The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: W26-15/STF114565 Title : A Single-Center, Randomized, Open-Label Study to Evaluate the Bioavailability of,.1%, and,.1%, in Subjects with Acne Vulgaris Rationale: Tazarotene, a retinoid prodrug, is indicated for the topical treatment of acne vulgaris. Following topical application, tazarotene rapidly converts to its active form, tazarotenic acid, which is highly bound to plasma proteins with little parent compound detected in the plasma. The purpose of this study is to assess systemic exposure of a new foam formulation of tazarotene,.1% compared with,.1%. The study design and dosing regimen are based on previous clinical studies with and Tazorac Cream. Phase: 1 Study Period: 8 October 29 (first subject first visit) / 19 November 29 (last subject last visit) Study Design: A single-center, randomized, open-label, phase 1, comparative bioavailability study in subjects with moderate to severe acne vulgaris. Approximately 3 subjects will be enrolled and randomized to 1 of the 2 study product groups in a 1:1 ratio (tazarotene foam: ). Study product will be applied once daily for 22 days to the face, upper chest, upper back, and shoulders. Following the baseline visit, subjects will return to the study center daily for study product application. Blood samples to determine plasma concentrations of tazarotenic acid will be collected before study product application on days 1, 8, 12, 15, 18, 2, and 22, and collected at multiple time points over a 72-hour period on days 22 through 25. Centres: 1 center in the United States Indication: Acne vulgaris Treatment: Study product was to be applied once daily for 22 days to the face, upper chest, upper back, and shoulders. Objectives: PRIMARY: Evaluate plasma exposure and relative bioavailability of tazarotene foam,.1%, compared with,.1%, as measured by circulating plasma concentrations of tazarotenic acid in subjects with acne vulgaris. SECONDARY: Evaluate the safety of tazarotene foam in subjects 12 years of age or older with acne vulgaris. Statistical Methods: Plasma concentrations of tazarotenic acid and tazarotene and PK parameter estimates of tazarotenic acid and tazarotene were summarized by study product group using descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient of variation, median, minimum, and maximum). Pharmacokinetic parameter estimates of tazarotenic acid were compared between the 2 groups using Analysis of Variance (ANOVA), with point estimate and associated 9% confidence interval for the geometric least-squares means ratios between tazarotene foam and for Cmax and AUC-tau. Vital sign data, including actual values and changes from baseline, were presented in tabular form with descriptive statistics. Adverse events were coded according to the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Frequencies and percentages were presented overall, for each system organ class, and for each preferred term. Summaries of treatment-emergent AEs, treatment-related AEs, AEs leading to discontinuation, and serious AEs were completed. Reasons for withdrawal were summarized using frequencies and percentages. Study Population: Males and females, 12 years of age or older, who were in good general health, had an Investigator s Static Global Assessment (ISGA) of 3 or greater, confined to the face, at baseline, and were eligible for enrollment in the study. Subjects must also have agreed to use a medically-acceptable method of contraception throughout the duration of the study. Additional criteria for women of childbearing potential (defined as being biologically capable of becoming pregnant), including perimenopausal women who were fewer than 2 years from their last menses, were (1) a regular menstrual cycle before study entry (as reported by the subject) and (2) a negative urine pregnancy test within 2 weeks of the first application of study product. Females who were pregnant, trying to become pregnant, or breastfeeding were not included. Number of Subjects: Tazarotene foam Planned N 15 15 Dosed N 14 16 Completed n (%) 13 (93) 16 (1) Total Number Subjects Withdrawn N (%) Withdrawn due to Adverse Events n (%) Withdrawn due to Lack of Efficacy n (%) Withdrawn for Other Reasons n (%) 1
Demographics: Tazarotene foam N (ITT) 14 (15) 16 (15) Females: Males 1:4 9:7 Mean Age in Years (sd) 2.6 (4.4) 22.5 (5.8) Mean Weight in Kg (sd) 74.8 (17.5) 78.1 (22.5) White n (%) 12 (86) 13 (81) Pharmacokinetics (PK), PK Endpoints: Summary of Mean Trough Plasma Concentrations of Tazarotenic Acid by Study Product (PK Analysis Set) Study Day Mean (SD) pg/ml 8 9.9 (35.61) 139.3 (137.54) 12 97.1 (42.91) 171.4 (118.28) 15 91.5 (4.17) 168.9 (126.72) 18 92.5 (42.74) a 154.4 (124.44) 2 12.2 (54.3) 159.9 (14.69) 22 129.3 (9.59) 154.5 (77.35) 23 b 127.1 (7.92) c 198.7 (85.31) Abbreviations: SD = standard deviation a N = 12 b Calculated from the 24-hour sample after Day 22 study product application c N = 11 2
Summary of Selected PK s for Tazarotenic Acid after Day 22 Administration (PK Analysis Set) Tazarotenic Acid AUC -tau (h*pg/ml) Mean (SD) 6976.7 (3558.55) 12463.7 (523.71) CV b (%) 5.3 42.15 Geometric mean 6268.8 11556.4 Median 624 12271 Minimum, Maximum 2913.8, 14348.7 6585.5, 2455.2 Mean (SD) 434.1 (192.39) 973.9 (493.92) CV b (%) 43.825 5.827 Geometric mean 399.5 873.2 Median 379 931 Minimum, Maximum 196., 821. 45., 233. AUC -t (h*pg/ml) Mean (SD) 9733.3 (4841.24) 15963.2 (6218.88) CV b (%) 48.99 4.769 Geometric mean 8788.5 14867.6 Median 8996 14991 Minimum, Maximum 382.7, 232. 8389.3, 3147.8 T max (hours) Mean (SD) 6.3 (2.16) 5.6 (1.37) CV b (%) 34. 24.4 Median 6. 5.2 Minimum, Maximum 4.4, 12. 4.5, 9. t 1/2 (hours) Mean (SD) 21.7 (15.67) 17.5 (7.36) CV b (%) 55.312 37.663 Geometric mean 18.6 16.4 Median 14.5 15.7 Minimum, Maximum 12., 67.9 1.4, 37.8 Abbreviations: AUC-t = area under the plasma concentration-time curve from time (time of application) to the last time point with measurable analyte concentration; AUC-tau = area under the plasma concentration-time curve from time under 1 application interval (24 hours); %CVb = between-subject coefficient of variation; Cmax = maximum measured plasma concentration; SD = standard deviation; t1/2 = the apparent terminal elimination half-life; Tmax = time of the maximum measured plasma concentration Results of the ANOVA for AUC-tau and Cmax of Tazarotenic Acid (PK Analysis Set) Geometric LS mean 9% CI (lower, upper) LSM ratio p value AUC -tau (h*pg/ml) 6268.754 11556.4 54.24 41.12, 71.57.8 399.5267 873.1959 45.75 34.29, 61.5.1 Abbreviations: ANOVA = analysis of variance; AUC-tau = area under the plasma concentration-time curve from time under 1 application interval (24 hours); CI = confidence interval; Cmax = maximum measured plasma concentration; LSM = least square means 3
Summary of Selected PK s for Tazarotene after Day 22 Administration (PK Analysis Set) Tazarotene AUC -tau (h*pg/ml) Mean (SD) 142.3 (87.33) a 25. (118.56) b CV b (%) 47.573 61.744 Geometric mean 127.4 176.5 Median 122 164 Minimum, Maximum 8.5, 365.4 67.1, 484.6 Mean (SD) 12.1 (6.29) 23.1 (16.43) CV b (%) 43.736 58.923 Geometric mean 11.1 19.7 Median 1. 19.6 Minimum, Maximum 6.3, 3. 8.1, 77.9 AUC -t (h*pg/ml) Mean (SD) 85.4 (83.12) c 164.8 (134.66) CV b (%) 81.36 1.555 Geometric mean 64.9 12.5 Median 59.5 11 Minimum, Maximum 24.1, 33.5 22.9, 466.5 T max (hours) Mean (SD) 3.2 (.54) 3.7 (1.32) CV b (%) 16.7 35.8 Median 3. 3. Minimum, Maximum 2.9, 4.5 3., 7.3 t 1/2 (hours) Mean (SD) 8.1 (3.66) a 9.4 (14.18) b CV b (%) 53.1 14.687 Geometric mean 7.3 5.8 Median 7.8 5.5 Minimum, Maximum 3.4, 14.3 2.2, 57.4 Abbreviations: AUC-t = area under the plasma concentration-time curve from time (time of application) to the last time point with measurable analyte concentration; AUC-tau = area under the plasma concentration-time curve from time under 1 application interval (24 hours); %CVb = between-subject coefficient of variation; Cmax = maximum measured plasma concentration; SD = standard deviation; t1/2 = the apparent terminal elimination half-life; Tmax = time of the maximum measured plasma concentration a N = 9 b N = 14 c N = 12 Safety results: An adverse event (AE) was defined as an AE encountered or spontaneously reported by the subject and/or elicited by investigators or designees after the consent document was signed or at any time throughout the study (prior to and after receiving study product). A serious adverse event (SAE) was defined as an SAE that happened at any time, including times prior to taking study products or occurred during the course of the study or its follow-up period (ie, following subject consent). Overall, 5 of the 14 subjects (36%) who received tazarotene foam and 7 of the 16 subjects (44%) who received experienced treatment-emergent AEs. The SOC with the largest number of AEs was infections and infestations (14% [2/14] for tazarotene foam, 19% [3/16] for ) and nervous system disorders (21% [3/14] 4
for tazarotene foam, 13% [2/16] for ). The only AEs reported by more than 1 subject per group were headache and upper respiratory tract infection. Both groups had 2 subjects (14%) with dosing-related AEs. The dosing-related AEs included severe application site erythema and moderate application site irritation (on 2 occasions). The tazarotene foam dosing-related AEs included application site irritation on 2 occasions (1 severe and 1 moderate) and moderate application site pruritus. Each of the related AEs resulted in interruption of study product application. No pregnancies were reported during this study. Adverse Events: Tazarotene foam N (ITT) 14 16 No. subjects with AEs n (%) 5 (36) 7 (44) Most Frequent AEs Nausea Application site erythema Application site irritation Application site pruritus Pharyngitis streptococcal Tonsillitis Upper respiratory tract infection Muscle spasms Headache Cough Dermatitis contact 2 (14) 3 (21) 2 (13) 2 (13) Serious Adverse Events, n (%) [n considered by the investigator to be related, possibly related, or probably related to study medication]: No deaths, other SAEs, or other significant AEs occurred during this study 5