
13SEP2018 CSR 1679-401-006
3


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Table 6-2 
Efficacy Analysis Visit Definitions ....................................................................... 21 
Table 6-3 
Safety Analysis Visit Definitions .......................................................................... 21 
Table 6-4 
Imputation Scenarios ............................................................................................ 22 
Table 6-5 
Initial Imputed Date Algorithm ............................................................................. 22 
Table 6-6 
Missing AE Intensity and Relationship Imputation Algorithms ........................... 23 
Table 6-7 
Vital Sign Descriptive Parameters ........................................................................ 23 
Table 6-8 
Local Dermal Tolerability Parameters .................................................................. 24 
 
2.2 
List of Figures 
Not applicable. 
13SEP2018 CSR 1679-401-006
4


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
3. 
List of Abbreviations and Definition of Terms 
Table 3-1 
Abbreviations and Definitions of Terms 
Abbreviation/Term 
Definition 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
CFB 
change from baseline 
DHA 
dapsone hydroxylamine 
eCRF 
electronic case report form 
IGA 
Investigator’s Global Assessment  
MedDRA 
Medication Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NAD 
N-acetyl dapsone 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Le Système International d’Unités (International System of Units) 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
13SEP2018 CSR 1679-401-006
5


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
4. 
Introduction 
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the final protocol 
of Study 1679-401-006 dated 23-Jun-2016. Specifications of tables, figures, and data listings are 
contained in a separate document. The SAP for pharmacokinetic (PK) data will be prepared 
separately. 
This document is organized into 3 main sections: 
1. Study Overview 
2. Statistical Methodology and Study Endpoints 
3. Data Handling and Analysis Conventions  
4.1 
Study Design Summary 
Structure:  Multicenter, open-label, non-comparative trial 
Duration:  Patient participation is up to approximately 16 weeks from screening to trial exit; 
treatment duration is up to 12 weeks 
Study Treatment Groups:  ACZONE 7.5%  
Controls:  No control group 
Dosage/Dose Regimen:  All patients will receive treatment with ACZONE 7.5% once-daily 
Pharmacokinetic (PK) Cohort (at least 16 evaluable PK patients): For the first 8 days (+ 2 days), 
study drug will be administered once-daily under maximal use condition (~2 grams/day) to the 
entire face, neck, upper chest, upper back and shoulders as instructed by the study site. The study 
drug should be rubbed in gently and completely. On Day 1, the study drug will be administered 
on site. From Day 2 through Day 7, the study drug will be administered in the morning at home 
by the patient’s legally authorized representative. At the Week 1/Visit 3 [Day 8 (+2 days)], the 
study drug will be administered on site in the morning. After the Week 1/Visit 3, patients or the 
patient’s legally authorized representative will apply a pea-sized amount of study drug in a thin 
layer to the patient’s face, once-daily, at home for the remaining 11 weeks, the same as the dose 
regimen for the Non-PK Cohort. Acne-affected areas on the upper chest, upper back, and 
shoulders should also be treated with a thin layer during the final 11 weeks.  Evaluable PK 
patients are defined as those that are administered at least 8 days of study drug under maximal 
use conditions, and provided PK samples for analysis without any major protocol deviations.  
Non-PK Cohort (approximately 84 patients): Patients or the patient’s legally authorized 
representative will apply a pea-sized amount of study drug in a thin layer to the patient’s face 
13SEP2018 CSR 1679-401-006
6


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
once-daily for 12 weeks as instructed by the study site. Acne-affected areas on the upper chest, 
upper back, and shoulders should also be treated with a thin layer. 
Randomization/Stratification: No randomization; all patients will receive ACZONE 7.5%.  
Assignment to PK or Non-PK Cohort will be based on patient/legally authorized representative 
choice and investigator’s judgment. 
Visit Schedule: up to 7 scheduled study visits (see Table 4-2 for further details): 
• Visit 1:  Screening (-30 to day -1) 
• Visit 2:  Day 1 (Baseline)a 
• Visit 3:  Week 1 (Day 8 + 2 days) 
• Visit 4:  Week 2 (±3 days) 
• Visits 5 and 6: Weeks 4 and 8 (±7 days) 
• Visit 7:  Week 12 / Early Exit (±7 days) 
a Can be combined with the screening visit if no washout period is required.  
Number of Participants: For the PK Cohort, at least 16 patients will be enrolled to ensure 16 
evaluable PK subjects at the Week 1 visit. For the Non-PK Cohort, approximately 84 additional 
patients will be enrolled in the study for a total of approximately 100 patients.  
 
4.2 
Study Objectives and Endpoints 
Each study objective is presented with corresponding endpoint(s) below: 
Table 4-1 
Study Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
• 
To evaluate the safety and tolerability of 
ACZONE 7.5% administered topically once-
daily for 12 weeks in 9 to 11 year-olds with acne 
vulgaris. 
 
 
 
Safety Assessments 
• Adverse events (AE) 
• Vital signs 
o 
Heart rate  
o 
Blood pressure 
o 
Respiratory rate 
o 
Body temperature 
• Local dermal tolerability (face only) 
o 
Dryness 
o 
Scaling  
o 
Erythema 
o 
Stinging/burning 
• 
To evaluate the peak and trough plasma drug 
concentrations in 9 to 11 year-olds with acne 
vulgaris following once-daily dosing of 
Pharmacokinetic Assessments 
• Peak and trough plasma concentrations of dapsone, 
N-acetyl dapsone (NAD), dapsone hydroxylamine 
13SEP2018 CSR 1679-401-006
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Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Objectives 
Endpoints 
ACZONE 7.5% under maximal use conditions 
for the first 8 days (+ 2 days). 
(DHA), and other metabolites or analytes (if 
warranted) at Week 1/Visit 3 
• 
To explore the efficacy of ACZONE 7.5% 
administered topically once-daily in 9 to 11 
year-olds with acne vulgaris. 
Efficacy Assessments 
• Lesion counts (face only) 
o    Change and percent change from baseline in 
inflammatory lesion counts  
o    Change and percent change from baseline in 
noninflammatory lesion counts 
o    Change and percent change from baseline in 
total lesion counts (Total lesion counts will 
be the sum of inflammatory lesion counts 
and noninflammatory lesion counts.) 
• Investigator’s Global Assessment (IGA) (face only) 
o    Proportion of patients with none (0) or 
minimal (1) score on the IGA at each visit 
o    Proportion of patients with none (0) or 
minimal (1) score plus at least a 2-grade 
improvement on the IGA at each visit 
 
13SEP2018 CSR 1679-401-006
8


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
4.3 
Schedule of Activities  
Table 4-2 
Schedule of Activities 
Study Period 
Screeninga 
Baseline/Day 1a 
Week 1 
Week 2 
Weeks 4 and 8 
Week 12/ 
Early Exit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 and Visit 6 
Visit 7 
Visit Windows  
Day -30 to 
Day -1  
N/A 
Day 8 (+ 2 
days) 
Day 15 (± 3 
days) 
Day 29 (± 7 days) 
and Day 57 (± 7 
days) 
Day 85 (± 7 
days) 
Informed consent/authorization and minor assentb 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Skin phototype assessment 
X 
 
 
 
 
 
Physical examination includes vital signs, height and 
weightc 
X 
 
 
 
 
X 
Pregnancy test (urine)d 
X 
X 
 
 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
Lesion count 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
PK Cohort: Dispense study drug, training on 
application/returne 
 
D 
R/D 
 
R/D 
R 
Non-PK Cohort: Dispense study drug, training on 
application/returnf 
 
D 
 
 
R/D 
R 
Standardized photographsg 
 
X 
 
 
 
X 
Local tolerabilityh 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Concomitant procedures 
X 
X 
X 
X 
X 
X 
13SEP2018 CSR 1679-401-006
9


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Study Period 
Screeninga 
Baseline/Day 1a 
Week 1 
Week 2 
Weeks 4 and 8 
Week 12/ 
Early Exit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 and Visit 6 
Visit 7 
Visit Windows  
Day -30 to 
Day -1  
N/A 
Day 8 (+ 2 
days) 
Day 15 (± 3 
days) 
Day 29 (± 7 days) 
and Day 57 (± 7 
days) 
Day 85 (± 7 
days) 
Adverse events 
X 
X 
X 
X 
X 
X 
PK samplingi 
 
 
X 
 
 
 
D = dispense; IGA = Investigator’s Global Assessment; N/A = not applicable; R = return; PK= pharmacokinetic 
a 
If a washout period is not required, then screening and baseline visits can occur on the same day, and the procedures required to be repeated at both visits 
should be performed once. 
b 
Consent for photography is included in the informed consent process at select centers. 
c 
Physical examination and vital signs are to be performed if inclusion/exclusion criteria are met at screening; not required for screen failures.  Vital signs 
include heart rate, blood pressure, respiratory rate, and body temperature. 
d 
Female patients only.  The urine pregnancy test can also be performed at any timepoint during the course of the trial at the investigator’s discretion. If a 
patient misses a menstrual cycle, a urine pregnancy test must be performed. 
e 
Patients in the PK cohort will be dispensed 1 kit with 14 tubes on Baseline/Day 1 (Visit 2). All patients in the PK cohort will start dosing on Day 1 using 
the 2.0 gram tubes dispensed for individual application.PK Cohort patients will return used study drug at Week 1/Visit 3. At Week 1/Visit 3, Week 4 (Visit 
5) and Week 8 (Visit 6) the patients in the PK Cohort are dispensed 60-gram pumps. Dispensed and returned study drug will be weighed at the study center. 
f 
All patients will start dosing on day 1. The patients in the Non-PK Cohort are dispensed 60-gram pumps on Baseline/Day 1 (Visit 2), Week 4 (Visit 5) and 
Week 8 (Visit 6).  Dispensed and returned study drug will be weighed at the study center.   
g 
At select centers, patients may have photographs taken of their face for illustration or presentation purposes. Patients who consent to being photographed 
will be required to remove any make-up at least 20 minutes prior to having photographs taken. 
h 
Local tolerability will be assessed prior to drug administration on day 1, as well as postdose on the face only. 
i 
Only applies to patients in the PK Cohort at the Week 1/Visit 3. Blood samples will be collected within 30 minutes prior to dosing in clinic in the morning 
and at approximately 10 hours post dose (± 3 hour) (patients are allowed to leave and come back if needed) under maximal use conditions to determine the 
peak and trough plasma drug concentrations.
 
 
13SEP2018 CSR 1679-401-006
10


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
5. 
Statistical Methodology and Study Endpoints 
5.1 
Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
This SAP will be approved prior to database lock. The SAP expands the statistical section of the 
protocol and contains a detailed description of methods to analyze data collected in the study. 
The text portion of the SAP will be included in the CSR report as Appendix 16.1.9. Information 
on the PK analyses can be found in the PK data analysis plan. 
5.1.1 
Statistical and Analytical Plans 
Statistical analyses will be conducted using SAS Version 9.3 or newer. 
5.1.1.1 
Common Conventions 
5.1.1.1.1 
Analysis Populations 
The analysis populations will consist of participants as defined below: 
Table 5-1 
Analysis Populations 
Population 
Definition 
Study Treatment 
Screened 
All screened participants who sign informed consent. 
— 
Safety 
All participants who received at least one application of study 
drug. 
Actual received 
Modified Intent-to-
Treat (mITT) 
All enrolled participants who have a baseline assessment and at 
least one post-baseline assessment. 
Actual received 
 
5.1.1.1.2 
Study Treatments 
The following treatment group is defined for this study: 
• ACZONE 7.5% 
5.1.1.1.3 
Statistical Methodology 
The methodologies defined below apply as specified to individual endpoints defined in this SAP.  
Table 5-2 
Statistical Methodology 
Methodology 
Description 
Categorical counts 
• 
Number of participants in individual categories 
o 
Participants with ≥ 1qualifying event counted once per individual category 
Categorical 
descriptives 
• 
Number and percentage of participants in individual categories 
o 
Participants with ≥ 1qualifying event counted once per individual category 
• 
N1 if percentage denominator ≠ number of participants in the population (standard 
percentage denominator) 
o 
N1 = participants with non-missing baseline value 
13SEP2018 CSR 1679-401-006
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Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Methodology 
Description 
Continuous 
descriptives 
• 
N1, mean, standard deviation (SD), median, minimum, maximum 
• 
N1 = participants with non-missing value 
CFB1 descriptives 
• 
Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values 
• 
N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit 
1 CFB = change from baseline 
 
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document. 
5.1.1.1.4 
Missing Data 
No imputation of missing efficacy data for this study is specified for methodologies in Section 
5.1.1.1.3. 
5.1.1.1.5 
Site Pooling 
Unless specifically detailed, data will be pooled over sites for the summary analyses. 
5.1.1.2 
Demographics 
The Screened Population, Safety, and mITT Populations will be used to summarize in this 
section. 
5.1.1.2.1 
Participant Disposition 
Participant disposition encompasses the distribution of participants who enter, complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Participant disposition will be summarized as follows: 
Table 5-3 
Participant Disposition Summaries 
Parameter 
Description 
Timing 
Methodology 
Screening and 
disposition 
Distribution in the screened population in 
total and by screen failure/screen success 
• 
Age 
• 
Sex 
• 
Ethnicity 
• 
Race group 1  
o 
White 
o 
Black or African American 
o 
Asian 
o 
American Indian or Alaska 
Native 
o 
Native Hawaiian or Other 
Pacific Islander 
• 
Race group 2  
o 
White 
Screening Period 
Continuous 
descriptives and 
categorical 
descriptives 
13SEP2018 CSR 1679-401-006
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Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Parameter 
Description 
Timing 
Methodology 
o 
Non-white 
• 
Reasons for screen failure in the 
screened population 
o 
eCRF categories 
Study disposition 
• 
Distribution in the safety population in 
total and by cohort (PK and Non-PK 
cohorts) 
Treatment Period 
Categorical 
descriptives 
 
5.1.1.2.2 
Protocol Deviations 
Protocol deviations will be listed as follows: 
Table 5-4 
Protocol Deviations  
Parameter 
Description 
Timing 
Methodology 
Important protocol 
deviations 
Protocol deviations are defined as any variation from the 
protocol, including enrollment of a participant who did 
not meet all inclusion criteria and/or met any exclusion 
criteria and failure to perform the assessments and 
procedures within the required time frame. 
— 
Listing 
 
 
 
 
5.1.1.2.3 
Demographics 
Demographics will be summarized in total and by cohort (PK cohort and Non-PK cohort) for the 
Safety Population, as follows: 
Table 5-5 
Demographic Summaries 
Parameter 
Description 
Timing 
Methodology 
Age 
Age (years) relative to informed consent 
date 
Informed consent 
Continuous 
descriptives 
Sex, ethnicity and race  
• 
Sex 
• 
Ethnicity 
• 
Race group 1  
o 
White 
o 
Black or African 
American 
o 
Asian 
o 
American Indian or 
Alaska Native 
o 
Native Hawaiian or 
Other Pacific Islander 
• 
Race group 2  
o 
White 
o 
Non-white 
Screening Period 
Categorical 
descriptives 
 
5.1.1.2.4 
Baseline Characteristics  
Baseline characteristics will be summarized in total and by cohort (PK cohort and Non-PK 
cohort) for mITT or Safety Populations as follows: 
13SEP2018 CSR 1679-401-006
13


Allergan Confidential 
SAP 1679-401-006 
ACZONE (Dapsone, AGN-225678) Gel, 7.5% 
Table 5-6 
Baseline Characteristics Summaries 
Parameter 
Description 
Timing 
Methodology 
Baseline characteristics 
For Safety Population only: 
• 
Height (m) 
• 
Weight (kg) 
• 
Body mass index (BMI) 
o 
Weight (kg) / height (m)2 
Latest assessment in 
Screening Period  
Continuous 
descriptives 
Baseline characteristics 
For Safety Population only: 
• 
Skin phototype assessment 
o 
I: Always burns easily; never 
tans (sensitive) 
o 
II: Always burns easily; tans 
minimally (sensitive) 
o 
III: Burns moderately; tans 
gradually (light brown) 
(normal) 
o 
IV: Burns minimally; always 
tans well (moderate brown) 
(normal) 
o 
V: Rarely burns; tans 
profusely (dark brown) 
(insensitive) 
o 
VI: Never burns; deeply 
pigmented (insensitive) 
Latest assessment in 
Screening Period  
Categorical 
descriptives 
Disease characteristics 
For mITT Population only: 
• 
Investigator's Global Assessment 
(IGA) (face only) 
Latest assessment in 
Screening Period  
Categorical 
descriptives 
Disease characteristics 
For mITT Population only: 
• 
Total lesion counts (face only) 
• 
Inflammatory lesion counts (face 
only) 
• 
Non-inflammatory lesion counts 
(face only) 
Latest assessment in 
Screening Period  
Continuous 
descriptives 
 
5.1.1.2.5 
Medical History 
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 19.0 or newer. Unique participants who report medical history events will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) in total and by 
cohort (PK cohort and Non-PK cohort) for the Safety Population as follows: 
Table 5-7 
Medical History Summary 
Parameter 
Description 
Timing 
Methodology 
Medical history 
Abnormalities and surgeries occurring 
before the Screening Visit 
Screening Period 
Categorical 
descriptives 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the total group. 
 
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5.1.1.2.6 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary 
Enhanced (DDE), version MAR2016 or newer. Unique participants who reported medications 
will be summarized by Anatomical Therapeutic Chemical (ATC) 4 class and PT in total and by 
cohort (PK cohort and Non-PK cohort) for the Safety Population as follows: 
Table 5-8 
Medication Summaries 
Parameter 
Description 
Timing 
Methodology 
Prior medications1 
Medications taken ≥ 1 time before the 
study treatment start date, regardless of 
medication end date 
Screening Period 
Categorical 
descriptives 
Concomitant 
medications1 
Medications taken ≥ 1 time on or after the 
study treatment start date, regardless of 
medication start date 
Treatment Period 
Categorical 
descriptives 
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the total group. 
1 If the available date information is not sufficient for classification, the medication will be classified as both a prior 
medication and a concomitant medication. 
 
5.1.1.3 
Efficacy Analyses 
Efficacy analyses are to be considered exploratory and no inferential statistics will be presented 
for this study. Efficacy analyses will be based on the mITT Population.  
The following efficacy assessments and terms are defined: 
 
 
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Table 5-9 
Efficacy Assessments 
Assessment/Term 
Description 
Investigator’s Global 
Assessment (IGA) 
Overall severity of acne vulgaris evaluated using a 5-point IGA (face only):  
• 
Clear (0) 
o 
No comedones, papules or pustules 
o 
Residual hyperpigmentation and erythema may be present 
• 
Almost clear (1) 
o 
Rare comedones  
o 
No more than a few small papules and pustules  
• 
Mild (2) 
o 
Easily recognizable comedones in limited numbers  
o 
+/- Presence of small papules and pustules  
• 
Moderate (3) 
o 
Many comedones  
o 
+/- Easily recognizable small and medium-sized papules  
o 
No nodules or cysts. 
• 
Severe (4) 
o 
Widespread and numerous comedones  
o 
Many small, medium-sized and large papules and pustules  
o 
Nodules or cysts may or may not be present. 
Inflammatory lesion counts 
Inflammatory lesion counts will be the sum of counts of the following lesion types 
(face only): 
• 
Papule – a small, red, solid elevation less than 1.0 cm in diameter 
• 
Pustule – a small, circumscribed elevation of the skin that contains yellow-
white exudate 
• 
Nodule – a circumscribed, elevated, solid lesion generally more than 1.0 
cm in diameter with palpable depth 
• 
Cyst – a smooth, dome-shaped, elevated, freely moveable, skin colored, 
round to ovoid lesion greater than 0.7 cm in diameter 
Noninflammatory lesion 
counts 
Noninflammatory lesion counts will be the sum of counts of the following lesion 
type (face only): 
• 
Open Comedone – a pigmented dilated pilosebaceous orifice (blackhead) 
• 
Closed Comedone – a tiny white papule (whitehead) 
Total lesion counts 
Total lesion counts will be the sum of inflammatory lesion counts and 
noninflammatory lesion counts (face only). 
 
Baseline assessments for IGA and lesion count will be the latest assessment pre-treatment on or 
before day 1 (visit 2).  
The efficacy endpoints will be summarized in total (both study cohorts combined) as follows:  
Table 5-10 
Efficacy Analyses 
Endpoint 
Description 
Timing 
Methodology 
IGA 
Summary by analysis visit: 
• 
Proportion of patients with none 
(0) or minimal (1) score  
• 
Proportion of patients with none 
(0) or minimal (1) score plus at 
least a 2-grade improvement from 
baseline  
Baseline (day 1), 
and Weeks 1, 2, 4, 
8, and 12/early exit 
Categorical 
descriptives 
Inflammatory lesion 
counts1 
Summary by analysis visit: 
• 
Change from baseline 
Baseline (day 1), 
and Weeks 1, 2, 4, 
CFB descriptives 
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Endpoint 
Description 
Timing 
Methodology 
• 
Percent change from baseline  
8, and 12/early exit 
Noninflammatory lesion 
counts1 
Summary by analysis visit: 
• 
Change from baseline 
• 
Percent change from baseline 
Baseline (day 1), 
and Weeks 1, 2, 4, 
8, and 12/early exit 
CFB descriptives 
Total lesion counts 
Summary by analysis visit: 
• 
Change from baseline 
• 
Percent change from baseline 
Baseline (day 1), 
and Weeks 1, 2, 4, 
8, and 12/early exit 
CFB descriptives 
1 If a number of patients have fewer than 5 inflammatory or noninflammatory lesions at baseline, an additional 
analysis may be conducted for that lesion type including only those patients with at least 5 lesions of that type at 
baseline. 
 
5.1.1.4 
Pharmacokinetic Analyses 
The PK analysis plan is beyond the scope of this document and will be outlined in a separate 
document. 
5.1.1.5 
Safety Analyses 
Safety analyses will be based on the Safety Population. 
5.1.1.5.1 
Study Treatment Exposure and Compliance 
Study treatment exposure and compliance will be summarized in total and by cohort (PK cohort 
and Non-PK cohort) for the Safety Population as follows: 
Table 5-11 
Study Treatment Summaries 
Parameter 
Description 
Timing 
Methodology 
Study treatment 
exposure (days) 
Treatment end date - treatment start date + 1 
Treatment Period 
Continuous 
descriptives 
Mean daily dose for 
PK cohort 
For PK cohort only, summary by visit 
interval: 
 
Weight of study drug dispensed - 
Weight of study drug returned 
Interval duration1 
 
Baseline (day 1)- 
Week 1 (visit 2-3); 
Week 1–4 (visit 3-5); 
Week 4–8 (visit 5-6); 
Week 8–12 (visit 6-7) 
Treatment Period 
Continuous 
descriptives 
Mean daily dose for 
non-PK cohort 
For Non-PK cohort only, summary by visit 
interval: 
 
Weight of study drug dispensed - 
Weight of study drug returned 
Interval duration1 
 
Baseline (day 1)- 
Week 4 (visit 2-5); 
Week 4–8 (visit 5-6); 
Week 8–12 (visit 6-7) 
Treatment Period 
Continuous 
descriptives 
Study treatment 
compliance (%) 
Summary by visit interval and by cohort (PK 
cohort and Non-PK cohort): 
 
100 × 
Number of days treatment 
taken as prescribed2 
Interval duration1 
 
Baseline (day 1)- 
Week 1 (visit 2-3), 
Week 1–2 (visit 3-4), 
Week 2–4 (visit 4-5), 
Week 4–8 (visit 5-6), 
Week 8–12 (visit 6-7) 
Treatment Period 
Continuous 
descriptives 
1 Interval duration=Interval end date – interval start date + 1, for the visit interval starting from baseline (day 1). 
2 An individual usage tube containing 2 grams of study drug is expected for PK cohort in the first 8 (+2) days; 
otherwise, an approximately pea-sized amount of study drug is expected. Number of days treatment taken as 
prescribed = interval duration – number missed – number extra during interval. 
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5.1.1.5.2 
Adverse Events 
The following adverse event (AE) terms are defined: 
Table 5-12 
AE Terms 
Term 
Description 
Treatment-
emergent adverse 
event (TEAE) 
An adverse event recorded on the eCRF would be considered treatment-emergent if either of 
the following conditions are met: 
    AE onset date ≥ first study treatment date; or 
    AE onset date < first study treatment date and either:  
• 
the severity of the event worsened on or after the first study treatment date, or 
• 
the event became serious on or after the first study treatment date 
Serious 
Treatment-
emergent adverse 
event (TEAE) 
An event identified as TEAE that further meets serious adverse event (SAE) criteria at any 
time would be a treatment-emergent SAE. 
 
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.0 or newer. Unique participants reporting AEs in the 
following AE categories will be summarized in total and by cohort (PK cohort and Non-PK 
cohort) for the Safety Population as follows: 
Table 5-13 
AE Summaries 
Parameter 
Description 
Timing 
Methodology 
Overall summary 
Overall summary only for the following 
categories: 
• 
TEAEs 
• 
Treatment-related TEAEs  
• 
Serious TEAEs 
• 
TEAEs leading to study 
discontinuation 
• 
Deaths 
 
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
TEAEs 
Overall summary and by SOC and PT  
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
TEAEs by severity 
Overall summary and by SOC, PT and  
worst severity  
 
The worst severity is defined as the greater 
of the onset severity and maximum severity 
following onset recorded on the eCRF. If 
the same TEAE term has been reported 
more than once for a subject with different 
severity grades, the worst severity grade 
will be used in the tabulation. 
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
Treatment-related 
TEAEs 
Overall summary and by SOC and PT  
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
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Parameter 
Description 
Timing 
Methodology 
Treatment-related 
TEAEs by severity 
Overall summary and by SOC, PT and  
worst severity  
 
The worst severity is defined as the greater 
of the onset severity and maximum severity 
following onset recorded on the eCRF. If 
the same TEAE term has been reported 
more than once for a subject with different 
severity grades, the worst severity grade 
will be used in the tabulation. 
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
Serious TEAEs 
Overall summary and by SOC and PT  
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
TEAEs leading to study 
discontinuation 
Overall summary and by SOC and PT  
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
Common TEAEs 
Summary by SOC and PT 
• 
Includes TEAEs occurring in ≥ 
5% of participants in either PK 
cohort or Non-PK cohort 
From treatment start 
date until Week 12 or 
early termination date, 
whichever comes first 
Categorical 
descriptives 
SOCs will be sorted alphabetically; PTs will be sorted by descending proportions in the total group. 
 
5.1.1.5.3 
Vital Signs 
Vital signs will be summarized in total for the Safety Population as follows: 
Table 5-14 
Vital Signs Summaries 
Endpoint 
Description 
Timing 
Methodology 
Descriptives 
Summary by parameter and analysis visit 
• 
Parameters specified in Table 6-7 
Screening (visit 1), 
Week 12/early exit  
CFB1 descriptives 
1 The measurement at the screening (visit 1) will be determined using the latest pre-dose measurement on or before 
day 1. 
 
5.1.1.5.4 
Local Dermal Tolerability  
The local tolerability examination of the face is to be performed by the investigator (or 
appropriately trained designee), who will assess dryness, scaling, and erythema, and the patient 
will assess stinging/burning. The assessor will examine the skin area where study drug is applied 
in comparison to the surrounding skin from day 1 to week 12. The same assessor will rate 
dryness, scaling, and erythema at each visit, where possible. Local tolerability signs and 
symptoms will be rated using a severity scoring of 0 (none), 1 (mild), 2 (moderate), or 3 (severe), 
as further defined in Table 6-8. 
Local dermal tolerability data will be summarized in total and by cohort (PK cohort and Non-PK 
cohort) for the Safety Population as follows:   
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Table 5-15 
Local Dermal Tolerability Summaries 
Endpoint 
Description 
Timing 
Methodology 
Descriptives1   
Summary by parameter and analysis visit 
• 
Parameters specified in Table 6-8. 
Pre-dose on baseline 
(day1), post-dose on 
baseline (day 1), 
Weeks 1, 2, 4, 8, 
and 12/early exit 
Categorical 
Descriptives 
1 All local dermal tolerability data will be listed. 
 
5.1.1.5.5 
Urine Pregnancy Test 
All patients with positive pregnancy test results will be listed. 
5.1.1.6 
Subgroup Analyses 
No subgroup analyses are planned for this study. 
5.1.1.7 
Interim Analyses 
No interim analyses are planned for this study. 
5.1.2 
Determination of Sample Size 
The sample size for the trial was determined empirically, and is consistent with that requested by 
the FDA in the post-marketing requirement for ACZONE 7.5%. 
5.2 
Changes in the Conduct of the Study or Planned Analyses 
5.2.1 
Changes in the Conduct of the Study 
Not applicable. 
5.2.2 
Changes to Analyses Prior to Database Lock 
Not applicable. 
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6. 
Data Handling and Analysis Conventions  
6.1 
Study Treatment Conventions 
6.1.1 
Analysis Days 
Treatment days are defined as follows: 
Table 6-1 
Analysis Day Definitions 
Term 
Description 
Treatment Day 
 
Relative to treatment start date 
If analysis date ≥ treatment start date: 
• 
Day = analysis date – treatment start date + 1 
o 
Day 1 = treatment start date 
If analysis date < treatment start date: 
• 
Day = analysis date – treatment start date 
o 
Day -1 = day before treatment start date 
o 
There is no Day 0 
 
6.2 
Analysis Visit Windows 
Unless otherwise specified, if there are multiple valid measurements within the same analysis 
window, the one closest to the target day of the visit will be used. If multiple valid scores are 
equidistant from the target day of the visit, the latter observation will be used to represent the 
analysis window.  All assessments will be included in respective listings. 
6.2.1 
Efficacy 
The analysis visit windows for efficacy endpoints are defined as follows: 
Table 6-2 
Efficacy Analysis Visit Definitions 
Analysis Phase 
Analysis Visit (Derived) 
Target/Study Visit (eCRF) 
Window 
Pretreatment 
Baseline 
Day 1/Visit 2 
Treatment Day ≤ 1, pre-dose 
Treatment 
Week 1 
Day 8/Visit 3 
Treatment Day [6, 11]  
 
Week 2 
Day 15/Visit 4 
Treatment Day [12, 21]  
 
Week 4 
Day 29/Visit 5 
Treatment Day [22, 42]  
 
Week 8 
Day 57/Visit 6 
Treatment Day [43, 70]  
 
Week 12 
Day 85/Visit 7 
Treatment Day [71, last dose + 14 
days]  
 
6.2.2 
Safety 
The analysis visit windows for safety endpoints are defined as follows (note that not all safety 
endpoints are collected at each visit): 
Table 6-3 
Safety Analysis Visit Definitions 
Analysis Phase 
Analysis Visit (Derived) 
Study Visit (eCRF) 
Window 
Pretreatment 
Baseline 
Day 1/Visit 2 
Treatment Day ≤ 1 
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Analysis Phase 
Analysis Visit (Derived) 
Study Visit (eCRF) 
Window 
Treatment 
Week 1 
Day 8/Visit 3 
Treatment Day [6, 11]  
 
Week 2 
Day 15/Visit 4 
Treatment Day [12, 21]  
 
Week 4 
Day 29/Visit 5 
Treatment Day [22, 42]  
 
Week 8 
Day 57/Visit 6 
Treatment Day [43, 70]  
 
Week 12 
Day 85/Visit 7 
Treatment Day [71, last dose + 14 
days]  
  Local dermal tolerability data will be collected both pre-dose and post-dose at day 1 (visit 2) 
 
6.3 
Missing/Incomplete Date Conventions 
Dates may be imputed with year, month, and day values under certain scenarios: 
Table 6-4 
Imputation Scenarios 
 
 
Complete
 
Scenario 
Year 
Month 
Day 
Imputable 
1 
Yes 
Yes 
Yes 
Complete 
2 
Yes 
Yes 
— 
Yes 
3 
Yes 
— 
Yes 
No1 
4 
Yes 
— 
— 
Yes 
5 
— 
Yes 
Yes 
No1 
6 
— 
Yes 
— 
No1 
7 
— 
— 
Yes 
No1 
8 
— 
— 
— 
Yes 
1 Not allowed per database design. 
 
Dates will be imputed initially toward a specified target date for imputable scenarios 2, 4, and 8, 
and adjusted against the latest reasonable dates. The initial imputed date is determined by the 
following algorithm: 
Table 6-5 
Initial Imputed Date Algorithm 
Available Year 
Available Month (MM) 
(YYYY) 
Missing 
< Target Month 
= Target Month 
> Target Month 
Missing 
Target Date 
 
— 
 
< Target Year 
YYYY-12-31 
 
YYYY-MM-LD 
 
= Target Year 
Target Date 
YYYY-MM-LD 
Target Date 
YYYY-MM-01 
> Target Year 
YYYY-01-01 
 
YYYY-MM-01 
 
YYYY = available start date year; MM = available start date month; LD = last day of the month. 
 
6.3.1 
Missing/Incomplete AE Start Date 
AE start dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment start date 
• Complete end date 
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6.3.2 
Missing/Incomplete Medication Start Date 
Medication start dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment start date – 1 
• Complete end date 
6.3.3 
Missing/Incomplete AE/Medication End Date 
AE and medication end dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment end date + 28 
• Death date 
6.4 
Safety Endpoint Conventions 
6.4.1 
Adverse Events 
6.4.1.1 
Missing Intensity or Relationship 
If the investigator is unable to provide the actual values, the following imputations will be 
applied: 
Table 6-6 
Missing AE Intensity and Relationship Imputation Algorithms 
Missing Value 
Imputation 
Timing 
Intensity 
Mild 
Screening Period, Pretreatment Period 
 
Severe 
Treatment Period 
Relationship 
— 
Screening Period, Pretreatment Period 
 
Related 
Treatment Period 
 
6.4.2 
Vital Signs 
6.4.2.1 
Continuous Descriptives Parameters 
The following vital sign parameters will be summarized: 
Table 6-7 
Vital Sign Descriptive Parameters 
Parameters
Systolic blood pressure (mmHg) 
Diastolic blood pressure (mmHg) 
Heart rate (bpm) 
Respiratory Rate (bpm) 
Body temperature (°C) 
Weight (kg) 
Height (cm) 
 
 
 
6.4.3 
Local Dermal Tolerability  
The following local dermal tolerability parameters will be summarized: 
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Table 6-8 
Local Dermal Tolerability Parameters 
 
 
Parameter 
Grade 
Stinging/burning 
Prickling pain sensation immediately after (within 5 minutes of dosing, except baseline; 
patient-rated): 
• 
None (0) = No stinging/burning 
• 
Mild (1) = Slight warm, tingling/stinging sensation; not really bothersome 
• 
Moderate (2) = Definite warm, tingling/stinging sensation that is somewhat 
bothersome  
• 
Severe (3) = Hot, tingling/stinging sensation that has caused definite discomfort 
Dryness 
Brittle and/or tight sensation (investigator- or designee rated): 
• 
None (0) = No dryness 
• 
Mild (1) = Slight but definite roughness 
• 
Moderate (2) = Moderate roughness 
• 
Severe (3) = Marked roughness 
Scaling 
Abnormal shedding of the stratum corneum (investigator- or designee rated): 
• 
None (0) = No scaling 
• 
Mild (1) = Barely perceptible shedding, noticeable only on light scratching or rubbing 
• 
Moderate (2) = Obvious but not profuse shedding 
• 
Severe (3) = Heavy scale production 
Erythema 
Abnormal redness of the skin (investigator- or designee rated): 
• 
None (0) = No erythema 
• 
Mild (1) = Slight pinkness present 
• 
Moderate (2) = Definite redness, easily recognized 
• 
Severe (3) = Intense redness 
 
6.5 
Imputed Value Listing Conventions 
Missing data will not be imputed and listings will present the actual partial or missing values as 
they appear on the eCRFs. 
7. 
References 
No references are cited in this document.  
8. 
Amendment(s) 
The following changes have been made and comprise Amendment 1 of this document: 
Changes:  
• 
Section 5.1.1.1.1: The PK analysis population has been removed as this will be defined and discussed in a 
separate PK analysis plan.  
• 
Section 6.4.2.1: Weight (kg) and height (cm) have been added as vital signs parameters to be analyzed.  As 
this is a pediatric study, it is important to review these parameters and any changes from baseline to Week 
12. 
• 
Throughout the document, undefined link errors have been corrected. 
13SEP2018 CSR 1679-401-006
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1 
Table of Contents 
1 
Table of Contents ........................................................................................ 2 
2 
List of Abbreviations................................................................................... 3 
3 
Introduction ................................................................................................. 4 
4 
Objectives ................................................................................................... 4 
5 
Methods....................................................................................................... 4 
5.1 
Study Design ............................................................................................... 4 
5.2 
Analysis Populations ................................................................................... 7 
5.3 
Sample Size Considerations ........................................................................ 7 
5.4 
Software ...................................................................................................... 7 
5.5 
Methodology of Measurements .................................................................. 7 
5.5.1 
Pharmacokinetic Methodology ................................................................... 7 
5.6 
Data Handling and Storage ......................................................................... 8 
6 
Data Analysis .............................................................................................. 9 
6.1 
Pharmacokinetics ........................................................................................ 9 
7 
Statistical Analysis ...................................................................................... 9 
7.1 
Statistical Summarization ........................................................................... 9 
8 
Presentation of Final Results ...................................................................... 9 
9 
References ................................................................................................... 9 
 
13SEP2018 CSR 1679-401-006
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3 
 
2 List of Abbreviations 
ADaM 
Analysis Data Model 
BLQ 
Below Limit of Quantitation 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DAP 
Data Analysis Plan 
 
DHA 
Dapsone Hydroxylamine  
NAD 
N-acetyl Dapsone 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SDTM 
Study Data Tabulation Model 
sFTP 
secure File Transfer Protocol 
 
 
13SEP2018 CSR 1679-401-006
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4 
 
3 Introduction 
The data analyses outlined in this document are to support clinical study 1679-401-006.    
In this study, measurements will be made for plasma concentrations of dapsone, N-acetyl 
dapsone (NAD), and dapsone hydroxylamine (DHA).  This data analysis plan (DAP) outlines 
how data analysis of these measurements will be conducted.  Additional analyses may be 
conducted if necessary. 
4 
Objectives 
The objectives of this study are: 
• To evaluate the safety and tolerability of ACZONE 7.5% administered topically once-
daily for 12 weeks in 9 to 11 year-olds with acne vulgaris. 
• To evaluate the peak and trough plasma drug concentrations in 9 to 11 year-olds with 
acne vulgaris following once-daily dosing of ACZONE 7.5% under maximal use 
conditions for the first 8 days (+ 2 days). 
• To explore the efficacy of ACZONE 7.5% administered topically once-daily in 9 to 
11 year-olds with acne vulgaris. 
 
5 
Methods 
5.1 
Study Design 
This study is a multicenter, open label, non-comparative, 12-week trial to evaluate the safety, 
tolerability, pharmacokinetics, and efficacy of ACZONE 7.5% in 9 to 11 year-old patients 
with mild, moderate, or severe acne vulgaris. 
Patient participation is up to approximately 16 weeks. Patients will attend up to the following 
7 visits: Screening, Baseline/Day 1 (Screening and Baseline/Day 1 may be combined if no 
washout is needed), and Weeks 1, 2, 4, 8, and 12/early exit. The total treatment duration of 
trial participation for each patient is up to 12 weeks. Safety measures include adverse events, 
physical examination, and vital signs. Efficacy measures include the Investigator’s Global 
Assessment (IGA) and lesion counts in the face. 
The 2 cohorts will enroll concurrently; the PK cohort and the non-PK Cohort. 
13SEP2018 CSR 1679-401-006
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5 
 
The PK Cohort will include at least 16 evaluable PK patients. Evaluable PK patients are 
defined as those that are administered at least 8 applications of study drug under maximal use 
conditions, and have provided evaluable PK samples for analysis without any major protocol 
deviations. For the first 8 days, study drug will be administered once-daily under maximal 
use condition (~2 grams/day) to the entire face, neck, upper chest, upper back and shoulders 
as instructed by the study site. The study drug should be rubbed in gently and completely. On 
Day 1, the study drug will be administered on-site. From Day 2 through Day 7, the study 
drug will be administered in the morning at home by the patient’s legally authorized 
representative. At the Week 1/Visit 3 [Day 8 (+2 days)], the study drug will be administered 
on-site in the morning. Also at the Week 1/Visit 3 visit, blood samples will be collected at 2 
timepoints 1) prior to dosing, and 2) approximately 10 hours post dose (± 3 hours). This 
collection scheme is designed to minimize the number of blood draws in this challenging 
patient population while still being able to determine the peak and trough plasma 
concentrations of dapsone, NAD, DHA, and other metabolites or analytes (if warranted) for 
steady-state pharmacokinetic assessment. This limited blood collection scheme is appropriate 
as the systemic drug concentrations of dapsone at steady state were reached after 7 days and 
appeared to be relatively constant in male and female acne patients 11 years of age or older 
following once daily topical administration of Dapsone 7.5% Gel under maximal use 
conditions for 28 days (Study 225678-004). Similarly, steady-state systemic concentrations 
of dapsone metabolites were also relatively constant. 
After the Week 1/Visit 3, patients or the patient’s legally authorized representative will apply 
a pea-sized amount of study drug in a thin layer to the patient’s face, once-daily, at home for 
the remaining 11 weeks, the same as the dose regimen for the Non-PK Cohort. Acne-affected 
areas on the upper chest, upper back, and shoulders should also be treated with a thin layer 
during the final 11 weeks.  
For the Non-PK Cohort (approximately 84 patients), patients or the patient’s legally 
authorized representative will apply a pea-sized amount of study drug in a thin layer to the 
patient’s face once-daily at home for 12 weeks as instructed by the study site. Acne-affected 
areas on the upper chest, upper back, and shoulders should also be treated with a thin layer. 
13SEP2018 CSR 1679-401-006
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6 
 
Study Period 
Screening
a 
Baseline/Day
 1a 
Week 1 
Week 2 
Weeks 4 
and 8 
Week 12/ 
Early Exit 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 and 
Visit 6 
Visit 7 
Visit Windows  
Day -30 to 
Day -1  
N/A 
Day 8 (+ 2 
days) 
Day 15 (± 3 
days) 
Day 29 (± 7 
days) and 
Day 57 (± 7 
days) 
Day 85 (± 7 
days) 
Informed consent/authorization and minor 
assentb 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Skin phototype assessment 
X 
 
 
 
 
 
Physical examination includes vital signs, 
height and weightc 
X 
 
 
 
 
X 
Pregnancy test (urine)d 
X 
X 
 
 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
Lesion count 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
PK Cohort: Dispense study drug, training on 
application/returne 
 
D 
R/D 
 
R/D 
R 
Non-PK Cohort: Dispense study drug, 
training on application/returnf 
 
D 
 
 
R/D 
R 
Standardized photographsg 
 
X 
 
 
 
X 
Local tolerabilityh 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Concomitant procedures 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
PK samplingi 
 
 
X 
 
 
 
D = dispense; IGA = Investigator’s Global Assessment; N/A = not applicable; R = return; PK= pharmacokinetic 
a 
If a washout period is not required, then screening and baseline visits can occur on the same day, and the procedures required to be 
repeated at both visits should be performed once. 
b 
Consent for photography is included in the informed consent process at select centers. 
c 
Physical examination and vital signs are to be performed if inclusion/exclusion criteria are met at screening; not required for screen 
failures.  Vital signs include heart rate, blood pressure, respiratory rate, and body temperature. 
d 
Female patients only.  The urine pregnancy test can also be performed at any timepoint during the course of the trial at the investigator’s 
discretion. If a patient misses a menstrual cycle, a urine pregnancy test must be performed. 
e 
Patients in the PK cohort will be dispensed 1 kit with 14 tubes on Baseline/Day 1 (Visit 2). All patients in the PK cohort will start dosing 
on Day 1 using the 2.0 gram tubes dispensed for individual application.PK Cohort patients will return used study drug at Week 1/Visit 3. 
At Week 1/Visit 3, Week 4 (Visit 5) and Week 8 (Visit 6) the patients in the PK Cohort are dispensed 60-gram pumps. Dispensed and 
returned study drug will be weighed at the study center. 
f 
All patients will start dosing on day 1. The patients in the Non-PK Cohort are dispensed 60-gram pumps on Baseline/Day 1 (Visit 2), 
Week 4 (Visit 5) and Week 8 (Visit 6).  Dispensed and returned study drug will be weighed at the study center.   
g 
At select centers, patients may have photographs taken of their face for illustration or presentation purposes. Patients who consent to 
being photographed will be required to remove any make-up at least 20 minutes prior to having photographs taken. 
h 
Local tolerability will be assessed prior to drug administration on day 1, as well as postdose on the face only. 
i 
Only applies to patients in the PK Cohort at the Week 1/Visit 3. Blood samples will be collected within 30 minutes prior to dosing in 
clinic in the morning and at approximately 10 hours post dose (± 3 hour) (patients are allowed to leave and come back if needed) under 
maximal use conditions to determine the peak and trough plasma drug concentrations. 
 
13SEP2018 CSR 1679-401-006
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7 
 
5.2 
Analysis Populations 
The following 3 analysis populations will be utilized: 
1. The safety population includes all patients who are treated with at least one 
application of study drug. 
2. The modified intent-to-treat (mITT) population includes all enrolled patients who 
have a baseline assessment and at least one post-baseline assessment. 
3. The PK population will be defined as all patients who received applications of study 
drug for at least 8 days under maximal use conditions and have evaluable blood 
samples for PK analysis.  
Safety analyses will be based on the safety population. Efficacy analyses will be based on the 
mITT population. PK analyses will be based on the PK population. 
5.3 
Sample Size Considerations 
The FDA approval of ACZONE 7.5% included a post-marketing requirement (PMR 3017-1) 
to assess the product in patients 9 to 11 years of age, including pharmacokinetic (PK) 
evaluation in a subset of patients. The sample size for the trial was determined empirically, 
and is consistent with that requested by the FDA in the postmarketing requirement for 
ACZONE 7.5% (FDA Letter, 2016).  
5.4 
Software 
Descriptive statistics of plasma concentrations will be calculated with the software program 
Phoenix® WinNonlin® (version 6.3 or newer)  
5.5 
Methodology of Measurements 
5.5.1 
Pharmacokinetic Methodology 
For patients in the PK Cohort who will be dosed under maximal use conditions for the first 8 
days, blood samples will be collected within 30 minutes prior to dosing (in the clinic in the 
morning) and at approximately 10 hours post dose (± 3 hours) at the Week 1/Visit 3 [Day 8 
(+ 2 days)] to determine the peak and trough plasma concentrations of dapsone, NAD, DHA, 
and other metabolites or analytes (if warranted). Blood will be collected in 2 mL prechilled 
K3EDTA tubes, chilled for 20-30 minutes in an ice water bath and centrifuged within 30 
13SEP2018 CSR 1679-401-006
32


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• All postdose time points for which no sample is collected will be treated as missing. 
No value will be imputed for these missing values. 
• Concentration data below the lower limit of quantitation (BLQ) will be defaulted to 
0.00. 
 
6 Data Analysis 
6.1 
Pharmacokinetics 
No PK parameters will be calculated in the PK analysis of this study.  
 
7 Statistical Analysis 
7.1 
Statistical Summarization 
No formal inferential statistics will be performed with the PK data.  Descriptive statistics 
(arithmetic mean, standard deviation, relative standard deviation, maximum, median, 
minimum) will be reported for peak and trough plasma concentrations of dapsone, NAD, 
DHA, and other metabolites or analytes (if warranted). 
If warranted, graphical methods may be used to examine the relationships between systemic 
drug concentrations and the changes in lesion counts and safety parameters.  Also, as 
appropriate, additional pharmacokinetic analysis by gender may be included in the final 
report. 
8 Presentation of Final Results 
All summarization will be done using Phoenix® WinNonlin® (version 6.3 or newer). 
Tabulations may be exported into Word 2010 (or newer) for formatting or exported to pdf.  
9 References 
FDA Letter 2016:  
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/207154Orig1s000ltr.pdf. 
 
13SEP2018 CSR 1679-401-006
34


ALLERGAN
 
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