RESUMO
Current drug development strategies present many challenges that can impede drug approval by regulatory agencies. Alternative study models, such as adaptive trial designs, have recently sparked interest, as they provide a flexible and more efficient approach in conducting clinical trials. Adaptive trial designs offer several potential benefits over traditional randomized controlled trials, which include decrease in costs, reduced clinical development time and limiting exposure of patients to potentially ineffective treatments allowing completion of studies with fewer patients. This article explores the current use of adaptive trial designs in non-oncologic skin diseases and highlights the most common types of adaptive designs used in the field. We also review the operational challenges and statistical considerations associated with such designs and propose clinical development strategies to successfully implement adaptive designs. The article also proposes instances where adaptive trial designs are particularly beneficial, and other situations where they may not be very useful.
Assuntos
Dermatologia , Projetos de Pesquisa , Humanos , Dermatologia/métodos , Dermatopatias/terapia , Ensaios Clínicos como Assunto , Ensaios Clínicos Adaptados como Assunto/métodosRESUMO
Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.
Assuntos
Dermatite Atópica , Modelos Estatísticos , Humanos , Dermatite Atópica/tratamento farmacológico , Prova Pericial , Interpretação Estatística de Dados , Projetos de PesquisaRESUMO
Tapinarof is a topical, aryl-hydrocarbon receptor agonist that has recently received FDA-approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.
Assuntos
Dermatite Atópica , Psoríase , Estilbenos , Humanos , Dermatite Atópica/tratamento farmacológico , Psoríase/tratamento farmacológico , Resorcinóis/uso terapêutico , Estilbenos/uso terapêuticoRESUMO
The rising prevalence of atopic dermatitis (AD) in developing countries and its substantial socioeconomic impact have furthered research over the last two decades giving way to advances in its aetiopathogenesis and treatment. Topical therapies targeting newly identified AD signalling pathways are being developed. Numerous clinician-assessed disease severity outcome measurement instruments (OMIs) are available to evaluate the efficacy of investigational treatments in proof-of-concept (POC) trials for AD. However, little is known about the comparative sensitivity of these efficacy OMIs. We performed a systematic review and meta-analysis to compare the sensitivity of different OMIs in controlled trials of topical therapies for AD published between January 1, 2000 and April 7, 2020. Treatment effect size of OMIs reported at Week 4 was calculated with 95% Confidence Interval (CI). The sensitivity of OMIs was compared by pooling the standardized difference between means (Cohen's d and Cohen's h) for any two OMI-parameter combinations that were reported in ≥3 studies identified in our systematic review. Assessed parameters were difference between active and vehicle at Week 4 and change from baseline [CFB] and percentage change from baseline [%CFB] at Week 4. We identified a total of 15 studies with 3313 subjects examining 14 different OMIs were included in this quantitative meta-analysis. Continuous OMIs had a significantly higher treatment effect size vs. dichotomous OMIs (P = 0.006). Comparisons of Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), body surface area (BSA) and SCORing Atopic Dermatitis (SCORAD) for available parameters were performed and generally had a similar sensitivity, with BSA showing smaller overall effect size estimates. In conclusion, continuous OMIs used in topical clinical trials for AD had significantly higher treatment effect sizes when compared to dichotomous OMIs. Continuous OMIs could provide more power for POC trials with a small sample size in atopic dermatitis with topical therapies.
Assuntos
Dermatite Atópica , Eczema , Superfície Corporal , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Humanos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.
Assuntos
Dermatite Atópica , Preparações Farmacêuticas , Adulto , Azetidinas , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Humanos , Purinas , Pirazóis , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas , Resultado do TratamentoRESUMO
BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
Assuntos
Dermatite Atópica , Corticosteroides , Adulto , Anticorpos Monoclonais Humanizados , Azetidinas , Dermatite Atópica/tratamento farmacológico , Humanos , Purinas , Pirazóis , Índice de Gravidade de Doença , Sulfonamidas , Resultado do TratamentoRESUMO
BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.
Assuntos
Acetonitrilas/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/administração & dosagem , Piperidinas/administração & dosagem , Piridazinas/administração & dosagem , Acetonitrilas/efeitos adversos , Acetonitrilas/farmacocinética , Adulto , Biomarcadores/sangue , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Selectina E/sangue , Feminino , Humanos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacocinética , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Placebos/administração & dosagem , Placebos/efeitos adversos , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: As novel systemic therapeutics for patients with atopic dermatitis (AD) are developed, ethical and methodological concerns regarding placebo-controlled-trials (PCT) have surfaced. OBJECTIVE: To guide the design and implementation of PCT in AD, focusing on trials with systemic medications. METHODS: A subgroup of the International Eczema Council (IEC) developed a consensus e-survey, which was disseminated to IEC members. RESULTS: The response rate was 43/82 (52%). Consensus was reached on 24/27 statements and on 3/11 options from multiple-selection statements, including: performing monotherapy studies in proof-of-concept phases; avoiding concomitant topical corticosteroids or calcineurin inhibitors until a predefined timepoint as rescue (borderline consensus); selection of sites and assessors with recognized expertise in AD clinical trials; clear definition and identification of baseline disease severity; minimizing time and proportion of patients on placebo; using daily emollients with several options provided; instigating open-label extension studies for enrolment after a predefined timepoint; and including outcomes which set a higher bar for disease clearance. CONCLUSION: Conducting PCT in AD requires balancing several, sometimes opposing principles, including ethics, methodology, regulatory requirements and real-world needs. This paper can provide a framework for conducting PCT with systemic medications for patients with AD.
Assuntos
Ensaios Clínicos como Assunto , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Placebos , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Inhibiting interleukin (IL)-23 in patients with psoriasis has demonstrated high levels of skin clearance. OBJECTIVES: To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. METHODS: Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. RESULTS: Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. CONCLUSIONS: At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist. OBJECTIVES: To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA). METHODS: Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale. RESULTS: At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo. CONCLUSIONS: Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Genitália , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Prurido/diagnóstico , Prurido/etiologia , Psoríase/complicações , Psoríase/diagnóstico , Psoríase/psicologia , Qualidade de Vida , Índice de Gravidade de Doença , Saúde Sexual , Resultado do TratamentoRESUMO
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Psoríase/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Adulto , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Seguimentos , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate-to-severe psoriasis and psoriatic arthritis. OBJECTIVE: To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate-to-severe psoriasis. METHODS: In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double-blinded until the end of Year 3 and open-label from Year 4. Here, we focus on the 300 mg fixed-interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses. RESULTS: At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified. CONCLUSION: Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate-to-severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Palmoplantar psoriasis is a variant of psoriasis vulgaris which can severely impair quality of life. OBJECTIVES: The main objectives of this double-blind, placebo-controlled, randomized study were to assess the efficacy and impact on quality of life and work productivity of apremilast for the treatment of moderate-to-severe palmoplantar psoriasis. METHODS: A total of 100 patients with moderate-to-severe palmoplantar psoriasis were randomized to either apremilast 30 mg bid or placebo for 16 weeks. At Week 16, all patients received apremilast 30 mg bid until Week 32. The primary endpoint was the proportion of patients who achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 at Week 16. RESULTS: There was no significant difference in the proportion of patients who achieved a PPPGA of 0/1 at Week 16 between patients randomized to apremilast (14%) and placebo (4%; P = 0.1595). After 32 weeks of treatment with apremilast, 24% of patients achieved a PPGA of 0/1. In addition, apremilast was superior to placebo in achieving Palmoplantar Psoriasis Area Severity Index (PPPASI) 75 (apremilast: 22%; placebo: 8%; P = 0.0499), in improving PPPASI (apremilast: -7.4 ± 7.1; placebo: -3.6 ± 5.9; P = 0.0167), Dermatology Life Quality Index score (apremilast: -4.3 ± 5.1; placebo: -0.8 ± 4.5; P = 0.0004) and in reducing activity impairment (apremilast: -11.0 ± 22.3; placebo: 2.5 ± 25.5; P = 0.0063). CONCLUSION: Despite the absence of a significant difference between apremilast and placebo in proportion of patients achieving a PPPGA of 0/1, the presence of significant differences observed for several secondary endpoints suggests that apremilast may have a role in the treatment of moderate-to-severe palmoplantar psoriasis.
Assuntos
Dermatoses do Pé/tratamento farmacológico , Dermatoses da Mão/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/tratamento farmacológico , Talidomida/análogos & derivados , Método Duplo-Cego , Eficiência , Feminino , Dermatoses do Pé/fisiopatologia , Dermatoses da Mão/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Psoríase/fisiopatologia , Qualidade de Vida , Índice de Gravidade de Doença , Talidomida/uso terapêutico , TrabalhoRESUMO
BACKGROUND: Hyperhidrosis is a common medical condition which can have a significant impact on quality of life. Umeclidinium (UMEC) is a long-acting muscarinic antagonist (LAMA) developed as a dermal formulation. OBJECTIVES: This 2-week, double-blind, randomized, vehicle-controlled study evaluated systemic exposure, safety and tolerability of topically administered UMEC in subjects with primary axillary hyperhidrosis. Clinical effect was a secondary objective, measured by gravimetry and the hyperhidrosis disease severity scale (HDSS). Vehicle was included to evaluate safety. METHODS: Twenty-three subjects were randomized to either 1.85% UMEC (N = 18) or vehicle (N = 5) once daily. RESULTS: Measurable plasma concentrations were observed in 78% of subjects after the treatment. Nine subjects (50%) on UMEC and two subjects (40%) on vehicle reported AEs, most commonly application site reactions. At Day 15, seven subjects (41%) in UMEC and two subjects (40%) in vehicle had at least a 50% reduction in sweat production. Eight subjects (47%) in UMEC and one subject (20%) in vehicle had at least a two-point reduction in HDSS. No comparisons of treatment arms were planned prospectively. CONCLUSIONS: The measurable exposure, acceptable safety and preliminary clinical activity observed in this proof-of-concept study suggest the potential clinical utility of topical UMEC in subjects with axillary hyperhidrosis.
Assuntos
Hiperidrose/tratamento farmacológico , Antagonistas Muscarínicos/efeitos adversos , Quinuclidinas/efeitos adversos , Sudorese/efeitos dos fármacos , Administração Cutânea , Adulto , Axila , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/sangue , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/uso terapêutico , Estudo de Prova de Conceito , Quinuclidinas/sangue , Quinuclidinas/farmacocinética , Quinuclidinas/uso terapêutico , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long-term follow-up is needed to evaluate psoriasis therapies fully. OBJECTIVES: To determine the long-term (3-year) efficacy and safety of secukinumab in moderate-to-severe psoriasis. METHODS: Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double-blind regimens. Dosing regimens included a fixed-interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. RESULTS: In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63·8%, and of PASI 100 responders it was 42·6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality-of-life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. CONCLUSIONS: Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoAssuntos
Fármacos Dermatológicos/uso terapêutico , Interleucina-17/metabolismo , Psoríase/tratamento farmacológico , Células Th17/imunologia , Ustekinumab/uso terapêutico , Humanos , Interferon gama/metabolismo , Interleucinas/metabolismo , Psoríase/imunologia , RNA Mensageiro/metabolismo , Receptores de Interleucina/metabolismo , Pele/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina 22RESUMO
BACKGROUND: The efficacy of current topical acne treatments in mitigating the potential for acne scarring is not known. OBJECTIVE: To evaluate the effect of adapalene 0.1%/benzoyl peroxide 2.5% (A/BPO) gel compared to vehicle in reducing the risk of acne scarring. METHODS: Multicentre, randomized, investigator-blinded, vehicle-controlled, split-face study conducted over 6 months. Subjects were adults with active moderate facial acne vulgaris and at least 10 atrophic acne scars at baseline. Efficacy evaluations included counts of atrophic acne scars and primary acne lesions as well as a Scar Global Assessment (SGA; 5-point scale). RESULTS: After 6 months treatment, scar counts remained stable with A/BPO while increasing by approximately 25% with vehicle (mean scar count 11.58 vs. 13.55, respectively, at Month 6; P = 0.036). The percentage of subjects with a SGA of 'almost clear' (hardly visible scars) increased from 9.7% to 45.2% with A/BPO, whereas it did not change with vehicle (P = 0.0032). Total acne lesion counts decreased by 65% with A/BPO and 36% with vehicle (mean lesion count 8.5 vs. 16.1, respectively, at Month 6; P < 0.001). LIMITATIONS: Relatively small study group (31 subjects). CONCLUSION: Topical long-term treatment with A/BPO is effective in reducing the risk of atrophic scars and improving the global severity of scarring.