Name of Company:
`Allergan
`
`Name of Finished Product:
`AczoneTM Gel, 5%
`
`Name of Active Ingredient:
`Dapsone Gel, 5%
`
`Number and Title of Study:
`ACZ ROS 01: A Phase II, Randomized, Partial-Blind, Parallel-Group, Active- and Vehicle-Controlled,
`Multicenter Study of the Safety and Efficacy of AczoneTM (dapsone) Gel, 5% in Subjects with
`Papulopustular Rosacea
`
`Study Center(s): 27 US centers
`
`Publication (reference): None at the time of the clinical study report
`
`Studied Period:
`Date of First Enrollment: November 2005
`Date of Last Completed: May 2006
`
`Phase of Development: 2
`
`!Objectives:
`To evaluate the safety and preliminary efficacy of Aczone in subjects with papulopustular rosacea
`
`Methodology:
`Structure: This was a multicenter, randomized, partial-blind, parallel-group study in male and female adult
`subjects with papulopustular rosacea.
`
`Randomization: Subjects were assigned in a 1 : !: 1 : 1 : ! ratio to the five treatment groups.
`
`Visit Schedule: Visits were conducted at Screening/Day 0 (baseline), and Week 2, Week 4, Week 8,
`Week 12 or Early Termination, and Week 13.
`
`Number of Subjects (Planned and Analyzed):
`A total of 400 subjects were planned to be enrolled. Four hundred subjects were enrolled in the study;
`however, one subject was randomized in error and was not dispensed treatment. Therefore, data were only
`collected and analyzed on 399 subjects.
`
`Diagnosis and Main Criteria for Inclusion:
`Diagnosis: Subjects with papulopustular rosacea
`
`Key Inclusion Criteria: >18 years of age, diagnosis ofpapulopustular rosacea with >10 inflammatory lesions
`above the mandibular line at baseline, and an Investigator’s Global Assessment (IGA) score >2
`
`Key Exclusion Criteria: Presence of another skin disease and/or condition located on the face that would
`have confounded evaluation of the rosacea condition, current or past ocular rosacea of sufficient severity to
`require topical or systemic antibiotics, treatment with topical antibiotics, steroids, or other rosacea treatments
`on the face within 14 days of baseline, treatment with systemic corticosteroids within 30 days of baseline,
`treatment with systemic antibiotics within 30 days of baseline, treatment with systemic medication or
`therapy known to affect inflammatory responses within 30 days of baseline, treatment with topical retinoids
`within 30 days of baseline, treatment with systemic retinoids within 180 days of baseline, treatment with
`physical modalities within 30 days of baseline, facial surgery within 3 months of baseline, and any initiation
`or changes in hormonal therapy
`
`Test Product, Dose and Mode of Administration:
`Aczone (dapsone) Gel, 5% was applied once or twice daily depending on randomization assignment.
`
`AZC ROS 01 Web Results
`
`Page I of 4
`
`1 of 4
`
`Almirall EXHIBIT 2044
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`Name of Company:
`Allergan
`
`I Name of Finished Product:
`
`I AczoneTM Gel, 5%
`Duration of Treatment: 12 weeks
`
`I Name of Active Ingredient:
`I Dapsone Gel, 5%
`
`Reference Therapy, Dose and Mode of Administration:
`Vehicle control (VC) contained the inactive ingredients in the dapsone gel. VC was applied twice daily for
`subjects randomized to the VC treatment group.
`
`MetroGel® (metronidazole), 1% was applied once a day for subjects randomized to the MetroGel treatment
`group and Aczone + MetroGel treatment group.
`
`Criteria for Evaluation:
`Efficacy:
`Efficacy assessments included monitoring inflammatory lesion counts, IGA scores, erythema scores, and
`telangiectasia scores. Plasma dapsone concentrations were also measured to assess systemic exposure to
`study treatment.
`
`Safety:
`Safety was measured by monitoring adverse events, hematology and serum chemistry parameters,
`concomitant medications, vital signs, and local symptoms (dryness, itching, stinging, and burning).
`
`Statistical Methods:
`No statistical tests of any efficacy variable were planned. Only descriptive statistics and 95% confidence
`intervals were planned. The intent-to-treat (ITT) analysis was considered primary.
`
`The study had the following efficacy variables:
`
`¯ Change and percent change from baseline in inflammatory lesion counts.
`
`¯
`
`¯
`
`¯
`
`Lesion counts over time.
`
`"Success" rate, defined as the proportion of subjects with a score of 0 (clear) or 1 (almost clear) and
`at least a 2 point improvement from baseline on a 5-point IGA scale of disease severity.
`
`Erythema assessment scores.
`
`¯ Telangiectasia assessment scores.
`
`The change from baseline in inflammatory lesion counts, percent change from baseline in inflammatory
`lesion counts, and lesion counts over time were summarized
`
`The change from baseline in inflammatory lesion counts for each visit was calculated by subtracting the
`baseline inflammatory lesion count from the post-baseline study visit lesion counts for each subject.
`
`The percent change from baseline in inflammatory lesion counts was calculated by dividing the baseline
`inflammatory lesion count into the change from baseline in inflammatory lesion counts and then multiplying
`by 100 for each subject at each study visit.
`
`The IGA score, success rate from the IGA, erythema assessment scores, and telangiectasia assessment scores
`were summarized by frequencies and percents.
`
`An overall summary of the number and percentage of subjects who experienced any adverse event, death, a
`serious adverse event, or who withdrew from treatment was prepared by treatment group.
`
`The number and percentage of subjects with at least one event and the total number of events were tabulated
`by treatment group.
`
`Local symptom scores for each of dryness, itching, stinging, and burning were summarized by treatment
`group at each visit.
`
`AZC ROS 01 Web Results
`
`Page 2 of 4
`
`2 of 4
`
`

`

`Name of Company:
`Allergan
`
`Name of Finished Product:
`AczoneTM Gel, 5%
`
`I Name of Active Ingredient:
`I Dapsone Gel, 57/o
`
`Summary - Conclusions:
`Demographics and baseline characteristics were balanced across study treatment groups. The age of subjects
`ranged from 22 to 87 years, with a mean of 51 years. The majority of subjects were Caucasian (86%) and
`female (64%). There were 3 subjects with a glucose-6-phosphate dehydrogenase (D6PD) deficiency
`enrolled in the study; however, only 1 received active treatment (Aczone lx/day).
`
`Efficacy:
`In the ITT analysis, the mean change from baseline in lesion count at Week 12 for the Aczone 2x/day group
`(-8.0) was better than Aczone lx/day (-5.7), but there was no separation between Aczone 2x/day and VC
`(-8.3; also applied 2x/day). Treatment with the combination of MetroGel and Aczone was not different from
`treatment with MetroGel alone by Week 12 in terms of lesion count reduction.
`
`Success rates, defined in this study as a score of clear or almost clear with at least 2 points of improvement
`on a 5-point IGA, showed that more subjects treated with Aczone 2x/day had success (27.4%) than subjects
`treated with Aczone Ix/day (24.1%), but there was no difference from VC (27.5%). The success rate for the
`combination treatment ofAczone + MetroGel was higher than MetroGel alone (39.5% success rate
`compared with 32.5%), but since there was no difference in the reduction in lesion counts between these
`regimens, this result probably does not reflect a real additive effect of using these 2 treatments in
`combination.
`
`Erythema and telangiectasia were also evaluated, using a standardized 4-point grading system. Both
`erythema and telangiectasia were noted to improve, though not substantially, in all study treatment groups by
`Week 12. There were no differences apparent between treatment groups. No medical therapies have yet
`been proved to have an effect on either of these signs ofrosacea, so this fifiding is not surprising.
`
`In summary, subjects in all treatment groups experienced an improvement in the signs and symptoms of
`rosacea; however, there was no separation between Aczone 2x/day or Ix/day treatment and the VC group in
`the ITT population. However, there may have been an improved treatment effect with Aczone 2x/day
`treatment compared with VC in subjects with more moderate disease (i.e., _>20 inflammatory lesions at
`baseline). In all analyses, subjects treated with Aczone 2x/day demonstrated better responses than subjects
`treated with Aczone 1 x/day. These results suggest that any future studies of Aczone in this disease should
`include a twice-daily dosage regimen and a subject population with a higher number of baseline lesions.
`
`Safety:
`This study demonstrated that treatment with Aczone, either Ix/day or 2x/day, was safe and well tolerated in
`subjects with papulopustular rosacea. Most adverse events were at the application site, were mild, and
`transient. Systemic adverse events were infrequent and were generally indicative of the common cold or flu.
`There was 1 serious adverse event in the study (appendicitis), but it was not related to study treatment
`(Aczone + MetroGel) and does not indicate a safety concern for the use of Aczone in subjects with
`papulopustular rosacea.
`
`AZC ROS 01 Web Results
`
`Page 3 of 4
`
`3 of 4
`
`

`

`[ Name of Finished Product:
`
`I AczoneTM Gel, 5%
`
`I Name of Active Ingredient:
`I Dapsone Gel, 5%
`
`Name of Company:
`Ailergan
`
`Summary - Conclusions (continued):
`Safety (continued):
`As expected, the most frequent adverse events were application site events including dryness, pain, burning,
`pruritis, and erythema, which are also known signs and symptoms ofrosacea. Although the majority of
`application site adverse events were considered related to the study treatment by the study Investigators,
`rosacea is a cyclic disease and it is also possible that these events were related to flare-ups of the underlying
`condition. In general, the frequency of application site adverse events exhibited a dose-response
`relationship, being lowest in the Aczone 2x/day group and highest in the VC group. This finding suggests
`the possibility that active treatment with Aczone may have reduced the incidence of rosacea signs and
`symptoms compared with vehicle treatment. The frequency of application site adverse events was generally
`lowest in the MetroGel group, however the tolerability of both active treatments was considered reasonable
`and clinically acceptable. This is supported by the improvements of local symptom scores in all treatment
`groups over the course of the study. Most application site adverse events were mild and transient, and did
`not usually lead to discontinuation or interruption of treatment. The use of Aczone once-daily (AM) with
`MetroGel once-daily (PM) did not appear to result in any increase in the frequency of application site
`adverse events, nor was there any increase in the systemic exposure to dapsone, indicating that the use of
`these 2 products in combination is also safe and well-tolerated.
`
`Conclusion:
`Aczone appears safe and well-tolerated when used to treat subjects with papulopustular rosacea. Systemic
`levels of dapsone and its metabolites were low during the study with no evidence of increasing exposure
`over time. No subjects in the study demonstrated evidence of hemolysis or treatment related hematological
`adverse events. There was an overall improvement from baseline in local symptom scores with treatment.
`
`The results of this study support the following conclusions:
`
`¯
`
`¯
`
`¯
`
`Treatment with Aczone Ix/day or 2x/day was safe and well-tolerated in subjects with
`papulopustular rosacea.
`
`In the overall study population, Aczone was no better than the vehicle in reducing the signs and
`symptoms of papulopustular rosacea whether applied twice or once daily.
`
`The local tolerability and efficacy profile of Aczone used twice-daily was better than Aczone used
`once-daily. Both dosage regimes demonstrated low systemic exposure to dapsone and few systemic
`adverse events.
`
`AZC ROS 01 Web Results
`
`Page 4 of 4
`
`4 of 4
`
`