Protocol 0858A1 900-09November2011 -Finalart45-paediatric-studies-docs.ema.europa.eu/GROUP L... · 2014-06-11 · EMA Paediatric Web Synopsis Protocol 0858A1-900-09November2011 -Final

EMA Paediatric Web SynopsisProtocol 0858A1-900 - 09 November 2011 - Final

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PFIZER INC.

These results are supplied for informational purposes only.Prescribing decisions should be made based on the approved package insert.

For publications based on this study, see associated bibliography.

PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Alesse (Loette)®/Levonorgestrel/Ethinyl estradiol

PROTOCOL NO.: 0858A1-900 (B3121007)

PROTOCOL TITLE: Efficacy of Levonorgestrel 100 μg/Ethinyl Estradiol 20 μg for the Treatment of Moderate Acne

Study Centres: A total of 14 centres took part in the study, including 12 centres in the United States, and 1 centre each in Australia and in Canada.

Study Initiation Date and Primary Completion or Completion Dates:December 1997 to December 1999 (final completion date)

Phase of Development: Phase 3

Study Objective: To compare the efficacy and safety of levonorgestrel (LNG)/ethinyl estradiol (EE) 100 μg/ 20μg and placebo in the treatment of moderate acne vulgaris.

METHODS

Study Design: This was an outpatient, multicentre, randomised, double-blind, placebo-controlled study. At the pre-study visit, subjects were screened for participation. Eligible subjects were randomly assigned to receive either LNG/EE 100 μg/20 μg or placeboafter baseline acne scoring. Each subject enrolled was to participate for 6 consecutive cycles. Subjects were scheduled to visit once during each cycle between Days 17 and 24.

Number of Subjects (Planned and Analysed): A total of 350 subjects were enrolled (LNG/EE group 174, placebo group 176), and 226 subjects completed the study (LNG/EE group 109, placebo group 117). Efficacy was analysed in the intent-to-treat (ITT) population (LNG/EE group 174, placebo group 176); and safety was analysed in the safety population, which included 341 subjects (LNG/EE group 168, placebo group 173).

Diagnosis and Main Criteria for Inclusion: Subjects included healthy postmenarchal women, ≥14 years of age, who had regular menstrual cycles and moderate acne vulgaris. Moderate acne vulgaris was defined as a total count of 6 to 200 non-inflammatory lesions (comedones), 10 to 75 inflammatory lesions (papules and pustules), and ≤5 nodules.

Study Treatment: All study medication tablets were administered orally and were identical in colour (pink). Subjects were randomly assigned to receive either LNG/EE 100 μg/20 μg

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(28-day packs: 21 days of active drug then 7 days of inert tablets), or placebo (28-day packs: 28 days of placebo tablets).

Subjects began taking study medication on the first Sunday after the onset of menstruation. If menstruation began on a Sunday, the subject began taking study medication on that day. All subsequent 28-day courses of tablets were taken on the Sunday immediately after completion of the previous course, following the same 28-day schedule. Subjects were instructed to take 1 tablet daily at approximately the same time each day.

A total of 6 cycles of study medication was to be supplied to the subject. Two blister packs of study medication were dispensed at Visit 1 (Pre-study visit) to provide an adequate oversupply of study medication (28 days) for continuous use between visits during the study. One additional blister pack each was dispensed at Visits 2 to 5.

Efficacy Evaluations:

Primary Efficacy Variables

The 4 primary efficacy endpoints were:

1. Total inflammatory lesion count (total count of papules, pustules, and nodules);

2. Total non-inflammatory lesion count (total count of open and closed comedones);

3. Total lesion count (total count of the inflammatory and non-inflammatory lesions);

4. Clinician Global Assessment (CGA).

The primary efficacy values were measured at all the visits over the 6 cycles of treatment. For 9 (<3%) of the 350 enrolled subjects, the CGA was initially performed with a 7-point improvement scale. The scale was later revised by protocol amendment to a 4-point static scale rated as 1=clear; 2=almost clear/mild; 3=moderate; 4=severe.

Treatment compliance and concomitant medication usage were also evaluated at each study visit.

Secondary Efficacy Variables

The secondary efficacy variables were:

1. Subject self-assessment at baseline, Cycle 4 (Visit 5) and Cycle 6 (Visit 7);

2. Individual acne lesion counts (papules, pustules, nodules, open comedones, and closed comedones) measured at all study visits.

Safety Evaluations: Safety assessments were based on reports of adverse events (AEs) and results of routine physical examinations, Pap smears, and urine human chorionic gonadotropin test. The routine physical examinations included the recording of body weight and blood pressure (BP). Vital signs and weight were measured at baseline and at Cycles 1

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(Visit 2), 3 (Visit 4) and 6 (Visit 7). Any serious adverse event (SAE) was reported immediately.

Statistical Methods:

Efficacy

Statistical analyses were performed on 4 subject populations: the ITT population (included all subjects randomly assigned to a treatment group and to whom study medication was dispensed); the modified ITT (MITT) population (subjects who did not receive study medication or did not have at least 1 on-therapy efficacy assessment were excluded from the MITT population); the evaluable for efficacy (EFE) population (subjects who had substantive protocol violations or did not complete at least 4 cycles were excluded from the EFE analyses); and the per protocol (PP) population (subjects who had substantive protocol violations or did not complete all 6 cycles were excluded from the PP population).

A second set of analyses were performed on the ITT and MITT populations that excluded subjects whose acne lesions were measured by using a magnification device. p-Values and significance levels were based on 2-sided comparisons, with statistical significance at p≤0.05. Differences between treatment groups for baseline categorical variables were assessed by the Cochran-Mantel-Haenszel (CMH) test and for baseline continuous variables by analysis of variance (ANOVA) with centre and treatment as main effects.

Treatment-by-centre interactions were assessed. When the interaction effect was not significant (p>0.1), it was removed from the model. For the CGA, differences between the groups for treatment success (defined as clear or almost clear/mild) were assessed by logistic regression with treatment and centre as main effects, and antibiotic use and baseline total lesion count as covariates. Analysis of covariance (ANCOVA) was used to compare differences between the treatment groups in total and individual lesion counts. The general linear model contained the terms centre and treatment as main effects, antibiotic use, baseline, and variables, which were significant (p≤0.1) at baseline as covariates. Changes from baseline within groups for each on-therapy cycle were assessed by the paired t-test.

Subject self-assessment data were analysed by the CMH test with centre as a stratifying variable for categorical variables and by ANCOVA with baseline values, centre, and treatment for continuous variables. All analyses were performed by using the point-in-time data at each cycle and last observation carried forward.

Safety

Fisher’s exact test was used to evaluate the differences between treatment groups in AEs. Within- and between-group changes in body weight from baseline for each treatment cycle were assessed by using a paired t-test and ANCOVA, respectively.

RESULTS

Subject Disposition and Demography: The number of subjects in each subject population by treatment group was ITT population: LNG/EE group 174, placebo group 176; MITT

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population: LNG/EE group 156, placebo group 166; EFE population: LNG/EE group 101, placebo group 113; and the PP population: LNG/EE group 96, placebo group 105. The safety population included 341 subjects: 168 in the LNG/EE group and 173 in the placebo group 173.

Table 1 shows the number of subjects by treatment group. The most common reason for discontinuation was loss to follow-up.

Table 1. Disposition of Subjects

Population LNG/EE, n (%) Placebo, n (%)Subjects who were randomly assigned to treatment 174 (100) 176 (100)Subjects who were dispensed medication 174 (100) 176 (100)Subjects who used dispensed medicationa 160 (91.95) 170 (96.59)Subjects who completed the study 109 (62.64) 117 (66.48)Subjects who withdrew from the studyb 65 (37.36) 59 (33.52)

Lost to follow-up 28 (16.1) 16 (9.1)Personal reason 17 (9.8) 20 (11.4)Medical reason (adverse event) 9 (5.2) 6 (3.4)Protocol deviation 8 (4.6) 6 (3.4)Unintended pregnancyc 1 (0.6) 6 (3.4)Other 2 (1.1) 5 (2.96)

aDoes not include subjects for whom it was unknown whether they took study medication. However, these subjects (LNG/EE, 8 subjects; placebo, 3 subjects) are included in the safety population for analysis purposes; bBased on the investigator's assessment of completion; cOne (1) additional subject became pregnant before taking study medication. Reasons for discontinuation were not systematically captured for subjects who did not start study medication.EE=Ethinyl estradiol; LNG=Levonorgestrel; n=Number of subjects

Table 2 shows the demographic and baseline characteristics for all subjects who were assigned to treatment (the ITT population). The age of the subjects ranged from 14 to 50 years; with 18 subjects falling in the paediatric subgroup of subjects (aged 14 through 16 years). No statistically significant differences between treatment groups were observed, including acne lesion counts. However, on average, the LNG/EE treated subjects had approximately 8 more non-inflammatory and total lesions at baseline than did the placebo-treated subjects.

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Table 2. Demographic and Baseline Characteristics, ITT Population (N=350)

Characteristic LNG/EE (n=174) Placebo (n=176) p-ValueAge (years)

Mean ± SD 27.0±7.4 27.9±7.3 0.2782Range (minimum–maximum) 14.0-50.0 14.0-45.0

Age group, n (%)14 to <17 years 10 (5.7%) 8 (4.5%) 0.6475≥17 years 164 (94.3%) 168 (95.5%)

Race, n (%)White 134 (77.0%) 142 (80.7%) 0.1214Black 21 (12.1%) 27 (15.3%)Hispanic 9 (5.2%) 3 (1.7%)Asian 6 (3.4%) 3 (1.7%)Other 4 (2.3%) 1 (0.6%)

Height (cm)Mean ± SD 164.4±6.5 164.8±6.8 0.6726Range (minimum–maximum) 148.6-182.9 144.8-182.9

Weight (kg)Mean ± SD 65.8±14.1 68.6±16.1 0.0953Range (minimum–maximum) 40.9-123.5 42.7-124.4

Sitting Diastolic BP (mm Hg)Mean ± SD 72.4±8.7 72.0±9.1 0.6040Range (minimum–maximum) 48.0-92.0 48.0-94.0

Sitting Systolic BP (mm Hg)Mean ± SD 112.5±11.0 112.4±11.7 0.9172Range (minimum-maximum) 90.0-140.0 90.0-150.0

Cigarette use, n (%)No 124 (71.3%) 122 (69.3%) 0.4276Quit 13 (7.5%) 20 (11.4%)Yes 37 (21.3%) 34 (19.3%)

User of OCs, n (%)Former user 114 (65.5%) 126 (71.6%) 0.2399New user 60 (34.5%) 50 (28.4%)

Age at onset of acneMean ± SD 14.9±4.5 14.8±4.6 0.8344Range (minimum–maximum) 8.0-35.0 8.0-32.0

N= Total number of subjects; n=Number of subjects; OC: Oral contraceptive; SD=Standard deviation

Efficacy Results:

Primary Efficacy Results

Total Inflammatory Lesion Counts: Changes from baseline in the total inflammatory lesion counts for the ITT and PP populations are shown in Table 3. A numerically greater meanreduction in total inflammatory lesion counts was observed with LNG/EE compared with placebo from as early as Cycle 1 for the ITT population and Cycle 2 for the PP population. These differences were statistically significant at Cycles 5 and 6 for the ITT and PP populations, and also at Cycle 3 for the ITT population. Generally, the mean reductions from baseline in total inflammatory lesion counts became greater and the differences between treatment groups increased over time in both populations.

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A greater number of clinically meaningful reductions from baseline in the total inflammatory lesion counts were observed for the LNG/EE group (7.7 lesions, 32.6%) compared with the placebo group (5.4 lesions, 25.2%) for the end-of-study last observation carried forward (LOCF) analyses in the ITT population. Similar findings were observed for the PP population. The results for each cycle (i.e., observed cases) demonstrated that after 6 cycles of treatment, a significantly greater mean reduction from baseline was observed in the LNG/EE group (10.4 lesions, 46.8%) than in the placebo group (6.7 lesions, 32.6%) in the PP population. Similar differences between treatment groups were observed after 6 cycles in the ITT population.

Table 3. Changes from Baseline in Total Inflammatory Lesion Counts, ITT Population and PP Population

TreatmentStudy Period

n Observed Mean ± SD

Mean Change ± SD*

Mean Percent Change ± SD*

p-Value†

ITT PopulationLNG/EE

Baseline 174 19.84±10.72Cycle 6 110 9.64±7.29 -10.70±11.62‡ -46.19±41.90 0.0250End of studya 174 12.13±10.26 -7.71±11.56‡ -32.59±50.29 0.1128

PlaceboBaseline 176 20.08±15.29Cycle 6 120 14.19±27.84 -5.53±17.53‡ -29.2752.30End of studya 176 14.7123.93 -5.3716.09‡ -25.1550.99

PP PopulationLNG/EE

Baseline 96 19.859.60Cycle 6 95 9.527.28 -10.4010.97‡ -46.8240.58 0.0236End of studya 96 9.637.32 -10.2311.04‡ -45.8941.39 0.0272

PlaceboBaseline 105 18.119.11Cycle 6 105 11.458.86 -6.6710.38‡ -32.5848.43End of studya 105 11.468.85 -6.6610.38‡ -32.4848.32

*For mean change and mean percent change from baseline values, a negative sign indicated improvement; †Indicates between-treatment group comparisons based on mean change values adjusted for baseline, study centre, antibiotic use, and weight; ‡Statistically significant change from baseline (p < 0.01), significance not indicated for percent change; aIndicates the last observation carried forward for each subject in the ITT population. For subjects who withdrew from the study before taking study medication, the baseline value was used in the analysis.EE=Ethinyl estradiol; ITT=Intent-to-treat; LNG=Levonorgestrel; n=Number of subjects; PP=Per protocol;SD=Standard deviation

Total Non-inflammatory Lesion Counts: Changes from baseline in the total non-inflammatory lesion counts for the ITT and PP populations are shown Table 4. A numerically greater mean reduction in total non-inflammatory lesion counts were observed with LNG/EE compared with placebo from as early as Cycle 1 for the ITT population and Cycle 2 for the PP population. The difference between the groups in the mean reduction in total non-inflammatory lesion counts was significant at Cycles 2 and 3 for the ITT population and at Cycles 3, 5, and 6 for the PP population. Generally, the mean reductions from baseline in total non-inflammatory lesion counts and the differences between treatment groups increased over time in both populations.

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Greater reductions from baseline in total non-inflammatory lesion counts were observed for the LNG/EE group (21.3 lesions, 20.5%) compared to the placebo group (11.4 lesions, 13.4%) for the end-of-study (LOCF) analyses for the ITT population. Similar findings were observed for the PP population. The results for each cycle (i.e., observed cases) demonstrated greater mean reductions from baseline lesion counts (indicative of improvement) in the LNG/EE group compared with the placebo group, with the exception of Cycle 1 in the PP population. The mean percent decreases from baseline were 25.0% and 13.5% for the LNG/EE and placebo groups, respectively. In the ITT population, mean reductions were not significantly different between treatment groups; however, the mean percent decreases from baseline were similar to those observed for the PP population (28.0% and 14.8% for the LNG/EE and placebo groups, respectively).

Table 4. Changes from Baseline in Total Non-inflammatory Lesion Counts: ITT Population and PP Population

TreatmentStudy Period

n Observed Mean ± SD

Mean Change ± SD* Mean Percent Change ± SD*

p-Value†

ITT PopulationLNG/EE


PlaceboBaseline 176 42.9942.11Cycle 6 120 29.9825.93 -12.9341.12‡ -14.7963.05End of studya 176 31.5527.13 -11.4436.98‡ -13.3858.20

PP PopulationLNG/EE


PlaceboBaseline 105 39.6431.34Cycle 6 105 30.1725.77 -9.4727.03‡ -13.4864.70End of studya 105 30.7526.06 -8.8926.79§ -12.7364.47

*For mean change and mean percent change from baseline values, a negative sign indicated improvement; †Indicates between-treatment group comparisons based on mean change values adjusted for baseline, study centre, antibiotic use, and weight; ‡Statistically significant change from baseline (p < 0.01), significance not indicated for percent change;.§Statistically significant change from baseline (p < 0.05), significance not indicated for percent change; aIndicates the last observation carried forward for each subject in the ITT population. For subjects who withdrew from the study before taking study medication, the baseline value was used in the analysis.EE=Ethinyl estradiol; ITT=Intent-to-treat; LNG=Levonorgestrel; n=Number of subjects; PP=Per protocol; SD=Standard deviation

Total Lesion Counts: Changes from baseline in the total lesion counts for the ITT and PP populations were evaluated. A numerically greater mean reduction in total lesion counts (total inflammatory plus total non-inflammatory lesion counts) with LNG/EE was observed compared with placebo from as early as Cycle 1 for the ITT population and Cycle 2 for the PP population. As observed with the 2 individual components of the total lesion count, the mean reductions from baseline and the differences between treatment groups generally

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increased over time in both populations. Statistically significant differences between the groups in the mean reduction in total lesion counts were observed from Cycle 2 for the ITT and PP population and continued through Cycles 3, 5, and 6 for both populations, and also at Cycle 4 for the ITT population.

Statistically significant mean reductions from baseline in the total lesion counts were observed for the LNG/EE group (29.0 lesions, 29.6%) compared with the placebo group (16.8 lesions, 20.3%) for the end-of-study (LOCF) analyses in the ITT population. Similarly,significant mean reductions were demonstrated for the PP population. The results for each cycle (i.e., observed cases) demonstrated greater mean reductions from baseline lesion counts (indicative of improvement) in the LNG/EE group than in the placebo group, with the exception of Cycle 1 in the PP population. After 6 cycles of treatment, a significantly greater mean reduction from baseline was observed in the LNG/EE group (25.2 lesions, 39.9%) than in the placebo group (16.1 lesions, 23.4%) in the PP population. The differences between treatment groups in mean reduction of total lesion counts from baseline were statistically significant for all cycles after Cycle 1 in both the ITT and PP populations, with the exception of Cycle 4 in the PP population.

Clinician Global Assessment: All subjects were included in the statistical analysis of treatment success regardless of whether the CGA was performed by using the original or the revised scale. Treatment success was defined as a rating score of 1 or 2 (i.e., clear or almost clear/mild). A greater percentage of subjects in the LNG/EE group had treatment success in CGA at each cycle, starting at Cycle 2, than in the placebo treatment group. The differences between the treatment groups were statistically significant at Cycle 4 for the ITT and PP populations, and also at Cycle 6 for the PP population. Generally, the mean reductions from baseline and the differences between treatment groups increased over time in both populations.

For the ITT population, the end-of-study CGA success rates were not statistically significantly different between groups, although the differences were statistically significant at Cycle 4 and approached statistical significance at Cycle 6 (p=0.0734). The end-of-study success rates for the PP population demonstrated that LNG/EE (57.3%) was significantly superior to placebo (46.7%; p=0.0139).

Secondary Efficacy Results

Subject Self-assessment: Subjects who received LNG/EE reported more favourableresponses to treatment than did subjects who received placebo. For the ITT population, in response to the question about change in acne since the study began, approximately 81% of LNG/EE-treated subjects rated their acne as ‘much improved’ or ‘somewhat improved’ after 6 cycles of treatment compared with approximately 61% of placebo-treated subjects(p=0.0472). Similar findings were observed for the PP population.

Individual Acne Lesion Counts: After 6 cycles of treatment and at the end of study evaluation, no significant differences between treatment groups in mean change from baseline in papule, pustule, nodule counts or open comedo counts were observed for the ITT and PP populations.

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Safety Results:

The safety evaluation was based on all subjects who were known to have taken at least 1 dose of the assigned study medication, plus an additional 11 subjects for whom it was not known if they took the dispensed medication. Thus, the safety data set consisted of 168 subjects in the LNG/EE group and 173 subjects in the placebo group.

One or more AEs were reported by 135 (80.36%) subjects who took LNG/EE and 136 (78.61%) subjects who took placebo; the difference between treatment groups was not statistically significant. Since a conservative definition of treatment-emergent adverse events (TEAEs) was used, most of the reported AEs were considered as treatment emergent. Table 5 shows the most common TEAEs (reported by at least 5% of subjects in 1 group), grouped by body system. Overall, TEAEs were reported by 134 (79.76%) subjects in the LNG/EE group and by 133 (76.88%) subjects in the placebo group.

Headache was the most commonly reported TEAE in both treatment groups. The rates of metrorrhagia, emotional lability, menstrual disorder and acne were significantly higher in the LNG/EE group than in the placebo group. However, the reports of acne occurred during the first or second cycle for 8 of 10 subjects in the LNG/EE group, which is not unexpected with oral contraceptive (OC) therapy. Overall, the percentage of subjects who discontinued due to lack of improvement was similar for the LNG/EE (4.0%) and placebo (4.5%) groups.

AEs were a cause for discontinuation of treatment for 9 (5.4%) and 11 (6.4%) subjects in the LNG/EE and placebo groups, respectively. Three subjects had a SAE; 1 LNG/EE subject had depression; 1 placebo subject had acute appendicitis and probable mesenteric adenitis, and 1 placebo subject had an anaphylactic allergic reaction. All of these SAEs were resolved. No subjects died during this study or within 30 days after completion.

Eight subjects (LNG/EE, 2 subjects; placebo, 6 subjects) became pregnant during the study; 2 subjects did not take study medication and 6 discontinued treatment. Six of the pregnancies were reported as AEs. Of the 2 LNG/EE-treated subjects, only 1 (0.6%) started study medication. The subject reported taking medication as scheduled through Cycle 1, Day 18, but her empty pill pack was not returned for verification. The expected OC failure rate reported with typical use was 5% in the first year.

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Table 5. Number (%) of Subjects Reporting the Most Common (≥5%) Treatment-Emergent Adverse Events

Body System Adverse Eventsa

LNG/EE(n=168)

Placebo(n=173)

p-Value

Any Event 134 (79.76) 133 (76.88) 0.5994Body as a whole

Headache 45 (26.79) 53 (30.64) 0.4734Pain 15 (8.93) 21 (12.14) 0.3805Abdominal pain 9 (5.36) 5 (2.89) 0.2856Flu syndrome 8 (4.76) 9 (5.20) 1.0000

Digestive systemNausea 22 (13.10) 23 (13.29) 1.0000

Nervous systemEmotional lability 9 (5.36) 1 (0.58) 0.0097

Respiratory systemPharyngitis 20 (11.90) 28 (16.18) 0.2785

Skin and appendagesAcneb 10 (5.95) 3 (1.73) 0.0499

Urogenital systemMetrorrhagia 30 (17.86) 8 (4.62) 0.0001Dysmenorrhoea 13 (7.74) 20 (11.56) 0.2735Menstrual disorder 12 (7.14) 3 (1.73) 0.0172Breast pain 9 (5.36) 5 (2.89) 0.2856

aA subject could report more than 1 event in the same body system. Percentages were based on the total number of subjects in each treatment group; bAcne was the condition under study and not systematically collected as an adverse event. Acne flares are not unexpected with the use of oral contraceptives during early treatment cycles.EE=Ethinyl estradiol; LNG=Levonorgestrel; n=Number of subjects

A treatment-emergent elevation in BP was reported as an AE for 1 subject in the placebo group. One additional subject in the LNG/EE group had a BP measurement of 126/77 mm Hg at baseline (Visit 1) that increased to 160/102 mm Hg at Cycle 6 (Visit 7); this was determined to be potentially clinically important but was not reported as an AE. The subject completed the study.

Six subjects in each treatment group reported mild to moderate weight gain (approximately 1 to 5 kg) as a TEAE. One of these subjects (LNG/EE) had a >10% increase in body weight from 74.8 kg at baseline to 96.2 kg at Cycle 6 (ie, potentially clinically important); however, the subject completed the study.

CONCLUSIONS: In this placebo-controlled trial, treatment with LNG/EE (100 mg/20 mg) produced a consistent and statistically significantly greater reduction in acne lesion counts that increased with the duration of treatment, as well as a higher rate of clear/almost clear ratings in the CGA. Treatment with LNG/EE also resulted in significantly higher rates of subject self assessments of improvement in acne and desire to continue the assignedtreatment. The results of this study demonstrate that LNG/EE (100 mg/20 mg) has a positive clinical effect when used in the treatment of acne. The safety profile with LNG/EE in this trial was similar to that for placebo except for the occurrence of more emotional lability, menorrhagia, menstrual disorder, and metrorrhagia with LNG/EE.09

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Protocol 0858A1 900-09November2011 -Finalart45-paediatric-studies-docs.ema.europa.eu/GROUP L... · 2014-06-11 · EMA Paediatric Web Synopsis Protocol 0858A1-900-09November2011 -Final

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