Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial.

BACKGROUND: The topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. OBJECTIVE: Roflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). METHODS: In this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. RESULTS: 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LIMITATIONS: Study limitations include the 8-week treatment period for this chronic condition. CONCLUSIONS: Once-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

Assessment of the Vehicle for Roflumilast Cream Compared to a Ceramide-Containing Moisturizing Cream in Mild Eczema.

BACKGROUND: Inflammatory dermatologic conditions suitable for topical treatments benefit from a hydrating vehicle that improves the skin barrier without irritation. OBJECTIVE: This research was designed to assess skin barrier effects and aesthetic attributes of the vehicle for topical roflumilast cream (vehicle) vs a currently marketed ceramide-containing moisturizing cream (moisturizer). METHODS: This was a single-site, randomized, intraindividual, double-blind, controlled study conducted over 17 days. Patients (aged 18 years or older) with mild, symmetric asteatotic eczema of the lower extremities were enrolled to receive lower leg applications of the vehicle on one leg and moisturizer on the other. The primary efficacy endpoint was a change in transepidermal water loss (TEWL) from baseline to day 15. Secondary efficacy endpoints included change from baseline in TEWL at other study visits, change from baseline in hydration as assessed via corneometry, and patient- and investigator-rated assessments of the products. Safety and tolerability were also assessed. RESULTS: A total of 40 patients enrolled in the study. The primary efficacy endpoint was met for both treatments. A statistically significant difference in TEWL on day 1 favored the moisturizer, but no difference was seen between vehicle and moisturizer at any other timepoint. Both vehicle and moisturizer also met the secondary efficacy endpoint of change from baseline in hydration. LIMITATIONS: The sample size was small. CONCLUSIONS: The vehicle for roflumilast cream performed similarly to a leading, currently marketed, dermatologist-recommended, ceramide-containing moisturizer across all patient- and investigator-rated assessments of efficacy, tolerability, and aesthetic properties in patients with mild asteatotic eczema. J Drugs Dermatol. 2024;23(10):834-840. doi:10.36849/JDD.7958  .

Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study.

BACKGROUND: Scalp psoriasis affects most patients with psoriasis, but it can be difficult to treat. OBJECTIVES: To evaluate the efficacy and safety of once-daily roflumilast foam 0.3% on scalp and body psoriasis. METHODS: In a phase IIb randomized controlled trial, adults and adolescents aged ≥ 12 years with scalp and body psoriasis were randomized (2 : 1) to roflumilast foam 0.3% or vehicle for 8 weeks. The primary efficacy endpoint was scalp Investigator Global Assessment (S-IGA) success (score of 'clear' or 'almost clear' plus ≥ 2-grade improvement from baseline) at week 8. Safety and tolerability were also evaluated. RESULTS: Significantly more roflumilast-treated patients (59.1%) than vehicle-treated patients (11.4%) achieved S-IGA success at week 8 (P < 0.001); differences favoured roflumilast as early as the first postbaseline visit at week 2 (P < 0.001). Significant improvements were also seen for secondary endpoints, including body IGA success, Scalp Itch Numeric Rating Scale and the Psoriasis Scalp Severity Index. The safety of roflumilast was generally similar to vehicle. Patients treated with roflumilast experienced low rates of treatment-emergent adverse events (AEs), with few discontinuations due to an AE. Few patients with skin of colour (11%) and few adolescents (0.7%) were included. CONCLUSIONS: The results support the further development of roflumilast foam for treating scalp and body psoriasis.

Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials.

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis. Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis. Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively. Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks. Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points). Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2. Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

A Phase 2 Open-Label Study to Evaluate VP-102 for the Treatment of Molluscum Contagiosum.

BACKGROUND: This Phase 2, open-label study evaluated the safety, efficacy, systemic exposure, and impact on quality of life (QoL) with treatment using VP-102, a drug-device combination containing cantharidin (0.7% w/v) in subjects with molluscum contagiosum (MC). STUDY DESIGN: Pediatric subjects with MC (2–15 years of age) were eligible to enroll in this 12-week study. MC lesions were treated topically with VP-102 every 21 days until clearance (maximum of 4 treatments). Adverse events (AEs) and QoL outcomes (using the Children's Quality of Life Index, CDLQI) were documented at each visit. Rate of complete clearance and the percent reduction in lesions were measured at each visit on days 21, 42, 63, and 84 (end of study [EOS] visit). A group of 17 subjects with at least 21 MC lesions was evaluated for systemic cantharidin exposure via plasma samples obtained before the first application of VP-102, and at 2 hours, 6 hours, and 24 hours post-application. RESULTS: A total of 33 subjects enrolled in the study (n=17 systemic exposure group, n=16 standard group). There were an equal number of male and female subjects. Subject mean (SD, range) age was 6.7 (3.3, 2–15) years, with a mean lesion count of 30 (26.1, 3–113). Complete lesion clearance was achieved in 48.5% of subjects, with a 90.4% reduction in lesions from baseline to the EOS visit. Mean CDLQI score decreased from 2.6 at baseline to 0.38 at the EOS visit. AEs were mild to moderate in severity and expected due to the pharmacodynamic action of cantharidin. There were no serious treatment-related adverse events and no study discontinuations due to treatment. In the systemic exposure group plasma cantharidin levels were below the lower limit of quantitation (LLOQ, 2.5 ng/mL) in 65 of 66 samples. CONCLUSIONS: VP-102 treatment resulted in a reduction in lesion counts and improved QoL. Treated subjects had a 48.5% rate of complete clearance of molluscum lesions. Negligible systemic cantharidin exposure was observed in the systemic exposure group. This data demonstrates safety and efficacy of treatment with VP-102 in MC; a widespread viral infection that does not have any current FDA-approved treatments. Significant Finding: Treatment of subjects with MC using VP-102 resulted in negligible systemic cantharidin exposure, as well as a reduction in lesion counts, improved QoL, and a demonstrated efficacy in clearance of new and baseline MC lesions. Meaning: Results of this Phase 2 study demonstrate efficacy and safety outcomes in using VP-102 in MC subjects, and large randomized clinical trials are warranted to compare topical VP-102 with a vehicle control in order to fully evaluate the use of the medication. ClinicalTrials.gov identifier: NCT03186378 J Drugs Dermatol. 2021;20(1):70-75. doi:10.36849/JDD.5626.

Margins of freedom: a field-theoretic approach to class-based health dispositions and practices.

Pierre Bourdieu's theory of practice situates social practices in the relational interplay between experiential mental phenomena (habitus), resources (capitals) and objective social structures (fields). When applied to class-based practices in particular, the overarching field of power within which social classes are potentially made manifest is the primary field of interest. Applying relational statistical techniques to original survey data from Toronto and Vancouver, Canada, we investigated whether smoking, engaging in physical activity and consuming fruit and vegetables are dispersed in a three-dimensional field of power shaped by economic and cultural capitals and cultural dispositions and practices. We find that aesthetic dispositions and flexibility of developing and established dispositions are associated with positioning in the Canadian field of power and embedded in the logics of the health practices dispersed in the field. From this field-theoretic perspective, behavioural change requires the disruption of existing relations of harmony between the habitus of agents, the fields within which the practices are enacted and the capitals that inform and enforce the mores and regularities of the fields. The three-dimensional model can be explored at: http://relational-health.ca/margins-freedom.

The social dynamics of safe sex practices among Canadian sex industry clients.

Much of what we know about the safe sex practices of people who pay for sexual services (clients) remains firmly grounded in empirical and interpretive tendencies to overemphasise the causal link between social, cultural or individual characteristics and sexual decision-making. In this study we apply Adam Green's Bourdieu-inspired sexual fields theory to examine the ways in which safe sex practices are interdependently shaped by social, personal and interpersonal forces. Using data from 697 questionnaires and 24 semi-structured interviews with Canadian clients, we implemented a series of six additive logistic regression models and contextualised the results with the interview data to reveal the relational interdependencies of intra-psychic, macro, meso and micro-level factors related to safe sex practices. The questionnaire responses and interview data used in the study were gathered from a diverse sample of clients who were over the age of 19, had paid money for sexual services on one or more occasions during their lifetime and who resided in Canada at the time of participation. Our results illustrate the ways in which factors related to the venue where sexual acts take place, clients' relationships with commercial and non-commercial partners and personal choices related to substance use interdependently inform safe sex practices.

Towards a relational health promotion.

The Ottawa Charter for Health Promotion exhibits a substantialist approach to the agency-structure dichotomy. From a substantialist point of view, both individual agency and social structure come preformed and subsequently relate to and influence one another, starkly positioning the choices made by individuals against the structured sets of opportunities and constraints in reference to which choices are made. From a relational perspective, however, relations between elements, not the elements themselves, are the primary ontological focus. We advocate for a relational approach to the structure-agency dichotomy, one that locates both agency and structure in social relations and thereby dissolves the stark distinction between them, suggesting that relational theories can provide useful insights into how and why people 'choose' to engage in health-related behaviours. Pierre Bourdieu's theory of practice, predicated upon the notions of field, capital and habitus, is exemplary in this regard.

A relational approach to health practices: towards transcending the agency-structure divide.

Many health scholars find that Pierre Bourdieu's theory of practice leaves too little room for individual agency. We contend that, by virtue of its relational, field-theoretic underpinnings, the idea of leaving room for agency in Bourdieu's theory of practice is misguided. With agency manifested in interactions and social structures consisting of relations built upon relations, the stark distinction between agency and structure inherent to substantialist thinking is undermined, even dissolved, in a relational field-theoretic context. We also contend that, when treated as relationally bound phenomena, Bourdieu's notions of habitus, doxa, capital and field illuminate creative, adaptive and future-looking practices. We conclude by discussing difficulties inherent to implementing a relational theory of practice in health promotion and public health.

When Patient Diversity Informs Formulation: Reimagining Treatment for Seborrheic Dermatitis.

Seborrheic dermatitis (SD) impacts a diverse demographic, with treatment effectiveness and suitability varying across hair types and cultural practices. Available shampoo treatments contain surfactants that compromise hair moisture and integrity as well as requiring frequent use, which may not align with the routines of various hair types and cultural hair care practices. Most available topical foams and gels contain high concentrations of drying alcohols that damage hair color and moisture. Newly US Food and Drug Administration (FDA)-approved roflumilast 0.3% foam presents a significant advancement in the treatment of SD owing to its pH-balanced, residue-free formulation that is suited for all hair types, including patients with curly or coiled hair. It presents a culturally inclusive treatment option that offers effective management of SD while maintaining hair health and respecting diverse hair care needs and practices.

Putting the Formulation Back in Foam: Optimizing Seborrheic Dermatitis Treatment Across Diverse Hair Types.

Seborrheic dermatitis (SD) is a chronic inflammatory skin condition that commonly involves the scalp, and thus, affects a diverse demographic with varying hair care needs. Current SD treatments are limited based on optimized formulation, efficacy, adverse events, and lack of placebo-controlled trials. A novel roflumilast foam formulation has emerged as a promising therapeutic option optimally designed for use on the scalp and other hair-bearing areas. We conducted a comprehensive assessment of beauty industry standards, confirming the foam formulation's alignment with industry guidelines and exclusion of potentially harmful ingredients. In addition, consultation with an expert dermatologist panel yielded a strong endorsement, underscoring a high level of confidence in prescribing the foam across diverse hair and skin types.

Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials.

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates. Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD. Design, Setting, and Participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic Dermatitis (assessed on a 5-point scale ranging from 0 [clear] to 4 [severe]). Intervention: Patients were randomized 2:1 to receive roflumilast cream, 0.15%, or vehicle cream once daily for 4 weeks. Main Outcomes and Measures: The primary efficacy end point was Validated Investigator Global Assessment for Atopic Dermatitis success at week 4, defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline. Secondary end points included Eczema Area and Severity Index and Worst Itch Numeric Rating Scale. Safety and local tolerability were also evaluated. Results: Among 1337 patients (654 patients in INTEGUMENT-1 and 683 patients in INTEGUMENT-2), the mean (SD) age was 27.7 (19.2) years, and 761 participants (56.9%) were female. The mean body surface area involved was 13.6% (SD = 11.6%; range, 3.0% to 88.0%). Significantly more patients treated with roflumilast than vehicle achieved the primary end point (INTEGUMENT-1: 32.0% vs 15.2%, respectively; P < .001; INTEGUMENT-2: 28.9% vs 12.0%, respectively; P < .001). At week 4, statistically significant differences favoring roflumilast also occurred for the achievement of at least 75% reduction in the Eczema Area and Severity Index (INTEGUMENT-1: 43.2% vs 22.0%, respectively; P < .001; INTEGUMENT-2: 42.0% vs 19.7%, respectively; P < .001). Roflumilast was well tolerated with low rates of treatment-emergent adverse events. At each time point, investigators noted no signs of irritation at the application site in 885 patients who were treated with roflumilast (≥95%), and 885 patients who were treated with roflumilast (90%) reported no or mild sensation at the application site. Conclusions and Relevance: In 2 phase 3 trials enrolling adults and children, once-daily roflumilast cream, 0.15%, improved AD relative to vehicle cream, based on multiple efficacy end points, with favorable safety and tolerability. Trial Registration: ClinicalTrials.gov Identifiers: NCT04773587, NCT04773600.

Quantification of skin lesions with a 3D stereovision camera system: validation and clinical applications.

BACKGROUND/PURPOSE: Three-dimensional (3D) imaging of the skin is a challenging technique. A new 3D digital camera system has been developed that enables 3D reconstruction of the skin and subsequently allows volumetric quantification. Herein we present validation data on calibrated phantoms and the clinical application of this technology. METHODS: Absolute and relative geometric 3D measurements were validated with a static imaging phantom manufactured by a metrology institution and a dynamic imaging phantom adjustable for different volume quantities, respectively. Consecutively, in a clinical study, 3D baseline and follow up images from 27 basal cell carcinomas under topical therapy were captured for volumetric analysis. RESULTS: Validation experiments have demonstrated an average accuracy for surface position of 55 µm and a precision of 8 µm, as well as excellent correlation (0.999) between injected and measured volumes. The geometric baseline analysis of 27 basal cell carcinomas exhibited a high correlation and agreement between 2D and 3D surface measurements. Under topical therapy, it was possible to gain statistically significant differences between verum- and vehicle-treated basal cell carcinomas when analyzing geometric measurements of 3D volume (P = 0.01) and 3D surface (P = 0.001). CONCLUSION: In our study we were able to demonstrate that this newly developed 3D camera system offers a precise objective dimensional representation of the skin. This technique is easily applicable and sensitive enough to measure small differences in area and volume before and after intervention.

Pharmacokinetics of Roflumilast Cream in Chronic Plaque Psoriasis: Data from Phase I to Phase III Studies.

BACKGROUND: Most patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis. OBJECTIVE: The aim of this study was to define the pharmacokinetic (PK) profile of roflumilast delivered topically from a phase I maximal usage study and data from phase II and phase III studies. METHODS: PK data for roflumilast and the active metabolite, roflumilast N-oxide, were determined from a phase I PK and safety maximal usage study of roflumilast cream 0.3% applied once daily for 14 days in patients with plaque psoriasis affecting body surface area (BSA) ≥20% (N = 26). Serial plasma samples were obtained on Days 1 and 15 to determine maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC). Plasma concentrations were also assessed at Weeks 3, 4, and 5 for terminal half-life (t½). Concentrations of roflumilast and roflumilast N-oxide in skin were assessed at Day 28 for 14 patients with psoriasis in a phase I/IIa study of once-daily roflumilast cream 0.5% and 0.15% for 28 days. Systemic exposure (Ctrough and AUC) of roflumilast and roflumilast N-oxide in two phase III trials (DERMIS-1, n = 245; DERMIS-2, n = 250) of roflumilast cream 0.3% for 8 weeks was assessed at Weeks 4 and 8. RESULTS: Bioavailability of roflumilast cream 0.3% after topical administration was 1.5%. Unlike after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2. Roflumilast N-oxide concentrations were eightfold higher than roflumilast concentrations. The t½ in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide following the last dose administered. Steady state was reached by Day 15. Concentrations of roflumilast in skin were, on average, 126- and 61.8-fold higher than corresponding mean plasma Ctrough following administration of roflumilast cream 0.15% and 0.5% daily for 28 days. Roflumilast N-oxide was quantifiable in only one skin sample (N = 27). Following 8 weeks of treatment in DERMIS-1, mean plasma Ctrough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. In DERMIS-2, mean plasma Ctrough was 1.72 ng/mL and 10.2 ng/mL, respectively. In the maximal usage study (mean BSA: 27.5%), eight patients (30.8%) experienced adverse events (AEs) and all were mild or moderate, with no reports of diarrhea, headache, insomnia, or application-site pain; no patients discontinued treatment due to an AE. CONCLUSION: Topical administration of roflumilast cream 0.3% results in concentrations in skin 126- and 61.8-fold higher relative to plasma, which are much higher than expected to be achievable with oral dosing. PDE4 inhibition in the skin is likely due to roflumilast as compared with its active metabolite, as there is no significant conversion to roflumilast N-oxide in the skin. Consistent with reservoir formation and retention of drug in the stratum corneum, roflumilast is slowly released from the skin (t½ 4 days) and peak-to-trough ratio is 1.2. GOV IDENTIFIERS: NCT04279119, NCT03392168, NCT04211363, NCT04211389.

IgE Depletion with Ligelizumab Does Not Significantly Improve Clinical Symptoms in Patients with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: The value, if any, of anti-IgE approaches in the treatment of atopic dermatitis has not been fully clarified. Studies using the anti-IgE omalizumab have yielded conflicting results. OBJECTIVE: Antibodies with an IgE-suppressive capacity stronger than omalizumab might be more efficacious. STUDY DESIGN: We assessed the safety and efficacy of the high-affinity anti-IgE antibody ligelizumab (280 mg, subcutaneous, every other week) in 22 adult patients with moderate-to-severe atopic dermatitis in a placebo and active (cyclosporine A) controlled, randomized, multicenter, double-blind clinical trial for 12 weeks. RESULTS: We found that ligelizumab treatment resulted in either complete (patients with baseline IgE < 1,500 IU/ml) or partial (baseline IgE > 1,500 IU/ml) suppression of serum and cell-bound IgE as well as of allergic skin prick tests. On the other hand, ligelizumab-as opposed to cyclosporine A-was not significantly superior to placebo in inducing Eczema Area and Severity Index 50 response or significantly reducing pruritus and sleep disturbance. Interestingly though, patients with high baseline IgE exhibited a slightly but not significantly better treatment response than those with low baseline IgE. CONCLUSION: Our study shows that an immunologically efficacious anti-IgE approach is not clearly superior to placebo in treating atopic dermatitis. Larger studies are needed to determine whether certain patient subgroups may benefit from this strategy. TRIAL REGISTRATION: The study was registered in 2011 at clinicaltrialsregister.eu, EudraCT Number 2011-002112-84.

Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis: A Double-blind, Vehicle-Controlled Phase 2a Randomized Clinical Trial.

Importance: Current topical treatment options for seborrheic dermatitis are limited by efficacy and/or safety. Objective: To assess safety and efficacy of roflumilast foam, 0.3%, in adult patients with seborrheic dermatitis affecting the scalp, face, and/or trunk. Design, Setting, and Participants: This multicenter (24 sites in the US and Canada) phase 2a, parallel group, double-blind, vehicle-controlled clinical trial was conducted between November 12, 2019, and August 21, 2020. Participants were adult (aged ≥18 years) patients with a clinical diagnosis of seborrheic dermatitis for a 3-month or longer duration and Investigator Global Assessment (IGA) score of 3 or greater (at least moderate), affecting 20% or less body surface area, including scalp, face, trunk, and/or intertriginous areas. Data analysis was performed from September to October 2020. Interventions: Once-daily roflumilast foam, 0.3% (n = 154), or vehicle foam (n = 72) for 8 weeks. Main Outcomes and Measures: The main outcome was IGA success, defined as achievement of IGA score of clear or almost clear plus 2-grade improvement from baseline, at week 8. Secondary outcomes included IGA success at weeks 2 and 4; achievement of erythema score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; achievement of scaling score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; change in Worst Itch Numeric Rating Scale (WI-NRS) score from baseline; and WI-NRS success, defined as achievement of 4-point or greater WI-NRS score improvement in patients with baseline WI-NRS score of 4 or greater. Safety and tolerability were also assessed. Results: A total of 226 patients (mean [SD] age, 44.9 [16.8] years; 116 men, 110 women) were randomized to roflumilast foam (n = 154) or vehicle foam (n = 72). At week 8, 104 (73.8%) roflumilast-treated patients achieved IGA success compared with 27 (40.9%) in the vehicle group (P < .001). Roflumilast-treated patients had statistically significantly higher rates of IGA success vs vehicle at week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at week 8 were 59.3% (52.5%) vs 36.6% (42.2%) in the roflumilast and vehicle groups, respectively (P < .001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the vehicle foam. Conclusions and Relevance: The results from this phase 2a randomized clinical trial of once-daily roflumilast foam, 0.3%, demonstrated favorable efficacy, safety, and local tolerability in the treatment of erythema, scaling, and itch caused by seborrheic dermatitis, supporting further investigation as a nonsteroidal topical treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04091646.

Effects of New Zealand Blackcurrant Extract on Sequential Performance Testing in Male Rugby Union Players.

Previous studies on performance effects by New Zealand blackcurrant (NZBC) extract used mainly a single exercise task. We examined the effects of NZBC extract in a battery of rugby union-specific tests including speed, agility and strength testing. University male rugby union players (n = 13, age: 21 ± 2 years, height: 182 ± 6 cm, body mass: 87 ± 13 kg) completed two full familiarisations and two experimental visits in an indoor facility. The study had a double blind, placebo-controlled, randomised, crossover design. For the experimental visits, participants consumed NZBC extract (210 mg/day of anthocyanins for 7 days) or placebo with a 7-day wash-out. Testing order was the running-based anaerobic sprint test, the Illinois agility test, seated medicine ball (3 kg) throw, and handgrip strength. With NZBC extract, there may have been an effect for average sprint time to be faster by 1.7% (placebo: 5.947 ± 0.538 s, NZBC extract: 5.846 ± 0.571 s, d = -0.18 (trivial), p = 0.06). However, with NZBC extract there may have been reduced slowing of sprint 2 (d = -0.59 (moderate), p = 0.06) and reduced slowing for sprint 6 (d = -0.56 (moderate), p = 0.03). In the Illinois agility test, there may have also been an effect for the mean time to be faster by 1.6% (placebo: 18.46 ± 1.44 s, NZBC extract: 18.15 ± 1.22 s, d = -0.24 (small), p = 0.07). The correlation between the %change in average sprint time and %change in mean agility time was not significant (Pearson R2 = 0.0698, p = 0.383). There were no differences for the seated medicine ball throw distance (p = 0.106) and handgrip strength (p = 0.709). Intake of NZBC extract in rugby union players seems to improve tasks that require maximal speed and agility but not muscle strength. NZBC blackcurrant extract may be able to enhance exercise performance in team sports that require repeated movements with high intensity and horizontal change of body position without affecting muscle strength.

Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities.

The multitargeted tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for good- and intermediate-risk metastatic renal cell carcinoma. Although generally associated with acceptable toxicity, sunitinib exhibits a novel and distinct toxicity profile that requires monitoring and management. Fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, and hypertension seem to be the most common and clinically relevant toxicities of sunitinib. Drug dosing and treatment duration are correlated with response to treatment and survival. Treatment recommendations for hypertension have been published but, currently, no standard guidelines exist for the management of noncardiovascular side effects. To discuss the optimal management of noncardiovascular side effects, an international, interdisciplinary panel of experts gathered in November 2009. Existing literature on incidence, severity, and underlying mechanisms of side effects as well as on potential treatment options were carefully reviewed and discussed. On the basis of these proceedings and the thorough review of the existing literature, recommendations were made for the monitoring, prevention, and treatment of the most common noncardiovascular side effects and are summarized in this review. The proactive assessment and consistent and timely management of sunitinib-related side effects are critical to ensure optimal treatment benefit by allowing appropriate drug dosing and prolonged treatment periods.