A 6-month, Multi-center, Double-blind, Controlled Study to Evaluate the Effect of a Biofilm Disrupting Acne Cream on Mild-to-Moderate Facial Acne in Female Volunteer Subjects.

Objectives: The primary aim of this study was to assess the change in acne lesions and severity within all treatment groups over the course of a six-month study. Methods: This was a six-month, multisite, randomized, double-blind, controlled study in female subjects with mild-to-moderate acne to assess the clinical and psychological outcomes of treatment with biofilm disrupting acne cream 2x, biofilm disrupting acne cream 1x, biofilm disrupting acne cream without salicylic acid, 2.5% benzoyl peroxide (BPO) gel, and placebo. Subjects applied the assigned product to their face twice daily and were evaluated for clinical acne and quality of life outcomes at baseline and after six, 12, 18, and 24 weeks of treatment. Results: After 24 weeks of use, subjects treated with biofilm disrupting acne cream 2x had a significantly greater improvement in the Investigator Global Assessment (IGA), compared to those treated with 2.5% BPO gel. Based on dermatologic assessments, biofilm disrupting acne cream 2x, biofilm disrupting acne cream 1x, biofilm disrupting acne cream without salicylic acid, and placebo control were associated with less erythema and dryness, compared to 2.5% BPO gel. Limitations: Assessments within this study had the potential for subjective differences due to variability between evaluators. Conclucion: Biofilm disrupting acne cream 2x and biofilm disrupting acne cream 1x provided equivalent efficacy to 2.5% BPO gel with less of the adverse effects commonly associated with BPO, such as erythema and dryness. Both the biofilm disrupting acne cream without salicylic acid and the placebo control were associated with mild improvements to acne symptoms over the course of the 24-week study. Trial Registry Information: ClinicalTrials.gov, NCT03106766.

Contact Sensitization and Phototoxic and Photoallergic Potential of Tirbanibulin 1% Ointment in Healthy Volunteers.

Tirbanibulin 1% ointment is approved for the topical treatment of actinic keratosis, applied once daily for 5 days. Three phase 1 randomized, single-center, controlled, within-subject comparison studies were conducted to evaluate the sensitization (KX01-AK-006), phototoxic (KX01-AK-008), and photoallergic (KX01-AK-009) potential of tirbanibulin 1% ointment in healthy adults. In KX01-AK-006 and KX01-AK-009, subjects received repeated applications of tirbanibulin or vehicle for induction (followed by irradiation in KX01-AK-009) and an additional application for the challenge on naïve sites. In KX01-AK-008, subjects received single applications, followed by irradiation. Sensitization was defined as a reaction scoring 3 at naïve sites, recurring at rechallenge. Photoallergy was assessed based on the dermal response of erythema + edema at naïve sites. Phototoxicity was assessed based on the average dermal response score (days 3‒4). Adverse events were collected. In KX01-AK-006, none of the 229 subjects scored 3 at naïve sites. In KX01-AK-008, none of the 31 subjects developed edema, not meeting the criteria for phototoxicity. In KX01-AK-009, none of the 59 subjects showed reactions compatible with photoallergy. Mild-to-moderate contact irritations were reported. The evidence provided by these phase 1 studies showed that tirbanibulin 1% ointment lacks sensitization and phototoxic or photoallergic potential, and supports the safety of its topical application.

Topical minocycline foam 4%: Results of four phase 1 studies evaluating the potential for phototoxicity, photoallergy, sensitization, and cumulative irritation.

FMX101 4% contains 4% micronized minocycline (as an HCl) formulated in a lipophilic foam vehicle for topical administration. FMX101 4% has been shown to be an effective and well-tolerated treatment for moderate-to-severe acne in three Phase 3 pivotal studies, however, skin sensitization and toxicity potential remains to be fully evaluated. Four single-center, randomized, controlled, within-subject comparison studies were conducted to evaluate the potential for phototoxicity, photoallergy, skin sensitization, and cumulative skin irritation with topical administration of FMX101 4% and the corresponding vehicle. Across the four studies, healthy male and non-pregnant female volunteers (age ≥18 years) were randomized to FMX101 4%, vehicle, or other controls. In the phototoxicity study, treated skin was irradiated at 3 and 24 hr post-application, and local tolerability was assessed pre- and post-irradiation. In the photoallergy study, the skin was treated and irradiated (post-24 hr) twice weekly for 3 wk (induction phase), rested for 10-17 d, and naive skin sites were treated and irradiated (challenge phase); skin reactions were assessed after patch removal and post-irradiation. In the sensitization study, the skin was treated for 3 wk (induction phase), then rested for 10-14 d, and naive skin sites were treated for 48 hr (challenge phase); contact sensitization was assessed for both phases. In the cumulative irritation study, treatment and vehicle were applied daily for 21 d; skin irritation was assessed after each application. In all studies, standard safety assessments were conducted. A total of 32, 56, 233, and 42 subjects were enrolled in the phototoxicity, photoallergy, sensitization, and skin irritation studies, respectively. There was no evidence of phototoxicity, photoallergy, skin sensitization, or skin irritation potential with FMX101 4%. Few adverse events, mostly mild to moderate, were reported. In conclusion, FMX101 4% appeared to be well tolerated and non-irritating, and was considered to be non-sensitizing, non-phototoxic, and non-photoallergic.

Skin Irritation and Sensitization Potential of Fixed-Dose Combination of Diclofenac 1% and Menthol 3% Topical Gel: Results of Two Phase I Patch Studies.

Phase I, randomized, controlled patch studies were conducted to evaluate skin sensitization and irritation potential of a new gel formulation containing 1% diclofenac and 3% menthol as a fixed-combination product.In study A, healthy volunteers were exposed to 4 test patches containing 1% diclofenac+3% menthol, diclofenac, menthol, or placebo gels during an induction (nine 48 to 72-h applications) and challenge phase (one 48-h application). Some subjects were re-challenged to evaluate suspected sensitization. Study B participants underwent 21 consecutive 24-h patch applications of the 4 treatments from study A, 0.2% sodium lauryl sulfate (positive control), 0.9% saline, and a marketed gel (1% diclofenac, Voltaren). Application sites were visually scored by blinded observers for skin sensitization/irritation.In study A, 77% of participants showed minimal erythema and signs of glazing and peeling with 1% diclofenac+3% menthol by the end of the induction phase, which diminished during the challenge phase. Similar patterns were seen with menthol gel. Only 1 subject exhibited possible sensitization to 1% diclofenac+3% menthol. In study B, mean cumulative irritation score with 1% diclofenac+3% menthol was significantly higher (P<0.0001) vs. reference treatments; however, the positive control failed to produce the expected level of irritation. No treatment-related adverse events were reported.The sensitization and irritation potential of 1% diclofenac+3% menthol was greater than with the reference treatments. Comparison with positive control was not possible because it did not produce irritation under semiocclusive patch conditions.

The DGAT1 inhibitor pradigastat does not induce photosensitivity in healthy human subjects: a randomized controlled trial using three defined sunlight exposure conditions.

The DGAT1 inhibitor, pradigastat, demonstrated a mild phototoxicity signal in preclinical studies. Therefore, this clinical trial was conducted to assess the risk of photosensitivity in humans. 47 healthy adults were randomized to part A (double-blind, placebo-controlled; 3 : 1 pradigastat : placebo) or part B (open-label positive control ciprofloxacin, investigator blind). Three irradiation conditions (1. full range UVB/UVA, 2. UVA only, 3. 1/2 MED from UVB/UVA + 16 J cm(-2) UVA) were applied to simulate different sunlight exposure conditions. Photosensitizing potential was assessed by determining the minimum erythemal dose (MED) and calculating the photosensitivity index (PI) at 1 and 24 h. Local skin reactions were recorded as a secondary endpoint. Following full UVB/UVA irradiation, there were no significant differences in MED or PI between groups. With UVA-only, no changes in MED or PI were observed for the pradigastat or placebo groups. For ciprofloxacin, there was a significant reduction in MED at 24 h (-32%, vs. 24 h baseline), which correlated to a PI of 1.61. The difference in mean PI between ciprofloxacin-pradigastat, and ciprofloxacin-placebo, was significant at 24 h (p < 0.001). Local skin erythema scores were comparable between pradigastat and placebo, but higher with ciprofloxacin. Pradigastat was not shown to induce photosensitivity reactions, while significant responses were seen with the positive control. These results strongly suggest that pradigastat will not induce photosensitivity reactions in individuals administered doses up to 40 mg per day, which is the highest intended clinical dose. Furthermore, the design of this clinical trial may serve as a prototype for future regulatory clinical photosensitivity studies.

Cumulative irritation, sensitizing potential, phototoxicity and photoallergy of ozenoxacin in healthy adult volunteers.

In this series of Phase I, randomized, placebo-controlled studies in healthy volunteers, the potential for ozenoxacin 1 and 2% cream formulations to cause irritation, sensitization, phototoxicity and photoallergy under occlusive patch conditions was evaluated. Both ozenoxacin formulations showed excellent dermal tolerability; in the vast majority of cases, only minimal signs of erythema were observed, with no evidence of edema or a papular response. No subject met the criteria for a phototoxic reaction with the ozenoxacin 1 or 2% cream formulations. Only a few adverse events were reported across repeated-dose studies, and virtually all events were considered to be unrelated or unlikely to be related to ozenoxacin application. Ozenoxacin was safe, well tolerated and showed little or no tendency to cause irritation, sensitization, phototoxicity or photoallergy.

Evaluation of the skin sensitization, photoirritation, and photoallergic potential of ingenol mebutate gel in healthy volunteers.

OBJECTIVES: Phase 1 studies were conducted to determine the sensitization (PEP005-005; NCT00357916; http://clinicaltrials.gov/ct2/show/NCT00357916), photoirritation (PEP005-023; NCT00850811; http://clinicaltrials.gov/ct2/show/NCT00850811?term=PEP005-023&rank=1), and photoallergic (photosensitizing) potential (PEP005-024; NCT00850681; http://clinicaltrials.gov/ct2/show/NCT00850681?term=PEP005-024&rank=1) of ingenol mebutate gel 0.01% versus vehicle on normal skin. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Healthy volunteers were enrolled in single-center, randomized, controlled, within-subject comparison trials. PEP005-005 was designed as a repeat-insult patch test study. In PEP005-023, treatment areas were examined after irradiation for photoirritation potential; dermal reactions were evaluated. In PEP005-024, irradiation was performed to determine the photoallergic (photosensitizing) potential of the medication. All treatment areas were graded immediately prior to irradiation and 24, 48, and 72 hours following irradiation. In all studies, local tolerability was assessed visually using an ordinal scoring system at set intervals before and after medication application/irradiation. RESULTS: In PEP005-005 (n=238), a significant difference (p<0.001) was seen between ingenol mebutate and vehicle for mean and total cumulative irritation scores. In PEP005-023 (n=34), mild erythema in all irradiated treatment areas was as expected for the ultraviolet dose. There was no clinically significant irritation in response to ingenol mebutate or vehicle, irrespective of irradiation. In PEP005-024 (n=60), there was no significant irritation in response to either ingenol mebutate or vehicle at their irradiated treatment areas. CONCLUSION: RESULTS from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirritation, or photoallergic potential.

Comparative irritation potential of two combination acne products: a randomized controlled, subject- and evaluator-blind, comparative study in healthy volunteers.

BACKGROUND: Two topical 1% clindamycin/5% benzoyl peroxide combination products (BenzaClin [Dermik Laboratories, Inc., Bridgewater, NJ, USA] and Duac [Stiefel Laboratories, Coral Gables, FL, USA]) are commonly used in the treatment of mild-to-moderate acne vulgaris. One adverse event reported with their use is local skin irritation. OBJECTIVE: The primary aim of this study was to compare the irritation potential of BenzaClin and Duac using a cumulative irritant patch test on healthy human skin. METHODS: A randomized controlled, subject- and evaluator-blinded design was used to compare the cumulative irritation potential of BenzaClin, Duac, a positive control (0.2% sodium laurilsulfate [SLS]), and a negative control (white petrolatum) in healthy volunteers at a single US research study center. Forty subjects were enrolled and 37 completed the study. Most subjects were women (83%) and Caucasian (68%), and the mean age was 47 years. The 21-day cumulative irritation patch test was used to measure the irritation potential of the products applied under occlusive conditions. Evaluation of dermal reactions to the four products was assessed visually using an ordinal scoring system at the time of removal of each patch. The four patches were applied once daily over 21 days, excluding Saturdays and Sundays, resulting in a total of 15 applications. The primary endpoint, determined prior to data collection, was mean cumulative irritation score at the end of the study on day 22. RESULTS: At the end of the study, the mean cumulative irritation scores were not significantly different between BenzaClin and Duac (1.39 vs 1.36, respectively; p = 0.668). Both BenzaClin and Duac were significantly more irritating than white petrolatum and significantly less irritating than SLS (both p < 0.001). Based on mean cumulative irritation score, BenzaClin and Duac were classified as moderately irritating, SLS as highly irritating, and white petrolatum as not irritating. CONCLUSION: BenzaClin and Duac show similar propensity to cause moderate irritation compared with SLS and white petrolatum when applied to the skin of healthy subjects under occlusive patch conditions.

Tolerability comparison of adapalene gel, 0.3% versus tazarotene cream, 0.05% in subjects with healthy skin.

BACKGROUND: Topical retinoids, including adapalene and tazarotene, are a primary treatment choice for patients with acne. Adapalene is currently marketed in a 0.1% concentration in gel and cream formulation. A new gel containing a higher concentration (0.3%) of adapalene has been developed. In clinical studies, adapalene 0.1% concentration has proven to be better tolerated than other retinoids in skin treatment. However, the tolerability of adapalene gel 0.3% has yet to be compared to other topical retinoids. PURPOSE: The purpose of this study was to compare the local cutaneous tolerability of adapalene gel 0.3% once daily versus tazarotene cream 0.05% once daily. METHODS: Subjects reported to the investigative site each day Monday through Friday, cleansed the faced and then applied adapalene 0.3% gel to one side of the face and tazarotene 0.05% cream to the other in the presence of study personnel. For the weekends, subjects were instructed to apply the treatment at home according to the same procedure. Tolerability was assessed during each weekday visit. The study lasted for 3 weeks. RESULTS: Tolerability results for adapalene 0.3% gel and tazarotene 0.05% cream were statistically similar throughout the study. Investigator-assessed overall tolerability was in favor of adapalene at days 19 and 22 (P=.043). A cosmetic acceptability survey also showed results were better for adapalene 0.3% gel. CONCLUSION: Adapalene gel 0.3% is very well-tolerated with good cosmetic acceptability.

Brooke-Spiegler syndrome.

A 46-year-old woman with Brooke-Spiegler syndrome has multiple cutaneous adnexal neoplasms on her face and scalp. One of the lesions has concurrent features of cylindroma, trichoepithelioma, and spiradenoma in the same specimen. Etiology, clinical features, malignant transformation, and treatment modalities for Brooke-Spiegler syndrome are reviewed.

Cumulative irritancy comparison of topical retinoid and antimicrobial combination therapies.

BACKGROUND: The use of multiple topical drugs for the treatment of acne may cause elevated irritation. Therefore, the selection of a combination regimen should include a careful consideration of the irritation potential of the individual acne medications. OBJECTIVE AND METHODS: To compare the cumulative irritation potential of adapalene gel 0.1%, tazarotene cream 0.05%, and tretinoin microsphere 0.04% when applied in combination with two benzoyl peroxide/clindamycin topical gels in 35 healthy subjects in a 3-week, randomized, controlled study. RESULTS: The mean cumulative irritancy index of adapalene combinations was significantly lower relative to tretinoin and tazarotene regimens (all P<.01). Test areas exposed to tretinoin or tazarotene were also more likely to be discontinued for severe irritation than those exposed to adapalene. There were no serious adverse events. No significant difference in the irritancy potentials of tazarotene and tretinoin combination regimens was observed. CONCLUSIONS: Adapalene gel 0.1% has tolerability superior to both tazarotene cream 0.05% and tretinoin microsphere 0.04% when used in topical combination therapy. In view of the lower irritation potential observed in this study, along with its demonstrated efficacy, adapalene gel 0.1% in combination with antimicrobial agents may be used as part of an aggressive treatment regimen for the management of acne.

Cumulative irritation potential of adapalene 0.1% cream and gel compared with tazarotene cream 0.05% and 0.1%.

Despite the many beneficial effects of dermatologic applications, most of the current treatments for acne cause local irritation. The objective of this study was to compare the ability of the epidermis to tolerate adapalene 0.1% cream and gel and tazarotene cream in concentrations of 0.05% and 0.1%. A total of 30 subjects were enrolled in the study. The test products were applied under occlusive dressings at randomized sites on the upper back for approximately 24 hours, 4 times a week, and for 72 hours, once a week, for a period of 3 weeks. Skin reactions (erythema score plus other local reactions) at the product application sites were assessed 15 to 30 minutes after dressing removal. Twenty-six subjects completed the study. A total of 16 subjects discontinued use of 1 or more of the test products because of irritation scores reaching severe or greater; all but one of these discontinuations were at sites treated with the tazarotene products. The mean 21-day cumulative irritancy indices for adapalene 0.1% cream and gel were significantly lower (P=.05) than those for tazarotene cream 0.05% and 0.1% and not notably higher than that of the negative control product.

Cumulative irritation potential of adapalene 0.1% cream and gel compared with tretinoin microsphere 0.04% and 0.1%.

Despite the many beneficial effects of dermatologic applications, most of the current treatments for acne cause local irritation. The objective of this study was to compare the ability of the epidermis to tolerate adapalene 0.1% cream and gel and tretinoin microsphere in concentrations of 0.04% and 0.1%. A total of 31 subjects were enrolled in the study. The test products were applied under occlusive dressings on the upper back for approximately 24 hours, 4 times a week, and for 72 hours, once a week, for a period of 3 weeks. Skin reactions (erythema score plus other local reactions) at the product application sites were assessed 5 to 30 minutes after dressing removal. Twenty-six subjects completed the study. A total of 10 subjects discontinued use of 1 or more of the test products because of irritation scores reaching severe or greater, all of these discontinuations were at sites treated with the tretinoin products. The mean 21-day cumulative irritancy indices for adapalene 0. 1% cream and gel were significantly lower (P<.01) than those for tretirnoin microsphere 0.04% and 0. 1% and not higher than that of the negative control product.