CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`FIGURE 5. Summary of IGA Success Rate for Subjects
`with >20 Inflammatory Lesions at Baseline
`
`i
`
`+
`
`Source: Appendix A. 3.7.
`
`The percentage of subjects with _>20 lesions who had treatment success at Week 12 was
`highest in the Aczone + MetroGel group (39.5%) and lowest in the VC group (21.2%).
`Success rates were better in the Aczone 2x/day group (32.3%) than either the Aczone lx/day
`group (24.1%) or the VC (21.2%), equivalent to an 11.1% difference favoring Aczone 2x/day
`treatment. Comparing the Aczone + MetroGel group to the MetroGel alone group, there was
`a higher success rate for the combination treatment (39.5% compared to 29.7%).
`
`8.1.3.3 Erythema Assessment
`
`Erythema assessment scores for the subgroups of subj ects with _>20 lesions and subj ects with
`<20 lesions are summarized in Appendix A.3.9 and Appendix A.3.12, respectively. Table 20
`presents erythema scores for the subjects with _>20 lesions.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`TABLE 20. Summary of Erythema Assessment for Subjects with >20 Lesions
`
`Aczone +
`Vehicle Control Aczone 2x/day Aczone h/day MetroGel lx/day MetroGel lx/day
`(N=33)
`(N=31)
`(N=29)
`(N=37)
`(N=38)
`
`0
`6
`20
`7
`
`3
`13
`12
`5
`
`(18.2%)
`(60.6%)
`(21.2%)
`
`(9.1%)
`(39.4%)
`(36.4%)
`(15.2%)
`
`0
`4
`18
`9
`
`1
`13
`15
`2
`
`(12.9%)
`(58.1%)
`(29.0%)
`
`(3.2%)
`(41.9%)
`(48.4%)
`(6.5%)
`
`0
`0
`24
`5
`
`1
`10
`14
`4
`
`(82.8%)
`(17.2%)
`
`(3.4%)
`(34.5%)
`(48.3%)
`(13.8%)
`
`0
`4 (10.8%)
`25
`(67.6%)
`8
`(21.6%)
`
`3
`19
`10
`5
`
`(8.1%)
`(51.4%)
`(27.0%)
`(13.5%)
`
`0
`4
`26
`8
`
`3
`12
`20
`3
`
`(10.5%)
`(68.4%)
`(21.1%)
`
`(7.9%)
`(31.6%)
`(52.6%)
`(7.9%)
`
`Visit
`
`Baseline Absent
`Mild
`Moderate
`Severe
`
`Week 12 Absent
`Mild
`Moderate
`Severe
`
`Source: Appendix A.3.9.
`
`For the subgroup of subjects with >20 lesions at baseline, the distribution of erythema scores
`tended to shift towards improvement as the study progressed in all treatment groups. By
`Week 12, approximately half of the subjects in each group had improved to a score of absent
`(3.2% to 9.1%) or mild (31.6% to 51.4%) from mostly moderate at baseline (58.1% to
`82.8%). There were no consistent differences between the treatment groups.
`
`8.1.3.4 Telangiectasia Assessment
`
`Telangiectasia assessment scores for the subgroups of subjects with >20 lesions and subjects
`with <20 lesions at baseline are summarized in Appendix A.3.9 and A.3.12, respectively.
`Table 21 presents telangiectasia assessment scores for subj ects with >20 lesions.
`
`TABLE 21. Summary of Telangiectasia Assessment for Subjects with >20 Lesions
`
`Visit
`
`Baseline Absent
`Mild
`Moderate
`Severe
`
`Week 12 Absent
`Mild
`Moderate
`Severe
`
`Vehicle Control Aczone 2x/day Aczone h/day
`(N=33)
`(N=31)
`(N=29)
`
`3
`7
`21
`2
`
`3
`14
`14
`2
`
`(9.1%)
`(21.2%)
`(63.6%)
`(6.1%)
`
`(9.1%)
`(42.4%)
`(42.4%)
`(6.1%)
`
`1
`16
`8
`6
`
`4
`15
`10
`2
`
`(3.2%)
`(51.6%)
`(25.8%)
`(19.4%)
`
`(12.9%)
`(48.4%)
`(32.3%)
`(6.5%)
`
`3
`8
`14
`4
`
`5
`9
`12
`3
`
`(10.3%)
`(27.6%)
`(48.3%)
`(13.8%)
`
`(17.2%)
`(31.0%)
`(41.4%)
`(10.3%)
`
`Source: Appendix A.3.9.
`
`MetroGel
`h/day
`(N=37)
`
`Aczone +
`MetroGel lx/day
`(N=38)
`
`6
`9
`19
`3
`
`9
`12
`13
`3
`
`(16.2%)
`(24.3%)
`(51.4%)
`(8.1%)
`
`(24.3%)
`(32.4%)
`(35.1%)
`(8.1%)
`
`3
`7
`20
`8
`
`7
`12
`14
`5
`
`(7.9%)
`(18.4%)
`(52.6%)
`(21.1%)
`
`(18.4%)
`(31.6%)
`(36.8%)
`(13.2%)
`
`At baseline, the telangiectasia score was predominantly mild in subjects with >20 lesions in
`the Aczone 2x/day group (51.6%) and moderate (48.3% to 63.6%) for other treatments. This
`pattern was still evident at Week 12; however the percentages of subjects with moderate or
`severe telangiectasia generally decreased while the percentages of subjects with mild or
`absent generally increased.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`8.2 Discussion of Efficacy Results
`
`This study was designed to investigate the preliminary efficacy of Aczone in treating subj ects
`with papulopustular rosacea. Two Aczone dosage regimens (lx/day and 2x/day) were
`included in the study order to determine the better dosing regimen to use in any potential
`future studies. The study was controlled with the Aczone vehicle applied 2x/day (VC) in
`order to determine the potential efficacy of Aczone compared to its vehicle. An active control
`arm (MetroGel) was also included to determine the relative efficacy of Aczone against an
`approved treatment. No statistical comparisons were planned and the study was not powered
`to detect statistical differences.
`
`ITT Analysis (All Subj ects)
`
`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). A review of
`historical results for other approved therapies shows that the mean changes from baseline in
`lesion count for the Aczone 2x/day group was close to that of other approved products for
`rosacea, including Finacea® (azelaic acid) Gel, 15%, Oracea® (doxycycline) 40 mg
`capsules, and the active comparator in this study, MetroGel® (metronidazole), 1.0%. The
`changes from baseline in inflammatory lesion counts for Finacea were reported as -10.7 and
`-8.9 (differences of 3.6 and 2.5 lesions in favor of active treatment over vehicle) [14]. For
`Oracea, the changes from baseline in lesion counts were -11.8 and -9.5 (differences of 5.9
`and 5.2 lesions in favor of active treatment over vehicle) [15]. Historically, subjects treated
`with the 1% strength of MetroGel once-daily demonstrated a reduction in lesion count from
`baseline of-9.4 lesions, with a difference of 5.6 lesions over vehicle [13]. The historical
`response for MetroGel was less than the response observed in this study (-11.3 lesion
`decrease from baseline), which is most likely due to differences in study conditions and the
`fewer numbers of subjects enrolled in this phase 2 study. In the ITT analysis, 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 lx/day (24.1%), but there was no
`difference from VC (27.5%). The success rate for the combination treatment of Aczone +
`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 the 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 proven to have an effect on either of
`these signs ofrosacea, so this finding is not surprising.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`Subgroup Analysis: Subjects With >20 Lesions At Baseline
`
`In contrast to the ITT population, when the subgroup of subjects with >20 lesions at baseline
`was analyzed, the efficacy results do show a separation between Aczone 2x/day and VC. The
`size of this subgroup was relatively large (42% of the ITT population). The cut-off of
`20 lesions was chosen as the number closely approximated the baseline mean lesion count in
`subjects who entered the study with a baseline IGA in the moderate or severe categories. The
`mean change from baseline in lesion counts for the subgroup with >20 lesions was -15.5 for
`Aczone subjects treated 2x/day, -9.3 for Aczone subjects treated lx/day, and -11.6 for
`VC-treated subjects. This represents a difference over VC of 3.9 lesions in favor of Aczone
`2x/day, similar to the differences between active and vehicle for other approved treatments
`(as described above). There was also an 11.1% difference in favor of Aczone 2x/day
`treatment over VC in success rate (32.3% compared with 21.2%). Consistent with the ITT
`analysis, the success rate for Aczone lx/day (24.1%) was less than the success rate for
`Aczone 2x/day and the success rate for the group of subjects treated with the combination of
`Aczone + MetroGel was higher than for subjects treated with MetroGel alone (39.5%
`compared with 29.7%).
`
`Possible explanations for the divergence of the response to Aczone treatment between the
`ITT group, which included subjects with at least 10 lesions at baseline, and the subgroup of
`subjects with >20 lesions at baseline include the cyclic nature of this disease, in which
`subjects may improve spontaneously without treatment. It may be more difficult to
`distinguish between cyclic changes and treatment effects in subjects with few lesions.
`Patients with milder disease may also be more likely to reach the success category in the IGA
`with these cyclic improvements. In addition, the vehicle also appeared to provide a modest
`treatment benefit, thereby making clinical improvements due to active Aczone treatment less
`apparent in subj ects with milder disease.
`
`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 lx/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 subj ects with
`more moderate disease (i.e., >20 inflammatory lesions at baseline). In all analyses, subjects
`treated with Aczone 2x/day demonstrated better responses than subj ects treated with Aczone
`lx/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.
`
`9 SAFETY RESULTS AND DISCUSSION
`
`Safety analyses were performed on the safety data set, which included 393 subjects who were
`confirmed to have applied study treatment or reported at least 1 AE. Where the study
`treatment regimen actually used differed from the treatment regimen assigned at
`randomization, subjects were analyzed for safety according to the treatment regimen they
`actually used.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`9.1 Extent of Exposure
`
`9.1.1 Exposure to Trial Treatment(s)
`
`9.1.1.1 Study Treatment Usage
`
`Study treatment usage for the safety population is summarized in Appendix A.4.1 and
`Table 9 in Section 6.2. A listing of treatment usage by subject is provided in Appendix E.4.5.
`Missed applications are listed in Appendix E.4.2.
`
`Several subjects in the study missed at least 1 application of study treatment, but in general,
`the missed applications were not continuous over lengthy periods during the 84-day study
`period. The measured tube weights and calculated parameters for usage of study treatment
`are consistent with the usage expected based on the application instructions that were
`provided to subjects (i.e., apply a thin layer of treatment to the face).
`
`9.1.1.2 Plasma Dapsone and Metabolite Concentrations
`
`The amounts of dapsone and metabolites in plasma were measured at baseline, Week 2,
`Week 4, and Week 12. Plasma concentrations of dapsone, N-acetyl dapsone, and
`N-hydroxylamine dapsone are summarized in Appendix A.4.2 and Table 22, and listed by
`subj ect in Appendix E.4.3.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`TABLE 22. Plasma Dapsone and Metabolite Concentrations
`
`Visit
`
`Vehicle Control
`(N=79)
`
`Aczone 2x/day
`(N=83)
`
`Aczone lx/day MetroGel lx/day
`(N=81)
`(N=77)
`
`Aczone + MetroGel
`lx/day
`(N=73)
`
`Week 2
`
`Week 4
`
`Dapsone (ng/mL)
`Baseline n 76 82 80 76 73
`Mean
`0.000
`0.000
`0.032
`0.000
`0.000
`SD
`0.000
`0.000
`0.282
`0.000
`0.000
`n
`76
`81
`77
`74
`70
`Mean
`0.005
`10.555
`7.006
`0.000
`6.078
`SD
`0.045
`12.008
`6.962
`0.000
`5.822
`n
`73
`81
`75
`71
`71
`Mean
`0.073
`9.377
`7.348
`0.000
`6.193
`SD
`0.625
`10.714
`7.841
`0.000
`5.537
`n
`75
`76
`73
`72
`69
`Mean
`0.000
`6.732
`5.548
`0.000
`4.508
`SD
`0.000
`6.997
`6.191
`0.000
`4.016
`
`Week 12
`
`Week 2
`
`Week 4
`
`N-Aeetyl Dapsone (ng/mL)
`Baseline n 76 82 80 76 73
`Mean
`0.000
`0.000
`0.000
`0.000
`0.000
`SD
`0.000
`0.000
`0.000
`0.000
`0.000
`n
`76
`79
`75
`74
`70
`Mean
`0.000
`4.943
`3.112
`0.000
`2.891
`SD
`0.000
`5.548
`3.241
`0.000
`2.764
`n
`72
`79
`72
`72
`71
`Mean
`0.000
`4.260
`3.005
`0.000
`2.909
`SD
`0.000
`5.099
`3.402
`0.000
`2.751
`n
`75
`75
`73
`72
`69
`Mean
`0.000
`3.371
`3.110
`0.000
`2.002
`SD
`0.000
`4.630
`6.072
`0.000
`2.037
`
`Week 12
`
`N-Hydroxylamine Dapsone (ng/mL)
`Baseline n 76 81 78 74 72
`Mean
`0.000
`0.000
`0.000
`0.000
`0.000
`SD
`0.000
`0.000
`0.000
`0.000
`0.000
`n
`74
`79
`76
`74
`70
`Mean
`0.000
`0.622
`0.341
`0.000
`0.344
`SD
`0.000
`0.899
`0.439
`0.000
`0.482
`
`Week 2
`
`Week 4
`
`Week 12
`
`n
`Mean
`SD
`n
`Mean
`SD
`
`Source: Appendix A.4.2.
`
`72
`0.000
`0.000
`75
`0.000
`0.000
`
`81
`0.541
`0.661
`76
`0.288
`0.421
`
`74
`0.329
`0.484
`73
`0.202
`0.348
`
`71
`0.000
`0.000
`72
`0.000
`0.000
`
`70
`0.311
`0.469
`69
`0.156
`0.266
`
`Mean plasma concentrations of dapsone and metabolites were low in study treatment groups
`using Aczone at all time points measured in the study. The highest mean plasma
`concentrations were observed at Week 2, where subjects had a mean dapsone concentration
`of 10.6 ng/mL, 7.0 ng/mL, and 6.1 ng/mL in the Aczone 2x/day group, Aczone lx/day group,
`and Aczone + MetroGel group, respectively. The maximum plasma concentration of dapsone
`observed in any subject was 87.43 ng/mL, at Week 2 in Subject 035160 (Aczone 2x/day
`group). Plasma concentrations of N-acetyl dapsone were also highest at Week 2 (means of
`4.9, 3.1, and 2.9 ng/mL in the Aczone 2x/day, Aczone lx/day, and combination groups
`respectively). Plasma concentrations of the hydroxylamine metabolite, which is believed to
`
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`
`

`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`be the primary factor associated with dapsone hematological toxicities, were much lower
`than the parent (mean values <1 ng/mL in all Aczone-treated groups, maximum in any
`subject using Aczone 2x/day was 6.7 ng/m; Subject 035160).
`
`In subjects treated with the combination of Aczone and MetroGel, plasma levels of dapsone
`and metabolites were similar to or lower than subjects treated with the same amount of
`Aczone only (ix/day), suggesting that there are no pharmacokinetic interactions between
`these 2 drugs.
`
`Dapsone was found to be present in 1 sample apparently from a vehicle subject, but an
`examination of the data identified a probable switch in labeling of the Week 4 samples at the
`study center for Subjects 099812 (VC) and 091410 (Aczone 2x/day), as these samples were
`taken at the same study center, on the same day, within 30 minutes of each other.
`
`9.1.2 Exposure to Concomitant Treatment
`
`Concomitant medications are summarized by treatment group in Appendix A.4.3 and listed
`by subject in Appendix E.5.1. A total of 78% of subjects used at least 1 concomitant
`medication during the study. The most common classes of medications were for the
`Alimentary Tract and Metabolism (36%) and the Cardiovascular System (31%). A small
`percentage of subj ects took a dermatologic concomitant medication (5%), which was slightly
`higher in the MetroGel group (9% compared with 3% to 6% for other groups).
`
`9.2 Overview of Adverse Events
`
`Appendix A.4.4 and Table 23 present an overview of safety in the study.
`
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`

`
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`
`
`

`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`The overall frequency of adverse events ranged from 68.8% in the MetroGel group to 75.9%
`in the Vehicle Control group. With respect to adverse events that were considered associated
`to study treatment, the frequency was also lowest in the MetroGel group (43%) and highest
`in the Vehicle Control group (62%). There was 1 serious adverse event during the study,
`which occurred in a subject treated with Aczone + MetroGel and was unrelated to study
`treatment (refer to Section 9.3.3 below). There were more subj ects in the Vehicle Control and
`Aczone 2x/day groups who temporarily or permanently discontinued treatment due to an
`adverse event (6.3% and 7.2%, respectively) compared with Aczone lx/day, MetroGel, or
`the Aczone + MetroGel groups (2.5%, 2.6%, and 5.5%). Adverse events that led to
`discontinuation from both treatment and the study are discussed in more detail in
`Section 9.3.2 below.
`
`9.2.1 Common Treatment-Emergent Adverse Events
`
`All treatment-emergent adverse events are summarized in Appendix A.4.5.1 and listed by
`subject in Appendix E.5.2. There were a total of 772 events in 285 subjects (72.5% of the
`total study subjects); however most of the events occurred in only 1 or 2 subjects. Table 24
`summarizes the most frequent adverse events that occurred in the study (>2% [4 subjects]).
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`TABLE 24. Summary of Common Treatment-Emergent Adverse Events (Occurring in >2% of Subjects)
`
`Vehicle Control
`(N=79)
`
`Aczone 2x/day
`(N=83)
`
`Aczone 1x/day
`(N=81)
`
`MetroGel 1x/day
`(N=77)
`
`Aczone + MetroGel
`1x/day
`(N=73)
`
`SYSTEM ORGAN CLASS
`Subjects Events Subjects Events Subjects Events Subjects Events Subjects Events
`:
`- Preferred Term n %
`n
`n %
`n
`n %
`n
`n %
`n
`n %
`n
`
`ANYEVENT
`
`60 (75.9%) 187
`
`61 (73.5%) 155
`
`59 (72.8%/ 181
`
`53 (68.8%) 124
`
`52 (71.2%/ 125
`
`GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:
`-AnyEvent
`91
`49 (62.0%) 117
`47 (56.6%)
`50 (61.7%/ 113
`-APPLICATION SITE
`27 (32.5%) 30
`29 (36.7%) 32
`29 (35.8%/ 34
`DRYNESS
`- APPLICATION SITE
`PAIN
`- APPLICATION SITE
`BURNING
`-APPLICATION SITE
`PRURITUS
`- APPLICATION SITE
`ERYTHEMA
`
`23(29.1%) 28
`
`14(16.9%)
`
`14
`
`19 (23.5%/ 20
`
`15 (19.0%) 21
`
`16 (19.3%)
`
`17
`
`22 (27.2%/ 23
`
`16 (20.3%) 19
`
`17 (20.5%)
`
`17
`
`18 (22.2%/ 20
`
`11 (13.9%) 15
`
`11 (13.3%)
`
`11
`
`12 (14.8%/ 12
`
`6 (7.8%)
`
`7 (9.1%)
`
`INFECTIONS AND INFESTATIONS:
`-AnyEvent
`18 (22.8%) 21
`-NASOPHARYNGITIS
`6
`6 (7.6%)
`- UPPER RESPIRATORY
`4
`4 (5.1%)
`TRACT INFECTION NOS
`-SINUSITIS NOS
`
`4 (5.1%)
`
`4
`
`14 (16.9%)
`3 (3.6%)
`4 (4.8%)
`
`17
`3
`4
`
`16 (19.8%/ 20
`7
`5 (6.2%/
`6
`6 (7.4%/
`
`18 (23.4%)
`7 (9.1%)
`5 (6.5%)
`
`5 (6.0%)
`
`6
`
`1 (1.2%/
`
`1
`
`0
`
`33 (42.9%) 68
`26 (33.8%) 29
`
`37 (50.7%/ 68
`24 (32.9%/ 27
`
`11 (14.3%)
`
`12
`
`6 (8.2%/
`
`10 (13.0%)
`
`11
`
`8 (11.0%/
`
`8
`
`9
`
`7
`
`7
`
`8
`
`19
`7
`5
`
`0
`
`6 (8.2%/
`
`11 (15.1%/
`
`11
`
`16 (21.9%/ 21
`5
`4 (5.5%/
`6
`5 (6.8%/
`
`4 (5.5%/
`
`5
`
`SKIN AND SUBCUTANEOUS TIS SUE DISORDERS:
`-AnyEvent 10 (12.7%) 10
`10 (12.0%)
`- TELANGIECTASIA
`9
`9 (11.4%)
`9 (10.8%)
`
`10
`9
`
`14 (17.3%)
`11 (13.6%)
`
`16
`12
`
`16 (20.8%)
`11 (14.3%)
`
`19
`11
`
`10 (13.7%)
`9 (12.3%)
`
`10
`9
`
`Source: Appendix: A.4.5.1, A.4.5.2.
`
`Application site adverse events were the most common type of adverse event reported during
`the study (General Disorders and Administration Site Conditions System Organ Class). The
`majority of application site adverse events that were reported are signs and symptoms of
`rosacea that were solicited and scored using a standardized grading system throughout the
`study (dryness, itching, burning, and stinging; refer to Section 9.6 below for a discussion of
`local symptom scores). An increase from baseline in the score for any sign or symptom was
`recorded as an adverse event. The most frequent application site adverse event was dryness,
`which occurred at a similar frequency among study treatment groups (32.5% to 36.7%) and
`was typically mild to moderate in intensity. Other frequent application site adverse events
`were pain (8.0% to 29.1%), burning (10.7% to 27.8%), pruritis (8.0% to 22.8%), and
`erythema (9.1% to 13.9%). The frequency of these application site adverse events was
`numerically lower in groups treated with MetroGel alone or MetroGel + Aczone compared
`with the vehicle control or Aczone-only treated groups. For all groups, the intensity of
`application site pain, burning, and pruritus was mostly mild while the intensity of application
`site erythema was mostly moderate to severe. The higher severity of application site
`erythema compared with other signs/symptoms of rosacea may be explained by the presence
`of erythema at baseline (which was mostly moderate) as part of the underlying rosacea
`characteristics whereas other local signs and symptoms were mostly absent or mild (refer to
`Appendix A.2.1.1).
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`Skin and Subcutaneous Disorders occurred at a frequency ranging from 12.0% to 20.8%. The
`frequency was higher in the MetroGel group (20.8%) compared with other groups (12.0% to
`17.7%). Telangectasia, reported as a worsening of baseline telangiectasia that was part of the
`subject’s underlying rosacea, was the only adverse event in this System Organ Class to occur
`with a frequency higher than 1% (10.8% to 14.3%). The incidence of telangiectasia was
`slightly higher in groups treated with MetroGel or MetroGel + Aczone than the vehicle or
`Aczone-only treated group.
`
`Adverse events that are related to the common cold or flu were the most frequent types of
`systemic adverse events, affecting System Organ Classes that are related to infections,
`musculoskeletal, and respiratory systems. Nasopharyngitis, upper respiratory tract infections,
`bronchitis, influenza, arthralgia, headaches, sinusitis, nasal congestion, pharyngitis, and
`cough each occurred in 1%-8% of subjects. There was no trend among treatment groups and
`this incidence is consistent with the timing of conducting this study through the winter
`months.
`
`9.2.2 All Associated Adverse Events
`
`Associated adverse events, defined as those judged to have a suspected relationship to the
`study treatment by the study Investigator, are summarized in Appendix A.4.5.3 and Table 25.
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`SYSTEM ORGAN CLASS:
`- Preferred Term
`
`TABLE 25. Summary of All Associated Adverse Events
`
`Aczone 2x/day
`Vehicle Control
`(N=83)
`(N=79)
`Subjects Events Subjects Events
`n %
`n
`n %
`n
`
`Aczone 1x/day
`(N=81)
`Subjects Events
`n %
`n
`
`Aczone +
`MetroGel 1x/day MetroGel 1x/day
`(N=77)
`(N=73)
`Subjects Events Subjects Events
`n %
`n
`n %
`n
`
`ANY ASSOCIATED EVENT
`
`49 (62.0%)123
`
`46 (55.4%) 92
`
`49(60.5%) 119
`
`33(42.9%) 71
`
`34(46.6%) 67
`
`BLOOD AND LYMPHATIC SYSTEM DISORDERS:
`- Any Event 1 (1.3%)
`- ANISOCYTOSIS
`1 (1.3%)
`
`1
`1
`
`EYE DIS ORDERS:
`- Any Event 0
`- CONJUNCTIVITIS
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`85
`29
`14
`16
`17
`8
`0
`1
`
`0
`0
`0
`
`0
`0
`
`0
`0
`
`47(58.0%)
`27(33.3%)
`19(23.5%)
`22(27.2%)
`17(21.0%)
`9(11.1%)
`1 (1.2%)
`1 (1.2%)
`
`G
`G
`G
`
`0
`0
`
`0
`0
`
`105
`32
`20
`23
`19
`9
`1
`1
`
`0
`0
`0
`
`0
`0
`
`1 (1.3%)
`1 (1.3%)
`
`31(40.3%)
`23(29.9%)
`1C(13.0%)
`9(11.7%)
`6 (7.8%)
`5 (6.5%)
`G
`0
`
`1 (1.3%)
`G
`G
`
`0
`0
`
`1
`1
`
`60
`26
`11
`10
`7
`5
`0
`0
`
`1
`0
`0
`
`G
`G
`
`G
`G
`
`34(46.6%)
`23(31.5%)
`6 (8.2%)
`8(11.0%)
`6 (8.2%)
`1G(13.7%)
`1 (1.4%)
`G
`
`G
`1 (1.4%)
`G
`
`G
`G
`
`0
`0
`
`0
`0
`
`62
`26
`8
`9
`7
`10
`1
`0
`
`0
`1
`0
`
`0
`0
`
`GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:
`- Any Event
`46(58.2%) 113
`45(54.2%)
`- APPLICATION SITE DRYNESS
`31
`28(35.4%)
`26(31.3%)
`- APPLICATION SITEPAIN
`28
`23(29.1%)
`14(16.9%)
`- APPLICATION SITE BURNING
`21
`15(19.0%)
`15(18.1%)
`- APPLICATION SITE PRURITUS
`19
`16(20.3%)
`17(20.5%)
`- APPLICATION SITE ERYTHEMA
`13
`9(11.4%)
`8 (9.6%)
`- APPLICATION SITE PAPULES
`0
`0
`0
`- APPLICATION SITE REACTION
`0
`0
`1 (1.2%)
`NOS
`- APPLICATION SITE RASH
`- NODULE
`- PAINNOS
`
`0
`0
`1 (1.3%)
`
`0
`0
`1
`
`0
`0
`0
`
`INJURY, POISONING AND PROCEDURAL COMPLICATIONS:
`- Any Event 1 (1.3%)
`1
`0
`- SUNBURN
`1
`0
`1 (1.3%)
`
`INVESTIGATIONS:
`- Any Event
`- BLOOD GLUCOSE INCREASED
`- HAEMATOCRIT DECREASED
`- HAEMOGLOBIN DECREASED
`- HAPTOGLOBIN INCREASED
`- WHITE BLOOD CELL COUNT
`DECREASED
`
`2 (2.5%)
`0
`0
`0
`1 (1.3%)
`1 (1.3%)
`
`NERVOUS SYSTEM DISORDERS:
`- Any Event 1 (1.3%)
`-DYSGEUSIA
`1 (1.3%)
`
`2
`0
`0
`0
`1
`1
`
`1
`1
`
`SKIN AND SUBCUTANEOUS TIS SUE DISORDERS:
`- Any Event
`5
`5 (6.3%)
`-TELANGIECTASIA
`5
`5 (6.3%)
`- ROSACEA
`0
`0
`- DRY SKIN
`0
`0
`- RASHNOS
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`1 (1.2%)
`1 (1.2%)
`
`6 (7.2%)
`6 (7.2%)
`0
`0
`0
`
`VASCULAR DISORDERS:
`- Any Event
`- HOT FLUSHES NOS
`
`Source: Appendix A.4.5.3.
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`1
`1
`
`6
`6
`0
`0
`0
`
`0
`0
`
`0
`0
`
`1(1.2%)
`1 (1.2%)
`1(1.2%)
`1 (1.2%)
`0
`0
`
`0
`0
`
`10(12.3%)
`8 (9.9%)
`2 (2.5%)
`0
`0
`
`0
`0
`
`0
`0
`
`3
`1
`1
`1
`0
`0
`
`0
`0
`
`11
`9
`2
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`
`8 (10.4%)
`7 (9.1%)
`0
`1 (1.3%)
`1 (1.3%)
`
`1 (1.3%)
`1 (1.3%)
`
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`
`9
`7
`0
`1
`1
`
`1
`1
`
`G
`G
`G
`G
`G
`G
`
`G
`G
`
`5 (6.8%)
`5 (6.8%)
`G
`G
`G
`
`G
`G
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`
`5
`5
`0
`0
`0
`
`0
`0
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`The frequency of any associated adverse event was highest in the Vehicle Control group
`(62%) and lowest in the MetroGel group (42.9%).
`
`Similar to the pattern for all adverse events, application site adverse events were the most
`frequent associated adverse event, including dryness (32.3%), pain (18.3%), burning
`(17.6%), pruritus (15.8%), and erythema (10.4%). The frequency of these adverse events was
`generally lowest in groups treated with MetroGel or MetroGel + Aczone compared with the
`Vehicle Control or Aczone only. Other types of events at the application site were rare
`(<1%), including application site reaction in the Aczone lx/day and 2x/day groups (reported
`as scaling), papules in the MetroGel group, and rash in the MetroGel + Aczone group.
`Application site reactions were mostly mild to moderate and transient.
`
`There was a low incidence of associated adverse events of rosacea (0.5%) and telangiectasia
`(7.9%), indicating that few subjects experienced treatment-related worsening of baseline
`disease. There appears to be no difference among the treatment groups in the frequency of
`these types of events.
`
`Dapsone, the active ingredient of Aczone, is known to be associated with hematological
`toxicities when taken orally. There were some associated adverse events related to the Blood
`and Lymphatic System and Investigations that indicate treatment-emergent changes in
`hematology parameters, however these occurred in only 1 subject each and were observed in
`subjects treated with Vehicle as well as Aczone or MetroGel. Furthermore, there were no
`clinical signs or symptoms reported as adverse events to correlate with these laboratory
`findings. This suggests that these hematology adverse events may be a chance finding. Please
`refer to Section 9.4 below for a more detailed discussion of the laboratory data.
`
`9.2.3 Special Safety Issues: Glucose-6-Phosphate Dehydrogenase Deficiency
`
`Subjects with G6PD-deficiency are known to be at higher risk of developing dapsone-related
`hematological toxicities following oral dapsone use. However, a topical mode of
`administration is not expected to result in systemic absorption of dapsone in sufficient
`amounts to result in any hematological toxicity, regardless of G6PD status. In this study,
`1 subject with G6PD-deficiency was enrolled and treated with Aczone (ix/day). Subject
`260080 was a 63 year old Caucasian woman with G6PD-deficiency (6.2 U/g Hgb). She used
`approximately 0.43 g of study treatment per application and did not report missing any
`applications throughout the study to completion at Week 12. When measured at Weeks 2, 4,
`and 12, her plasma dapsone levels were approximately 11 to 12 ng/mL and hydroxylamine
`levels <1 ng/mL. An examination of her laboratory data does not reveal any changes from
`baseline, except for slightly elevated non-fasting blood glucose at Week 4 and slightly low
`monocyte counts at Weeks 2 and 4 that were not deemed to be clinically significant. There
`were no changes in any hematological parameters. Furthermore, there were no adverse events
`reported indicative of systemic dapsone toxicity; only mild, transient application site adverse
`events were reported by this subject. Overall, there is no evidence to indicate that application
`of Aczone once daily to this G6PD-deficient subject resulted in any hematological toxicity.
`
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`

`CR 06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`9.3 Deaths, Withdrawals, and Serious or Clinically Significant Adverse Events
`
`9.3.1 Deaths
`
`No deaths occurred during the study.
`
`9.3.2 Withdrawal Due to Adverse Events
`
`Appendix E.5.4 list subjects who discontinued treatment because of adverse events. There
`are 6 subjects listed who only temporarily stopped the study treatment, generally due to a
`transient application site adverse event. This includes 3 subjects who belonged to the Vehicle
`Control group (065188, 083011, and 099812), 1 subject in the Aczone 2x/day group
`(200320), 1 subject in the Aczone 1x/day group (266191), and 1 subject in the Aczone +
`MetroGel group (067819). In each of these cases, subjects missed some or all applications of
`study treatment during the course of each adverse event, but all subjects began to re-apply the
`study treatment and did not permanently discontinue the study treatment or the study as a
`result of the adverse event. The adverse events generally resolved. There was 1 subject who
`experienced a systemic adverse event of muscle cramps (105308, Vehicle group) and she
`permanently stopped taking the study treatment as a result of this adverse event, but
`continued to be followed in the study. The study Investigator did not consider the muscle
`cramps to be related to the study treatment.
`
`Table 26 lists the subjects who permanently discontinued treatment and the study due to an
`adverse event (10 subjects [2.5%]).
`
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`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`TABLE 26. Subjects Who Permanently Discontinued Study Treatment and Study Follow-Up Due to
`Adverse Events
`
`Subject
`Number
`
`Agea/
`Sex
`
`Vehicle Control
`045915 56 / F
`
`Day of
`Study
`Discontin.
`
`Dayat Start Reported Term of Adverse
`of Event
`Event
`
`Intensity
`
`Association to
`Treatment
`
`Day 64
`
`Day 14
`Day 14
`
`Increased dryness (facial)
`Increased erythema
`
`Moderate
`Moderate
`
`Suspected
`Suspected
`
`Aczone 2x/Day
`080753 33 /