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BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.
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Lesiones Traumáticas del Encéfalo , Trasplante de Células Madre Mesenquimatosas , Humanos , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/cirugía , Lesiones Traumáticas del Encéfalo/terapia , Masculino , Adulto , Femenino , Método Doble Ciego , Trasplante de Células Madre Mesenquimatosas/métodos , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Mesenchymal stromal cells (MSCs) hold therapeutic potential for neurological disorders, but their impact on neuronal activity remains unclear. We investigated the effects of SB623 cells (Notch-1 intracellular domain-transfected MSCs) and parental MSCs on human induced pluripotent stem cell (iPSC)-derived neurons using multi-electrode arrays. SB623 cells significantly increased neuronal activity and oscillation in a dose-dependent manner, surpassing astrocytes in promoting network bursts. Strikingly, glutamatergic neurons showed a rapid increase in activity and bursts compared to GABAergic neurons, suggesting glutamate release from SB623 cells. We confirmed this by finding high glutamate levels in SB623 cell conditioned medium, which were reduced by glutaminase inhibition. Glutamate release was further implicated by the reduced excitability in co-cultures with astrocytes, known glutamate scavengers. Our findings reveal a novel mechanism for MSCs: promoting neuronal activity and network formation through tonic glutamate release, with potential implications for MSC-based therapies.
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Astrocitos , Técnicas de Cocultivo , Ácido Glutámico , Células Madre Pluripotentes Inducidas , Células Madre Mesenquimatosas , Neuronas , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Ácido Glutámico/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/fisiología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Astrocitos/metabolismo , Astrocitos/fisiología , Medios de Cultivo Condicionados/farmacología , Células Cultivadas , Potenciales de Acción/fisiologíaRESUMEN
The Extended Glasgow Outcome Scale (GOSE) is accepted as the primary outcome measure in registrational studies for traumatic brain injury (TBI). The Disability Rating Scale (DRS) is used to assess functional progress from initial acute injury, through rehabilitation and reintegration into the community and life. For these reasons, the DRS is an alternative measure for assessing meaningful global outcomes in chronic TBI. The objective of this study was to determine the minimally clinically important difference (MCID) for the DRS in chronic TBI, by determining the magnitude of DRS change associated with the MCID for the GOSE of 1 point. This study is a retrospective analysis of the multi-center, prospective, longitudinal, Traumatic Brain Injury Model Systems National Database of persons with outcomes at 1, 2, and 5 years and every 5 years thereafter post-injury. Spearman's correlations for dynamic and static relationships between the DRS and GOSE were significant. For the 1-point MCID for the GOSE, the dynamic MCID estimate for the DRS of a -0.68-point change was calculated as the mean DRS change associated with the difference of the GOSE score between year 1 and year 2 (score range, 3-8), using all persons in the study (n = 11,102), whereas the exploratory static MCID estimate for the DRS of -1.28 points was calculated from the slope of the best-fit line between the DRS and GOSE at year 1 follow-up (score range, 3-8; n = 13,415). The final MCID for the DRS was calculated by using the triangulation method (i.e., the arithmetic mean of the dynamic and exploratory static MCID estimates), which resulted in a -1.0-point change. The significant correlation between the DRS and GOSE has allowed for the establishment of a -1.0-point MCID for the DRS, which supports the use of the DRS as an alternative primary outcome measure for chronic TBI research studies, including clinical trials.
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Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.
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Lesiones Traumáticas del Encéfalo , Humanos , Lesiones Traumáticas del Encéfalo/terapiaRESUMEN
OBJECTIVE: To determine minimally clinically important differences (MCIDs) for Disability Rating Scale (DRS), Fugl-Meyer Upper Extremity Subscale (FM-UE), Fugl-Meyer Lower Extremity Subscale (FM-LE), and Fugl-Meyer Motor Scale (FMMS) in patients with chronic motor deficits secondary to traumatic brain injury (TBI). METHODS: Retrospective analysis from the 1-year, double-blind, randomized, surgical sham-controlled, Phase 2 STEMTRA trial (NCT02416492), in which patients with chronic motor deficits secondary to TBI (N = 61) underwent intracerebral stereotactic implantation of modified bone marrow-derived mesenchymal stromal (SB623) cells. MCIDs for DRS, FM-UE, FM-LE, and FMMS were triangulated with distribution-based, anchor-based, and Delphi panel estimates. RESULTS: Triangulated MCIDs were: 1) -1.5 points for the Disability Rating Scale; 2) 6.2 points for the Fugl-Meyer Upper Extremity Subscale; 3) 3.2 points for the Fugl-Meyer Lower Extremity Subscale; and 4) 8.4 points for the Fugl-Meyer Motor Scale. CONCLUSIONS: For the first time in the setting of patients with chronic motor deficits secondary to TBI, this study reports triangulated MCIDs for: 1) DRS, a measure of global outcome; and 2) Fugl-Meyer Scales, measures of motor impairment. These findings guide the use of DRS and Fugl-Meyer Scales in the assessment of global disability outcome and motor impairment in future TBI clinical trials.
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Lesiones Traumáticas del Encéfalo , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Lesiones Traumáticas del Encéfalo/complicaciones , Evaluación de la Discapacidad , Humanos , Evaluación de Resultado en la Atención de Salud , Recuperación de la Función , Estudios RetrospectivosRESUMEN
OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.
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Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.
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Trasplante de Médula Ósea/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Polidesoxirribonucleótidos/uso terapéutico , Trasplante de Médula Ósea/métodos , Fibrinolíticos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Insuficiencia Multiorgánica/dietoterapia , Insuficiencia Multiorgánica/etiologíaRESUMEN
AIMS: Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) associated with significant morbidity and mortality. Healthcare utilization, costs, and mortality were assessed in HSCT patients diagnosed with SOS, with and without multi-organ dysfunction (MOD). MATERIALS AND METHODS: This retrospective observational study identified real-world patients undergoing HSCT between January 1, 2009 and May 31, 2014 using the Premier Healthcare Database. In absence of a formal ICD-9-CM diagnostic code, SOS patients were identified using a pre-specified definition adapted from Baltimore and Seattle criteria and clinical practice. Severe SOS (SOS/MOD) and non-severe SOS (SOS/no-MOD) were classified according to clinical evidence for MOD in the database. RESULTS: Of the 5,418 patients with a discharge diagnosis of HSCT, 291 had SOS, with 134 categorized as SOS/MOD and 157 as SOS/no-MOD. The remaining 5,127 patients had HSCT without SOS. Overall SOS incidence was 5.4%, with 46% having evidence of MOD. Distribution of age, gender, and race were similar between the SOS cohorts and non-SOS patients. After controlling for hospital profile and admission characteristics, demographics, and clinical characteristics, the adjusted mean LOS was 31.0 days in SOS/MOD compared to 23.9 days in the non-SOS cohort (medians = 26.9 days vs 20.8 days, p < .001). The adjusted mean cost of SOS/MOD patients was $140,653, which was $41,702 higher than the non-SOS cohort (medians = $105,749 vs $74,395, p < .001). An almost 6-fold increased odds of inpatient mortality was associated with SOS/MOD compared to the non-SOS cohort (odds ratio = 5.88; 95% CI = 3.45-10.33). LIMITATIONS: Limitations of retrospective observational studies apply, since the study was not randomized. Definition for SOS was based on ICD-9 diagnosis codes from a hospital administrative database and reliant on completeness and accuracy of coding. CONCLUSIONS: Analysis of real-world data shows that SOS/MOD is associated with significant increases in healthcare utilization, costs, and inpatient mortality.
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Gastos en Salud/estadística & datos numéricos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/economía , Enfermedad Veno-Oclusiva Hepática/etiología , Adolescente , Adulto , Anciano , Baltimore , Femenino , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Enfermedad Veno-Oclusiva Hepática/complicaciones , Enfermedad Veno-Oclusiva Hepática/mortalidad , Mortalidad Hospitalaria , Hospitalización/economía , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/complicaciones , Insuficiencia Multiorgánica/economía , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post-VOD/SOS diagnosis affected Day +100 survival post-HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Polidesoxirribonucleótidos/uso terapéutico , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Adulto , Anciano , Niño , Preescolar , Esquema de Medicación , Femenino , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Polidesoxirribonucleótidos/administración & dosificación , Estudios Prospectivos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.
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Trasplante de Células Madre Hematopoyéticas/mortalidad , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/mortalidad , Polidesoxirribonucleótidos/administración & dosificación , Adolescente , Adulto , Femenino , Fibrinolíticos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/complicaciones , Enfermedad Veno-Oclusiva Hepática/terapia , Humanos , Hipotensión/inducido químicamente , Hipotensión/etiología , Masculino , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/mortalidad , Polidesoxirribonucleótidos/toxicidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/mortalidad , Adulto JovenRESUMEN
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.
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Ensayos de Uso Compasivo , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Polidesoxirribonucleótidos/administración & dosificación , Adolescente , Adulto , Anciano , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/complicaciones , Enfermedad Veno-Oclusiva Hepática/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Polidesoxirribonucleótidos/efectos adversos , Sepsis/etiología , Adulto JovenRESUMEN
Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Polidesoxirribonucleótidos/uso terapéutico , Enfermedades Vasculares/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Preescolar , Bases de Datos Factuales , Femenino , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Polidesoxirribonucleótidos/farmacología , Estudios Retrospectivos , Resultado del Tratamiento , Enfermedades Vasculares/etiología , Adulto JovenRESUMEN
Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.
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Fibrinolíticos/uso terapéutico , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Insuficiencia Multiorgánica/tratamiento farmacológico , Polidesoxirribonucleótidos/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Femenino , Enfermedad Veno-Oclusiva Hepática/complicaciones , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/diagnóstico , Insuficiencia Multiorgánica/epidemiología , Insuficiencia Multiorgánica/etiología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/líquido cefalorraquídeo , Anticuerpos Monoclonales Humanizados/efectos adversos , Apolipoproteínas E/genética , Biomarcadores/análisis , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Cognición/efectos de los fármacos , Método Doble Ciego , Edema/inducido químicamente , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fosforilación , Tomografía de Emisión de Positrones , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVE: Although Remicade (infliximab) is costly relative to non-biologic therapy, its impact on healthcare resource utilization and mucosal healing may make it a cost-effective option. This study aimed to compare gastrointestinal (GI)-related healthcare resource utilization and severity of mucosal damage before and during infliximab therapy in Crohn's disease (CD) or ulcerative colitis (UC) patients. METHODS: A retrospective chart review was conducted at 14 gastroenterology practices from across the country, which varied in practice sizes and types. Patients were aged ≥18 years, diagnosed with CD or UC, and had an infliximab index date between January 1, 2005 and September 30, 2007. GI-related utilization 12 months before and 12 months after the index date was compared. Endoscopic disease severity was categorized based on blinded review of abstracted reports. RESULTS: Results from 268 patients indicated significantly lower rates of surgery (29.7% to 9.9%, p < 0.0001, CD; 24.4% to 12.8%, p = 0.042, UC) and colonoscopy (54.4% to 17.6%, p < 0.0001, CD; 50.0% to 22.1%, p = 0.0007, UC) during infliximab therapy. The rates of hospitalizations in UC (15.1% to 3.5%, p = 0.0124) and radiology assessments in CD (23.1% to 10.4%, p = 0.006) also decreased. Based on severity data from 183 procedures, greater proportions of patients had normal or mild ratings during infliximab treatment compared with pre-treatment. LIMITATIONS: This retrospective descriptive study is limited by the type and quantity of information available in patient charts from 14 gastroenterology clinics during the first year of infliximab treatment. In addition, the number of patients with pre-treatment and post-treatment disease severity information was too small to make comparisons among disease severity groups. Further information about the severity of disease and the extent of mucosal healing could be helpful in determining the effect of therapy on resource utilization in future research. CONCLUSIONS: GI-related resource utilization was significantly lower and attenuation of mucosal damage severity was observed during infliximab treatment compared with the pre-treatment period.
Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Recursos en Salud/estadística & datos numéricos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Adulto , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/fisiopatología , Enfermedades Inflamatorias del Intestino/cirugía , Infliximab , Masculino , Auditoría Médica , Persona de Mediana Edad , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVE: To evaluate the healthcare costs and resource utilization associated with pediatric Crohn's disease (PCD) from a payer perspective. METHODS: A retrospective analysis was conducted using claims from 1 January 2003 through 31 December 2006 from the HealthCare Partners database. Patients were younger than 18 years of age, had a new diagnosis of PCD, and continuous health plan eligibility 6 months before and 12 months after the disease index date (the date of the first claim with a PCD diagnosis). For comparison, a non-PCD cohort was matched on age, sex, and birthday (within 30 days). RESULTS: Data from 30 patients with PCD and 10,864 non-PCD controls were included. The total cost per member per month (PMPM) for the PCD cohort was $2,547 compared with $101 for the non-PCD cohort. Inpatient admissions accounted for the largest portion (54%) of the total cost PMPM for PCD patients. There were 500 admissions per thousand members per year (PTMPY) for the PCD cohort and 11 admissions PTMPY for the non-PCD cohort. The average lengths of stay were 7.6 and 4.4 days for the PCD cohort and the non-PCD cohort, respectively, and the inpatient costs PMPM were $1,409 and $18, respectively. Costs and resource utilization were also higher for PCD patients treated with systemic therapies. CONCLUSION: PCD was associated with higher costs and resource utilization, compared with non-PCD controls, primarily driven by inpatient stays. Treating PCD appropriately before the disease progresses to a level requiring hospitalization may help reduce the costs associated with this disease.