RESUMEN
OBJECTIVES: Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). METHODS: 1041 patients with moderate-severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every fourâ weeks (120/Q4W) or 90 mg every twoâ weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24â weeks and modified Total Sharp Score (mTSS) change at 52â weeks. RESULTS: There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (-15.0%, -18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (-16.3%, -19.4%, -0.1%), IgA (-11.4%, -4.7%, 1.2%) and IgG (-8.6%, -7.8%, 0.1%). Discontinuations due to adverse events were similar between groups. Numerically more serious infections were reported in tabalumab groups (1.7%, 0.6%, 0.3%); numerically more injection-site reactions were reported in the 90/Q2W group (2.3%, 4.3%, 2.3%). CONCLUSIONS: Neither clinical efficacy nor significant safety signals were observed with tabalumab despite evidence of biological activity. This study was terminated early due to insufficient efficacy. TRIAL REGISTRATION NUMBER: NCT01198002.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor Activador de Células B/antagonistas & inhibidores , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antirreumáticos/uso terapéutico , Método Doble Ciego , Terminación Anticipada de los Ensayos Clínicos , Humanos , Análisis de Intención de Tratar , Metotrexato/uso terapéutico , Insuficiencia del TratamientoRESUMEN
OBJECTIVES: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. METHODS: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8â mg baricitinib for 12â weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12â weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. RESULTS: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8â mg baricitinib maintained or improved in all measures through 24â weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. CONCLUSIONS: Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. TRIAL REGISTRATION NUMBER: NCT01185353.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Azetidinas/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Sulfonamidas/administración & dosificación , Antirreumáticos/efectos adversos , Azetidinas/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Purinas , Pirazoles , Sulfonamidas/efectos adversosRESUMEN
The purpose of this analysis was to assess the association of osteoporosis-related vertebral fracture burden and pulmonary function. This study also examined the relationship between vertebral fracture burden and height loss, estimated by arm span - height. This was a single-site and single-visit study. Patients had a history of at least 1 moderate or severe vertebral fracture. Vertebral fracture burden was quantified using the spinal deformity index (SDI). Pulmonary function during inspiration was determined by spirometry. Forty-one women aged 70-91 completed the study. Vertebral fracture burden negatively correlated with forced inspiratory vital capacity and inspiratory time. For each unit increase in SDI, forced inspiratory vital capacity decreased by 1.62%, and inspiratory time decreased by 2.39%. There was no correlation between SDI and measures of inspiratory flow. For each unit increase in SDI, height decreased by about 0.5 cm. Vertebral fractures were associated with decreased lung volume and height loss.
Asunto(s)
Estatura , Pulmón/fisiopatología , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/fisiopatología , Traumatismos Vertebrales/etiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Traumatismos Vertebrales/fisiopatología , EspirometríaRESUMEN
OBJECTIVES: The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis. METHODS: In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24. RESULTS: At week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy across the treatment groups. Discontinuations due to adverse events (AE) were 3.4%, 2.7%, and 4.0%; incidence of treatment-emergent AEs were 64.1%, 58.2%, and 58.8%, with 23.2%, 25.9%, and 22.0% treatment-emergent infections; and incidence rates of serious AEs were 3.7%, 2.2%, and 2.8% with 1.1%, 0.3%, and 0.7% serious infections in the 120/Q4W, 90/Q2W, and placebo groups, respectively. Three deaths were reported (120/Q4W, n = 2; 90/Q2W, n = 1). Each tabalumab group had significant decreases versus placebo in CD3-CD20 B cells (P ≤ 0.05) and in serum immunoglobulins (P ≤ 0.001). CONCLUSIONS: Although tabalumab administration resulted in biologic activity, as demonstrated by changes in B cells and immunoglobulins, targeting BAFF-dependent pathways alone is not sufficient to significantly reduce rheumatoid arthritis disease activity.
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Anticuerpos Monoclonales/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide/inmunología , Factor Activador de Células B/antagonistas & inhibidores , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). METHODS: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). RESULTS: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. CONCLUSIONS: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Antirreumáticos/administración & dosificación , Antirreumáticos/farmacocinética , Artritis Reumatoide/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Medicamentos , Femenino , Estado de Salud , Humanos , Inyecciones Subcutáneas , Articulaciones/efectos de los fármacos , Articulaciones/patología , Articulaciones/fisiopatología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). RESULTS: At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. CONCLUSIONS: At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT00689728.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor Activador de Células B/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Estado de Salud , Humanos , Inyecciones Intravenosas , Articulaciones/efectos de los fármacos , Articulaciones/fisiopatología , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Increased mortality from infection in patients with pulmonary alveolar proteinosis occurs in association with high levels of autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We tested the hypothesis that neutrophil functions are impaired in patients with pulmonary alveolar proteinosis and that GM-CSF autoantibodies cause the dysfunction. METHODS: We studied 12 subjects with pulmonary alveolar proteinosis, 61 healthy control subjects, and 12 control subjects with either cystic fibrosis or end-stage liver disease. We also studied GM-CSF-/- mice and wild-type mice. We evaluated basal neutrophil functions, neutrophil functions after priming by GM-CSF to augment antimicrobial functions, and the effects of highly purified GM-CSF autoantibodies on neutrophil functions in vitro and in vivo. RESULTS: Neutrophils from subjects with pulmonary alveolar proteinosis had normal ultrastructure and differentiation markers but impaired basal functions and antimicrobial functions after GM-CSF priming. GM-CSF-/- mice also had reduced basal neutrophil functions, but functions after GM-CSF priming were unimpaired. The neutrophil dysfunction characteristic of pulmonary alveolar proteinosis was reproduced in a dose-dependent fashion in blood specimens from healthy control subjects after incubation with affinity-purified GM-CSF autoantibodies isolated from patients with pulmonary alveolar proteinosis. The injection of mouse GM-CSF antibodies into wild-type mice also caused neutrophil dysfunction. CONCLUSIONS: The antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, owing to the presence of GM-CSF autoantibodies. The effects of these autoantibodies show that GM-CSF is an essential regulator of neutrophil functions.
Asunto(s)
Autoanticuerpos/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Neutrófilos/fisiología , Proteinosis Alveolar Pulmonar/inmunología , Adolescente , Adulto , Anciano , Animales , Estudios de Casos y Controles , Niño , Fibrosis Quística/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Humanos , Recuento de Leucocitos , Hepatopatías/inmunología , Masculino , Ratones , Ratones Endogámicos , Persona de Mediana Edad , Neutrófilos/ultraestructuraRESUMEN
OBJECTIVE: To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis. METHODS: Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64. RESULTS: A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64. CONCLUSION: Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64. TRIAL REGISTRATION NUMBER: NCT00966875.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Retratamiento , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor. OBJECTIVES: To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA). METHODS: This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120â mg every 4â weeks (120/Q4W) or 90â mg every 2â weeks (90/Q2W)) versus placebo, with loading doses (240 or 180â mg) at week 0. Patients were allowed background disease-modifying antirheumatic drugs and previously discontinued ≥1 tumour necrosis factor α inhibitors for lack of efficacy/intolerance. Primary end point was American College of Rheumatology 20% (ACR20) response at 24â weeks. This study was terminated early due to futility. RESULTS: Most patients had moderate-to-high baseline disease activity. There was no significant difference in week 24 ACR20 responses between 120/Q4W, 90/Q2W, and placebo (17.6%, 24.3%, 20%) per non-responder imputation analysis. Mean percent changes in CD20+ B-cell count (-10.8%, -9.6%, +10.9%) demonstrated expected pharmacodynamic effects. Treatment-emergent adverse events (AEs) were similar (59.5%, 51.7%, 52.6%), as were AE discontinuations (2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%), serious infectious events (1.3%, 0, 0) and events of interest: infections (23.5%, 25.9%, 24%), injection site reactions (13.1%, 25.8%, 11%) and allergy/hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence of treatment-emergent antidrug antibodies was similar to placebo (3.9%, 4.8%, 3.9%). No deaths or new/unexpected safety findings were reported. CONCLUSIONS: Tabalumab did not demonstrate clinical efficacy in patients with RA in this phase 3 study, despite evidence of biological activity. There were no notable differences in safety parameters between tabalumab treatment groups and placebo. TRIAL REGISTRATION NUMBER: NCT01202773.
RESUMEN
Patients with cystic fibrosis (CF) can be discriminated from healthy subjects by measurement of the nasal potential difference, which has become a useful outcome measure for therapies directed toward correcting defective electrolyte transport in CF. A standard operating procedure was developed by a CF Foundation clinical trials network, to be followed by all sites performing collaborative studies. Key variables in the measurement included type of voltmeter, exploring probe, reference electrodes, and solutions used to assess both sodium transport and chloride conductance. Eight sites submitted data on 3-8 normal and 4-5 CF subjects. Baseline voltage, an index of sodium transport, was -18.2 +/- 8.3 mV (mean +/- SD) for normals, and -45.3 +/- 11.4 mV for CF patients. There was no CFTR-mediated chloride secretion in CF subjects, as evidenced by the lack of response to perfusion with zero chloride + beta agonist solutions (+3.2 +/- 3.5 mV) vs. that in normals (-23.7 +/- 10.2 mV). The standardized nasal potential difference measurement minimizes variability between operators and study sites. Valid and consistent results can be attained with trained operators and attention to technical details. These data demonstrate the procedure to be sufficient for multicenter studies in the CF Foundation network.
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Protocolos Clínicos , Fibrosis Quística/diagnóstico , Mucosa Nasal/fisiopatología , Cloruro de Sodio/metabolismo , Adulto , Ensayos Clínicos como Asunto , Estudios de Factibilidad , Femenino , Humanos , Transporte Iónico , Masculino , Potenciales de la Membrana , Evaluación de Resultado en la Atención de Salud , Juego de Reactivos para DiagnósticoRESUMEN
INTRODUCTION: The objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients. METHODS: Patients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study. Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W). Regardless of prior treatment, all patients in this study received subcutaneous 60-mg tabalumab Q4W for the first 3 months, then a one-time increase to 120-mg tabalumab Q4W (60-mg/120-mg group) and a one-time decrease to 60-mg tabalumab Q4W per patient was allowed (60-mg/120-mg/60-mg group). RESULTS: There were 182 patients enrolled: 60 mg (n = 60), 60/120 mg (n = 121) and 60/120/60 mg (n = 1). Pretabalumab baseline disease activity was generally higher in the 60-mg/120-mg group. There was a higher frequency of serious adverse events and treatment-emergent adverse events, as well as infections and injection-site reactions, in the 60-mg/120-mg group. One death unrelated to the study drug occurred (60-mg/120-mg group). In both groups, total B-cell counts decreased by approximately 40% from the baseline level in the RCT originating study. Both groups demonstrated efficacy through 52 weeks of treatment relative to baseline pretabalumab disease activity based on American College of Rheumatology criteria improvement ≥20%, ≥50% and ≥70%; European League against Rheumatism Responder Index in 28 joints; Disease Activity Score in 28 joints-C-reactive protein; and Health Assessment Questionnaire-Disability Index. CONCLUSIONS: With long-term, open-label tabalumab treatment, no unexpected safety signals were observed, and B-cell reductions were consistent with previous findings. Despite differences in RCT originating studies, both groups demonstrated an efficacy response through the 52-week extension. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00837811 (registered 3 February 2009).
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Administración Intravenosa , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Factor Activador de Células B/inmunología , Linfocitos B/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To evaluate ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal antibody, in 2 populations of rheumatoid arthritis (RA) patients: biologics-naive patients and patients with an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: In this phase II, randomized, double-blind study, placebo or ixekizumab was administered subcutaneously to 260 biologics-naive patients and 188 patients with an inadequate response to TNF inhibitors at weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant disease-modifying antirheumatic drugs. The primary objective was to determine the dose-response relationship of ixekizumab as measured by the proportion of biologics-naive patients meeting the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Using a logistic regression model defined a priori, a statistically significant dose-response relationship as measured by ACR20 response rates at week 12 was detected in biologics-naive patients (P = 0.031). For patients with an inadequate response to TNF inhibitors, ACR20 responses at week 12 were significantly better with ixekizumab than placebo (P < 0.05). Decreases in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), Clinical Disease Activity Index (CDAI), and CRP level from baseline were observed at week 12 in the ixekizumab groups in both populations (P < 0.05 versus placebo). Onset of action was rapid in some dose groups in both populations, with improvements in the ACR20, DAS28-CRP, CRP levels, and CDAI observed by day 3 (P < 0.05). Adverse events occurred with similar frequencies overall in the ixekizumab and placebo groups. Infections were more frequent with ixekizumab than placebo (biologics-naive 25% versus 19%; inadequate responders to TNF inhibitors 27% versus 25%). No mycobacterial or invasive fungal infections were reported. CONCLUSION: Ixekizumab improved RA signs and symptoms in RA patients who were either naive to biologics treatment or had an inadequate response to TNF inhibitors. The safety profile was similar to that of other biologic agents, with no unexpected safety concerns.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Interleucina-17/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Medicamentos , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Placebos , Resultado del TratamientoRESUMEN
BACKGROUND: Long-term safety and efficacy of AIR((R)) inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) in patients with diabetes and concomitant lung disease remain to be established. METHODS: This 1-year, randomized, open-label, active comparator, two-arm, parallel study compared the safety and efficacy of AIR insulin to subcutaneous (SC) insulin in patients having type 1 or type 2 diabetes and asthma. Patients with type 2 diabetes continued taking their prestudy oral antihyperglycemic medication. RESULTS: Change in hemoglobin A1C from baseline to end point was similar for the AIR insulin and SC insulin groups (-0.063 +/- 0.128% and -0.315 +/- 0.128% respectively, P = 0.105), but noninferiority failed to be achieved (the upper limit of the 95% confidence interval [-0.053, 0.555] was >0.4%). The total daily prandial dose increased more in the AIR insulin group than in the SC insulin group (0.150 U/kg and 0.044 U/kg, respectively, P = 0.002). Safety profiles were generally comparable between treatments. At end point, forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) postbronchodilator (-0.016 +/- 0.005 vs. 0.002 +/- 0.005, P = 0.006) and diffusing capacity of the lung for carbon monoxide (-1.214 +/- 0.325 mL/min/torr vs. -0.383 +/- 0.311 mL/min/torr, P = 0.028) both decreased more in the AIR insulin group than in the SC insulin group, but the differences were not present at follow-up. FEV(1) and FVC were similar between treatment groups at end point. Incidences of hypoglycemia were comparable between groups. Insulin antibody binding increased more in the AIR insulin group. Cough was the most common adverse event; however, there was no difference in incidence between the AIR insulin (15.3%) and SC insulin (12.4%) treatment groups (P = 0.572). CONCLUSIONS: In patients who have diabetes and asthma, AIR insulin demonstrated glycemic efficacy similar to SC insulin. Additionally, the safety profile of AIR insulin in patients with and without asthma is consistent.
Asunto(s)
Administración por Inhalación , Asma/complicaciones , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Hemoglobina Glucada/metabolismo , Insulina/administración & dosificación , Insulina/uso terapéutico , Adulto , Edad de Inicio , Anciano , Índice de Masa Corporal , Monóxido de Carbono/análisis , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Hemoglobina Glucada/efectos de los fármacos , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Fumar , Capacidad Vital/efectos de los fármacosRESUMEN
BACKGROUND: Insulin initiation in patients with type 2 diabetes is often delayed because of concerns about injections. Our objective was to compare the effects of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) with those of injectable insulin on glycemic control and safety. METHODS: This was planned as a 24-month, open-label, randomized study in adults with diabetes inadequately controlled by one or more oral antihyperglycemic medications (OAMs). Following a 2-week baseline period, patients continued OAMs and were randomized to AIR insulin (n = 208) or insulin lispro (n = 203) before meals. The primary end point was hemoglobin A1C (A1C) change from baseline to 6 months. Noninferiority was established if the upper limit of the 95% confidence interval of the difference in A1C change was < or =0.4%. RESULTS: Early termination of the study diminished the number of patients for the 12- and 24-month analyses, but not for the primary 6-month end point analyses. AIR insulin and injectable insulin groups had comparable baseline A1C values (8.18% vs. 8.21%, respectively). Change in A1C from baseline to 6-month end point was similar (least squares mean, -0.81 +/- 0.09% and -0.87 +/- 0.09%; 95% confidence interval for the difference -0.117, 0.234; P = 0.51) and so were final A1C values of 7.36% and 7.31% for AIR insulin and injectable insulin, respectively. At 6 months, no differences were observed in eight-point profiles, overall and nocturnal hypoglycemia, and weight gain. Greater decreases in spirometry were observed in the AIR insulin group at 12 months. Cough was the most frequently reported adverse event (20% [AIR insulin] vs. 10% [insulin lispro]; P = 0.002). CONCLUSIONS: Treatment with AIR insulin resulted in similar improvement in glycemic control compared with insulin lispro. More frequent cough and greater decrease in spirometry were observed with AIR insulin.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Insulina/análogos & derivados , Insulina/uso terapéutico , Administración por Inhalación , Anciano , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Insulina/administración & dosificación , Insulina Lispro , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Selección de Paciente , Capacidad Vital/efectos de los fármacosRESUMEN
BACKGROUND: Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. METHODS: This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. RESULTS: In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. CONCLUSIONS: The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.
Asunto(s)
Administración por Inhalación , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/análogos & derivados , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Peso Corporal , Diabetes Mellitus Tipo 1/sangre , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/epidemiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Insulina Glargina , Insulina Lispro , Insulina de Acción Prolongada , Masculino , Persona de Mediana Edad , Seguridad , Capacidad Vital/efectos de los fármacosRESUMEN
Using data from NHANES III, we evaluated the effect of diabetes on the age-related decline in lung function. The Diabetes group (n=471) had significantly lower mean FEV(1) and FVC values than the No Diabetes group (n=4317), but pulmonary function declined with increasing age at a similar rate for both groups.
Asunto(s)
Factores de Edad , Diabetes Mellitus/fisiopatología , Adulto , Anciano , Femenino , Volumen Espiratorio Forzado , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos , Capacidad VitalRESUMEN
OBJECTIVE: This study evaluated pharmacokinetic and glucodynamic responses to AIR inhaled insulin relative to subcutaneous insulin lispro, safety, pulmonary function, and effects of salbutamol coadministration. RESEARCH DESIGN AND METHODS: Healthy, mildly asthmatic, and moderately asthmatic subjects (n = 13/group, aged 19-58 years, nonsmoking, and nondiabetic) completed this phase I, open-label, randomized, crossover euglycemic clamp study. Subjects received 12 units equivalent AIR insulin or 12 units subcutaneous insulin lispro or salbutamol plus AIR insulin (moderate asthma group only) before the clamp. RESULTS: AIR insulin exposure was reduced 34 and 41% (both P < 0.01) in asthmatic subjects (area under the curve(0-t'), 24.0 and 21.1 nmol x min x l(-1) in mild and moderate asthma subjects, respectively) compared with healthy subjects (35.2 nmol x min x l(-1)), respectively. Glucodynamic (G) effects were similar in healthy and mildly asthmatic subjects (G(tot) = 38.7 and 23.4 g, respectively; P = 0.16) and were reduced in moderately asthmatic subjects (G(tot) = 10.7 g). Salbutamol pretreatment (moderately asthmatic subjects) improved bioavailability. AIR insulin had no discernable effect on pulmonary function. AIR insulin adverse events (cough, headache, and dizziness) were mild to moderate in intensity and have been previously reported or are typical of studies involving glucose clamp procedures. CONCLUSIONS: This study suggests that pulmonary disease severity and asthma treatment status influence the metabolic effect of AIR insulin in individuals with asthma but do not affect AIR insulin pulmonary safety or tolerability. In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.
Asunto(s)
Asma/fisiopatología , Glucemia/metabolismo , Insulina/administración & dosificación , Insulina/farmacocinética , Pruebas de Función Respiratoria , Administración por Inhalación , Adulto , Albuterol/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/sangre , Asma/tratamiento farmacológico , Glucemia/efectos de los fármacos , Estudios Cruzados , Volumen Espiratorio Forzado , Técnica de Clampeo de la Glucosa , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Capacidad Vital/efectos de los fármacosRESUMEN
Neutrophils are critical in the inflammatory process by moving rapidly to tissue sites of inflammation. Members of the small Rho GTPase family, Rac1, Rac2, CDC42, and RhoA, are central regulators of cell migration by cytoskeleton rearrangement. The role of Rac1 in neutrophil migration related to inflammatory processes has remained elusive and has yet to be determined in physiologic in vivo models. We previously demonstrated a role for Rac1 in tail retraction. Here, we present evidence that Rac1-mediated uropod formation may be due to crosstalk with a related Rho GTPase RhoA. To assess the physiologic relevance of these findings, we used adoptive transfer of Rac1flox/flox bone marrow cells which allows postengraftment in vivo deletion of Rac1 only in blood cells. We examined the specific role of Rac1 in neutrophil migration into the lung during the inflammatory process induced by formyl-methionyl-leucyl-phenylalanine exposure. The loss of Rac1 activity in neutrophils is associated with a significant decreased neutrophil recruitment into lung alveolar and attenuation of emphysematous lesions. Overall, this study suggests that Rac1 is a physiologic integrator of signals for neutrophil recruitment into lung tissue during an inflammatory response.
Asunto(s)
Pulmón/patología , Infiltración Neutrófila , Proteína de Unión al GTP rac1/fisiología , Animales , Células Sanguíneas , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Enfisema/patología , Inflamación/inducido químicamente , Ratones , Transducción de Señal , Transducción Genética , Proteína de Unión al GTP rac1/genéticaRESUMEN
Fibroblast growth factor-7 (FGF7) is a lung epithelial cell mitogen that is cytoprotective during injury. Transgenic mice that conditionally expressed FGF7 were used to dissect the mechanisms of FGF7 protection during lung injury. FGF7 improved survival when induced 3 days prior to acute lung injury. In contrast, FGF7 caused pulmonary inflammation and lung injury after 7 days or longer. Gene expression analysis of mouse lung mRNA identified mRNAs that contribute to the protective effects of FGF7. FGF7 improved survival during acute lung injury in adult mouse lung after short-term expression, but paradoxically induced inflammation and injury after persistent expression.
Asunto(s)
Citoprotección , Factor 7 de Crecimiento de Fibroblastos/fisiología , Inflamación/etiología , Pulmón/citología , Animales , Células Epiteliales/fisiología , Factor 7 de Crecimiento de Fibroblastos/análisis , Perfilación de la Expresión Génica , Ratones , Ratones Transgénicos , Níquel/toxicidad , Proteínas/genética , ARN Mensajero/análisis , Síndrome de Dificultad Respiratoria/prevención & control , Factores de TiempoRESUMEN
Alveolar macrophages (AMs) normally respond to lipopolysaccharide (LPS) by activating Toll-like receptor (TLR)-4 signaling, a mechanism critical to lung host defense against gram-negative bacteria such as Pseudomonas aeruginosa. Because granulocyte macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)) mice are hyporesponsive to LPS, we evaluated the role of GM-CSF in TLR-4 signaling in AMs. Pulmonary TNF-alpha levels and neutrophil recruitment 4 h after intratracheal administration of Pseudomonas LPS were reduced in GM(-/-) compared with wild-type (GM(+/+)) mice. Secretion of TNF-alpha by AMs exposed to LPS ex vivo was also reduced in GM(-/-) mice and restored in mice expressing GM-CSF specifically in the lungs (SPC-GM(+/+)/GM(-/-) mice). LPS-dependent NF-kappaB promoter activity, TNF-alpha secretion, and neutrophil chemokine release were reduced in AM cell lines derived from GM(-/-) mice (mAM) compared with GM(+/+) (MH-S). Retroviral expression of PU.1 in mAM cells, which normally lack PU.1, rescued all of these AM defects. To determine whether GM-CSF, via PU.1, regulated expression of TLR-4 pathway components, mRNA and protein levels for key components were evaluated in MH-S cells (GM(+/+), PU.1(Positive)), mAM cells (GM(-/-), PU.1(Negative)), and mAMPU.1+ cells (GM(-/-), PU.1(Positive)). Cluster of differentiation antigen-14, radioprotective 105, IL-1 receptor-associated kinase (IRAK)-M mRNA, and protein were dependent upon GM-CSF and restored by expression of PU.1. In contrast, expression of other TLR-4 pathway components (myeloid differentiation-2, TLR-4, IRAK-1, IRAK-2, Toll/IL-1 receptor domain containing adapter protein/MyD88 adaptor-like, myeloid differentiation primary-response protein 88, IRAK-4, TNF receptor-associated factor-6, NF-kappaB, inhibitor of NF-kappaB kinase) were not GM-CSF or PU.1-dependent. These results show that GM-CSF, via PU.1, enables AM responses to P. aeruginosa LPS by regulating expression of a specific subset of components of the TLR-4 signaling pathway.