Investigator's Static Global Assessment Research Articles

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults

Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P=.038; AD-302: 31.4% vs 18.0%, P<.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P=.005; 48.5% vs 29.7%, P<.001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P≤.001). Treatment-related adverse events were infrequent and mild to moderate in severity. Short study duration was a limitation. Crisaborole demonstrated a favorable safety profile and improvement in all measures ofefficacy, including overall disease severity, pruritus, and other signs of AD.

Sensitivity to change of the Dermatology Life Quality Index in adult females with facial acne vulgaris: a validation study.

The postadolescent form of acne papulopustulosa, also referred to as 'acne tarda' can have substantial negative impact on Quality of Life, especially in adult female patients. Although the Dermatology Life Quality Index (DLQI) is widely used, empirical evidence about its performance in adult female acne patients is lacking. In this prospective cohort study, we have investigated the sensitivity to change of the DLQI in 53 female adult acne patients with mild to moderate facial acne treated with azelaic acid (AzA) 15% gel twice daily over 24 weeks. Mean Investigator Static Global Assessment (ISGA) score was 2.3 (SD 0.5) at baseline and ranged from 0.9 (SD 0.3) to 2.1 (SD 0.4) at the end of the study in the 'Highly Improved' and 'Unchanged' responder groups respectively. The mean baseline DLQI score was 5.1 (SD 4.2). The Effect Size in the responder group 'Highly Improved' was 0.66; in group 'Improved' 0.62 and 0.23 in group 'Unchanged'. At the end of study, the mean DLQI score ranged from 1.1 (SD 1.5) in the 'Highly Improved' group to 3.7 (SD 6.0) in the 'Unchanged' group. The results support the sensitivity to change of the DLQI in this population.

A multicentre, randomized, single-blind comparison of topical clindamycin 1%/benzoyl peroxide 5% once-daily gel versus clindamycin 1% twice-daily gel in the treatment of mild to moderate acne vulgaris in Chinese patients.

Acne vulgaris affects up to 54% of Chinese adolescents. Combination therapy has become the recommended standard of care for acne. The aim of this study was to compare the efficacy and safety of clindamycin (1%) and benzoyl peroxide (5%) (CDP/BPO) gel once daily vs. clindamycin (1%) (CDP) monotherapy gel twice daily in Chinese patients with mild to moderate acne. 1020 patients (aged 12-45 years) with mild to moderate acne were randomized (1 : 1); 1016 patients were treated with CDP/BPO (n = 500) or CDP (n = 516) for a 12-week treatment period. Efficacy assessments were performed at baseline, and at weeks 1, 2, 4, 8 and 12; and primarily included change in total lesion count (inflammatory and non-inflammatory lesions), and proportion of patients with a minimum 2-grade improvement in Investigator's Static Global Assessment (ISGA) score. Patient safety and local tolerability were also evaluated. Patients in CDP/BPO group showed a greater per cent reduction in total lesion count compared with patients in CDP group at week 12 (delta = -0.05; 95% CI = -0.09, -0.02; P = 0.003); statistically significant reduction in lesion count was noted as early as week 1 and continued through week 12. A greater proportion of patients in CDP/BPO group showed a ≥2-grade improvement in ISGA score at week 12 compared with CDP group (30.2% vs. 22.7%; P = 0.018). Overall, the incidence of adverse events (AEs) was higher in the CDP/BPO group (14.4%) than in the CDP group (7.9%); the most commonly reported events were generally related to application site reactions (erythema, pruritus and swelling). Incidence of drug-related AEs was 8.6% in CDP/BPO group and 1.2% in CDP group. Both groups showed trends towards reduction in investigator and subject rated local tolerability scores. CDP/BPO gel demonstrated superior efficacy over CDP gel along with acceptable safety and tolerability in Chinese patients with mild to moderate acne. NCT01915732.

Follicular fluorescence quantity to characterize acne severity: a validation study

Porphyrins are native fluorophores in the follicle openings, visible under ultraviolet-A light. Acne severity might be associated with increased Propionibacterium acnes colonization and porphyrin production. Aim of this study was to investigate whether the parameter fluorescence quantity can be used to measure acne severity. A validation study was conducted in 24 patients with acne using split-face design. Acne severity was measured using Investigator Static Global Assessment scores and lesion counts. Reliability, construct validity and sensitivity to change in fluorescence quantity were investigated. Mean baseline Investigator Static Global Assessment score was 2.7 (SD 0.1). Mean baseline fluorescence quantities were 24.8 (SD 4.0) on the cheek and 20.3 (SD 4.6) on the chin. On day 25, values ranged from 6.0 (SD 6.0) to 18.1 (SD 18.4) on the cheek and from 2.6 (SD 4.4) to 14.7 (SD 16.2) on the chin. The intraclass correlation coefficients of fluorescence quantity ranged from 0.513 to 0.987. Effect sizes for fluorescence measurements were highest on the chin and cheek ranging from 0.24 to 0.77 and 0.32 to 0.75, respectively. Fluorescence quantity indicates acne severity, especially on the inner cheek and chin areas. Fluorescence quantity is reliable but is not as sensitive as manual lesion counting.

The tolerability profile of clindamycin 1%/benzoyl peroxide 5% gel vs. adapalene 0.1%/benzoyl peroxide 2.5% gel for facial acne: results of a randomized, single‐blind, split‐face study

Topical combination therapy, such as that with fixed-dose clindamycin/benzoyl peroxide (BPO) or adapalene/BPO, is the recommended first-line approach for the treatment of facial acne. To compare the tolerability of clindamycin 1%/BPO 5% gel vs. adapalene 0.1% BPO 2.5% gel for the first 2 weeks of treatment in patients with facial acne. Using a randomized, single-blind, split-face method, 48 patients with acne received both clindamycin/BPO and adapalene/BPO once daily for 2 weeks. The primary endpoint was investigator-assessed tolerability. Treatment efficacy, patient-assessed tolerability and satisfaction, and safety were also investigated. Forty-five patients completed treatment. Investigator-rated scores for erythema, dryness, and peeling were significantly higher with adapalene/BPO than clindamycin/BPO. Patients rated clindamycin/BPO as significantly more tolerable than adapalene/BPO for redness, dryness, burning, itching, and scaling. Investigator Static Global Assessment scores and lesion counts improved with both products, with no significant difference between treatments. Patients' Global Change Assessment showed a statistically significant difference in favor of clindamycin/BPO at week 1, but not week 2. Overall, >80% of patients were "satisfied" or "very satisfied" with treatment at week 2, but 63% of patients stated that they preferred clindamycin/BPO. Both products were well tolerated, with no serious adverse events (AEs), but a post hoc analysis indicated that treatment-related AEs, including irritation, dryness and erythema, were significantly less common with clindamycin/BPO. Clindamycin/BPO had a better tolerability profile than adapalene/BPO during 2 weeks of split-face treatment. Treatment satisfaction was highest with clindamycin/BPO.

Efficacy and Safety of Calcipotriene 0.005% Foam for the Treatment of Plaque-Type Psoriasis

Topical calcipotriene is frequently prescribed for the treatment of plaque-type psoriasis. Calcipotriene is currently available in the US as an ointment, a solution, a cream, and in a fixed-dose combination ointment with betamethasone dipropionate. Calcipotriene 0.005% has recently been formulated as a foam using a novel aqueous-based formulation to provide a new topical treatment option for patients with psoriasis. The objective of this study was to evaluate the efficacy and safety of topical calcipotriene 0.005% foam for the treatment of mild to moderate plaque-type psoriasis. Two identical, randomized, double-blind, vehicle-controlled, 8-week phase III clinical trials. Subjects with plaque-type psoriasis affecting 2-20% of the body surface area, with an identifiable target lesion affecting the trunk or extremities, were randomized in a 2:1 ratio to calcipotriene foam (n = 437) or vehicle foam (n = 222). Study medication was applied twice daily for 8 weeks. Treatment success was defined as a score of 0 or 1 (clear or almost clear) on the Investigator's Static Global Assessment (ISGA) psoriasis rating scale and a minimum improvement of ISGA score of at least 2 grades from baseline. Predefined target lesions were assessed for erythema, scaling, and plaque thickness. Primary endpoint was the proportion of subjects in each treatment group who achieved treatment success after 8 weeks, analyzed on an intent-to-treat (ITT) basis. In the primary endpoint analysis, subjects missing 8-week outcomes data were classified as treatment failures regardless of their outcomes at earlier evaluations. As part of the sensitivity analysis, a last-observation-carried-forward (LOCF) approach to impute missing 8-week efficacy outcomes also examined treatment. Secondary endpoints included treatment success as a function of baseline ISGA score (mild or moderate), ISGA score of 0 or 1 (clear or almost clear), and effects of treatment on target lesion. Adverse events (AEs) were recorded throughout the study. In the ITT population of Study 1, treatment success after 8 weeks was achieved by 14% of subjects in the calcipotriene foam group versus 7% of subjects in the vehicle foam group (p = 0.058). In the LOCF analysis, treatment success was achieved by more subjects with calcipotriene foam than with vehicle foam (15% vs 7%; p = 0.034). In Study 2, treatment success was achieved by more subjects in the calcipotriene foam group for the primary endpoint (27% vs 16%; p = 0.016) and the LOCF analysis (28% vs 16%; p = 0.010). Subjects in the calcipotriene foam group exhibited better response rates than did the vehicle foam group for most of the secondary outcomes. Calcipotriene foam was safe with an overall incidence of AEs similar to those experienced in the vehicle foam group. Application-site reactions were noted in approximately 1-2% of subjects in each group. No AE was reported in more than 2% of subjects in the calcipotriene foam group. Treatment was discontinued because of AEs in approximately 2% of subjects in both groups. In two identically designed, phase III clinical trials, calcipotriene 0.005% foam was safe and effective for the treatment of mild to moderate plaque-type psoriasis for up to 8 weeks. Registered at clinicaltrials.gov: NCT00688519 and NCT00689481.

Long-term safety of ketoconazole foam 2% in the treatment of seborrheic dermatitis: Results of a phase IV, open-label study

Ketoconazole foam, 2%, is approved in the United States for seborrheic dermatitis therapy in immunocompetent patients aged ≥12 years. While short-term trials have demonstrated its safety and efficacy, seborrheic dermatitis often requires long-term treatment.To assess the long-term safety of ketoconazole foam, 2%, twice daily, as required.A 12-month, open-label, multicenter study. Subjects were evaluated at baseline and at weeks 4, 8, 16, 26, 39, and 52 (or early termination [ET]) for adverse events (AEs), serious AEs (SAEs), target lesion erythema, scaling, and pruritus, as well as Investigator's Static Global Assessment (ISGA) scores. Physical examinations were performed at baseline and at week 52/ET, and laboratory evaluations at baseline and at weeks 8, 26, and 52. A poststudy product-preference questionnaire was completed.Of 500 subjects enrolled, 498 were included in the safety population, and 363 completed the study. Overall, 57% of subjects reported ≥1 AE. Treatment-related AEs occurred in 14% of subjects, including application-site irritation (8%), application-site pain (4%), application-site pruritus (1%), and increased alanine aminotransferase (1%). Seven subjects were withdrawn because of treatment-related AEs. No SAEs (21 in 17 subjects) were considered to be related to study drug. Mean target lesion erythema, scaling, and pruritus scores improved by 2 units from baseline at all study visits; mean ISGA score improved by 1 unit at week 4 and by 2 units at subsequent visits. The foam vehicle was preferred by 67% of subjects.Evaluation of severity was limited to target lesion; no objective measure of adherence.The long-term safety profile of ketoconazole foam, 2%, in subjects with seborrheic dermatitis was favorable and efficacy was maintained.

Efficacy of low-dose acitretin in the treatment of psoriasis

Objectives: Clinical experience favors low doses of acitretin to reduce adverse events but still maintain efficacy. We revisited the pivotal acitretin trials to compare the efficacy of high- versus low-dose acitretin. Materials and Methods: We analyzed data from two large randomized trials which had an 8-week, double-blinded (DB), placebo-controlled phase followed by a 16-week open-label (OL) phase. During the DB phase, patients received placebo, 10, 25, 50, or 75 mg of acitretin daily. Dose adjustment was allowed during the OL phase, during which high-dose treatment was defined as approximately 50 mg/day and low-dose as approximately 25 mg/day. Primary end points were improvement of psoriasis based on investigator static global assessment (ISGA) and reduction in affected body surface area (BSA). Results: At the end of the OL phase (week 24), treatment success rates were similar among all groups (29%–33%) — with the exception of the group receiving low-dose treatment for both DB and OL phases (47% success). Decrease in BSA was also highest in this group (73% vs. 28% to 54%). Conclusion: Individualization of acitretin dosing is crucial to minimize side effects and should lead to improved adherence and efficacy. This analysis supports the utility of low-dose acitretin for psoriasis over extended treatment periods.

Therapeutic Considerations for Severe Nodular Acne

Severe nodular acne, defined as grade 4 or 5 acne on the Investigator's Static Global Assessment scale, is a skin condition characterized by intense erythema, inflammation, nodules, cysts, and scarring. Both the well known risk of physical scarring and the more recent recognition that acne can be a chronic, psychologically distressing disease with significant adverse effects on a patient's quality of life, have prompted earlier, more aggressive treatment with more effective medications, in the hope of preventing progression to more severe, nodular forms of the disease. Oral antibacterials, primarily tetracyclines, have long been the first-line therapy for severe nodular acne, which frequently remained refractory to therapy. However, concerns of antibacterial adverse effects, patient adherence, and antimicrobial resistance prompted the search for alternate therapies and combinations thereof in order to target the multifactorial pathogenesis of the disease. Isotretinoin, an oral retinoid introduced in 1982, has since become the gold standard therapy in severe acne and has revolutionized its treatment. Several adjunctive agents exist. Oral antibacterials are indicated as an alternative for patients with severe acne who cannot tolerate oral retinoids, or for whom a contraindication exists. In order to prevent bacterial resistance, antibacterials should always be used in combination with benzoyl peroxide, a nonantibiotic antimicrobial agent with anti-inflammatory activity. Topical retinoids are often added to this regimen. In women, hormonal agents, which include oral contraceptives, spironolactone, and oral corticosteroids, and, in Europe, cyproterone acetate, may be used as monotherapy or concomitantly with isotretinoin. For rapid treatment of inflammatory nodules, intralesional corticosteroids are effective. These treatment modalities have been studied, refined, and combined in novel ways in order to target the multifactorial pathogenesis of the disease, and in this article we review each of their roles.

An open-label study of the safety and efficacy of sertaconazole nitrate in the treatment of seborrheic dermatitis

To demonstrate the efficacy and evaluate the safety of sertaconazole nitrate cream 2% in the treatment of seborrheic dermatitis (SD).Single-center, open-label study.One academic medical center.Twenty adult male and female subjects aged 22 to 85 years (average, 56 years) with mild-to-severe seborrheic dermatitis of the face.The primary efficacy evaluation was the proportion of subjects with a score of 0 or 1 at the end of treatment (week 4) on the Investigator's Static Global Assessment scale. Secondary end points included percent change from baseline to week 4 in sum individual scores of erythema, scaling, induration, and pruritus at a preselected target lesion. Other end points included change in scores on Subject's Global Assessment scale and the Dermatology Life Quality Index.Success on the primary end point was achieved by 10 of 17 evaluable subjects (58.8%). Improvements in Investigator's Static Global Assessment score from baseline were statistically significant at each week. Significant improvements were also demonstrated in erythema, scaling, induration, and pruritus at week 4 compared to baseline. Improvement in Subject's Global Assessment scores compared to baseline were significant only at week 1 (P=0.031). Change in total mean SD Dermatology Life Quality Index scores from baseline to week 4 was 0.34 (± 0.62, P=0.039).The results of this preliminary study support the efficacy and safety of sertaconazole nitrate cream, 2%, for the treatment of seborrheic dermatitis.

Treatment of Acne Using a 3-Milligram Drospirenone/20-Microgram Ethinyl Estradiol Oral Contraceptive Administered in a 24/4 Regimen

To assess the efficacy of the combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol (3-mg drospirenone/20-microgram ethinyl estradiol) administered as 24 consecutive days of active treatment after a 4-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. Healthy females aged 14-45 years with moderate acne were randomized in this double-blind study to 3-mg drospirenone/20-microgram ethinyl estradiol (n=270) or placebo (n=268) for six cycles of 28 days. The primary outcome measures of acne lesion counts and Investigator Static Global Assessment scale ratings were assessed at baseline and during cycles 1, 3, and 6. The percentage reduction from baseline to endpoint for total lesions is 46.3% for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6% for placebo group (P<.001). The likelihood of participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen group having "clear" or "almost clear" skin as rated by the investigators at endpoint was about threefold (odds ratio 3.13, 95% confidence interval 1.69-5.81; P=.001) greater than in the placebo group. The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen was well tolerated. The low-dose combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol administered in a 24/4 regimen significantly reduced acne lesion counts more effectively than placebo and demonstrated greater improvement in the Investigator Static Global Assessment rating of acne. The safety profile was consistent with low-dose combined oral contraceptive use.

Clobetasol propionate emulsion formulation foam 0.05%: Review of phase II open-label and phase III randomized controlled trials in steroid-responsive dermatoses in adults and adolescents

Clobetasol propionate 0.05% emulsion foam was recently developed for use on multiple body sites. We sought to evaluate safety and efficacy of clobetasol emulsion foam 0.05% to treat steroid-responsive dermatoses in multiple age groups. A phase II open-label study evaluated the effect of clobetasol foam on the hypothalamic-pituitary-adrenal axis in 52 participants aged 6 years or older with mild-to-severe atopic dermatitis (AD). Cosyntropin stimulation test was used to determine the effect of clobetasol foam on hypothalamic-pituitary-adrenal axis, with a normal response considered to be a postinjection serum cortisol level greater than 18 mug/dL. Another phase II open-label pharmacokinetic safety study was conducted in 32 participants aged 12 years or older with mild-to-moderate plaque-type psoriasis. Pharmacokinetic parameters evaluated included maximal plasma concentration of clobetasol propionate, time to achieve maximum concentration, and area under the curve. Two phase III, randomized controlled studies assessed treatment success in participants aged 12 years or older with moderate-to-severe AD (N = 377) or mild-to-moderate plaque-type psoriasis (N = 497). In all studies, participants received study drug for 2 weeks. In the AD study, treatment success was determined using a composite end point requiring an Investigator's Static Global Assessment (ISGA) score of 0 or 1, erythema score of 0 or 1, induration/papulation score of 0 or 1, and improvement in the ISGA score of at least two grades from baseline. Likewise, the study in plaque-type psoriasis used a composite end point requiring an ISGA score of 0 or 1, erythema score of 0 or 1, scaling score of 0 or 1, plaque thickness score of 0, and improvement in the ISGA score of at least two grades from baseline. Significantly more participants achieved treatment success on clobetasol foam than vehicle foam (P < .0001 and P = .0005 for each study). Reversible hypothalamic-pituitary-adrenal axis suppression was observed in 27% of participants aged 18 years or older and 47% in participants aged between 6 and younger than 12 years, but 0% in participants aged between 12 and younger than 18 years. The studies evaluated short-term use only. Clobetasol emulsion formulation foam is safe and effective for treatment of moderate-to-severe AD and mild-to-moderate plaque-type psoriasis in patients aged 12 years or older.

Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris

The development of a hydrogel to stabilize and solubilize clindamycin and tretinoin provides a single, once-daily treatment for acne vulgaris. Our aim was to compare the efficacy and safety of the combination of clindamycin (1%) and tretinoin (0.025%) with each agent alone and vehicle. Two randomized, double-blind, active drug- and vehicle-controlled 12-week studies evaluated inflammatory and noninflammatory lesion counts and the Investigator's Static Global Assessment in 2219 subjects with acne vulgaris. The combination demonstrated superior efficacy to clindamycin, tretinoin, and vehicle. Combination hydrogel was significantly more effective in reducing inflammatory (P < .005), noninflammatory (P < or = .0004), and total (P < .0001) lesion counts than the other treatments and vehicle. The proportion of subjects with clear or almost clear skin on the Investigator's Static Global Assessment was greater with the combination (P < .0001). A majority of subjects (82.6%) had grade 2-3 acne vulgaris at baseline; therefore these overall results may not be representative of the response in the subjects (17.4%) with grade 4-5 acne. The combination clindamycin/tretinoin hydrogel was well tolerated and significantly more effective than clindamycin, tretinoin, or vehicle for the treatment of acne vulgaris.