RESUMO
BACKGROUND: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56. METHODS: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100. RESULTS: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE. CONCLUSIONS: In these exploratory analyses, GUS, as a first-line systemic treatment or second-line systemic treatment in FAE nonresponders, was associated with long-term clinical efficacy up to week 100, including a withdrawal period.
Assuntos
Anticorpos Monoclonais Humanizados , Fumaratos , Psoríase , Humanos , Masculino , Fumaratos/administração & dosagem , Fumaratos/efeitos adversos , Feminino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Resultado do Tratamento , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Substituição de MedicamentosRESUMO
Importance: Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies. Objective: To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis. Design, Setting, and Participants: The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively. Interventions: In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks. Main Outcomes and Measures: Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood. Results: Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and ß defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified. Conclusions and Relevance: Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT03818035.
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RATIONALE: Patients with acute lung injury have impaired function of the lung surfactant system. Prior clinical trials have shown that treatment with exogenous recombinant surfactant protein C (rSP-C)-based surfactant results in improvement in blood oxygenation and have suggested that treatment of patients with severe direct lung injury may decrease mortality. OBJECTIVES: Determine the clinical benefit of administering an rSP-C-based synthetic surfactant to patients with severe direct lung injury due to pneumonia or aspiration. METHODS: A prospective randomized blinded study was performed at 161 centers in 22 countries. Patients were randomly allocated to receive usual care plus up to eight doses of rSP-C surfactant administered over 96 hours (n = 419) or only usual care (n = 424). MEASUREMENTS AND MAIN RESULTS: Mortality to 28 days after treatment, the requirement for mechanical ventilation, and the number of nonpulmonary organ failure-free days were not different between study groups. In contrast to prior studies, there was no improvement in oxygenation in patients receiving surfactant compared with the usual care group. Investigation of the possible reasons underlying the lack of efficacy suggested a partial inactivation of rSP-C surfactant caused by a step of the resuspension process that was introduced with this study. CONCLUSIONS: In this study, rSP-C-based surfactant was of no clinical benefit to patients with severe direct lung injury. The unexpected lack of improvement in oxygenation, coupled with the results of in vitro tests, suggest that the administered suspension may have had insufficient surface activity to achieve clinical benefit.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Lesão Pulmonar Aguda/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Troca Gasosa Pulmonar/efeitos dos fármacos , Proteína C Associada a Surfactante Pulmonar/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Respiração Artificial , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Studies to date have shown no survival benefit for the use of exogenous surfactant to treat patients with the ARDS. To identify specific patient subgroups for future study, we performed an exploratory post hoc analysis of clinical trials of recombinant surfactant protein-C (rSP-C) surfactant (Venticute; Nycomed GmbH; Konstanz, Germany). METHODS: We performed a pooled analysis of all five multicenter studies in which patients with ARDS due to various predisposing events were treated with rSP-C surfactant. Patients received either usual care (n = 266) or usual care plus up to four intratracheal doses (50 mg/kg) of rSP-C surfactant (n = 266). Factors influencing the study end points were analyzed using descriptive statistics, analysis of covariance, and logistic regression models. RESULTS: ARDS was most often associated with pneumonia or aspiration, sepsis, and trauma or surgery. For the overall patient population, treatment with rSP-C surfactant significantly improved oxygenation (p = 0.002) but had no effect on mortality (32.6%). Multivariate analysis showed age and acute physiology and chronic health evaluation (APACHE) II score to be the strongest predictors of mortality. In the subgroup of patients with severe ARDS due to pneumonia or aspiration, surfactant treatment was associated with markedly improved oxygenation (p = 0.0008) and improved survival (p = 0.018). CONCLUSIONS: rSP-C surfactant improved oxygenation in patients with ARDS irrespective of the predisposition. Post hoc evidence of reduced mortality associated with surfactant treatment was obtained in patients with severe respiratory insufficiency due to pneumonia or aspiration. Those patients are the focus of a current randomized, blinded, clinical trial with rSP-C surfactant.
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Surfactantes Pulmonares/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Síndrome do Desconforto Respiratório/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Instilação de Medicamentos , Masculino , Pessoa de Meia-Idade , Traqueia , Resultado do TratamentoRESUMO
BACKGROUND: Preclinical studies suggest that exogenous surfactant may be of value in the treatment of the acute respiratory distress syndrome (ARDS), and two phase 2 clinical trials have shown a trend toward benefit. We conducted two phase 3 studies of a protein-containing surfactant in adults with ARDS. METHODS: In two multicenter, randomized, double-blind trials involving 448 patients with ARDS from various causes, we compared standard therapy alone with standard therapy plus up to four intratracheal doses of a recombinant surfactant protein C-based surfactant given within a period of 24 hours. RESULTS: The overall survival rate was 66 percent 28 days after treatment, and the median number of ventilator-free days was 0 (68 percent range, 0 to 26); there was no significant difference between the groups in terms of mortality or the need for mechanical ventilation. Patients receiving surfactant had a significantly greater improvement in blood oxygenation during the initial 24 hours of treatment than patients receiving standard therapy, according to both univariate and multivariate analyses. CONCLUSIONS: The use of exogenous surfactant in a heterogeneous population of patients with ARDS did not improve survival. Patients who received surfactant had a greater improvement in gas exchange during the 24-hour treatment period than patients who received standard therapy alone, suggesting the potential benefit of a longer treatment course.
Assuntos
Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , APACHE , Análise de Variância , Causalidade , Método Duplo-Cego , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteína C Associada a Surfactante Pulmonar/efeitos adversos , Surfactantes Pulmonares/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Taxa de Sobrevida , Falha de TratamentoRESUMO
Up to 18% of acutely ill patients randomized into multicenter clinical trials may not satisfy inclusion/exclusion criteria. To improve compliance with such criteria in an ICU-based multicenter international drug trial, we established a novel Internet/telephone-based strategy for providing rapid case approval or disapproval by centralized panels of critical care physicians. We assessed whether these panels could acquire and record accurate patient information, and whether this approach would minimize enrollment of ineligible patients and could be accomplished in a timely fashion. Analysis of the first 1000 submitted patients showed accurate data capture for 98.7% of enrolled and randomized patients. Median response time from case submission to panel member decision was 34.7 min. Over 99% of enrolled patients met critical study criteria. We conclude that, an Internet-based communications strategy appears to be a valuable adjunct to multicenter clinical trials in acutely ill patients when rapid assurance of eligibility is required.