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1.
Blood ; 127(13): 1656-65, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-26825712

RESUMO

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 #.


Assuntos
Fibrinolíticos/uso terapêutico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hepatopatia Veno-Oclusiva/complicações , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/epidemiologia , Insuficiência de Múltiplos Órgãos/etiologia , Índice de Gravidade de Doença , Adulto Jovem
2.
Biol Blood Marrow Transplant ; 23(6): 997-1004, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28285079

RESUMO

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.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/mortalidade , Polidesoxirribonucleotídeos/administração & dosagem , Adolescente , Adulto , Feminino , Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/complicações , Hepatopatia Veno-Oclusiva/terapia , Humanos , Hipotensão/induzido quimicamente , Hipotensão/etiologia , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Polidesoxirribonucleotídeos/toxicidade , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Adulto Jovem
3.
Br J Haematol ; 178(1): 112-118, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28444784

RESUMO

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.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Polidesoxirribonucleotídeos/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Polidesoxirribonucleotídeos/administração & dosagem , Estudos Prospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adulto Jovem
4.
N Engl J Med ; 370(4): 322-33, 2014 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-24450891

RESUMO

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.).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados/efeitos adversos , Apolipoproteínas E/genética , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Cognição/efeitos dos fármacos , Método Duplo-Cego , Edema/induzido quimicamente , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fosforilação , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Falha de Tratamento , Proteínas tau/líquido cefalorraquidiano
5.
Lancet ; 368(9539): 929-37, 2006 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-16962882

RESUMO

BACKGROUND: No drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation. METHODS: We determined the efficacy of dapoxetine in a prospectively predefined integrated analysis of two 12-week randomised, double-blind, placebo-controlled, phase III trials of identical design done independently, in parallel, at 121 sites in the USA. Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity). The primary endpoint was intravaginal ejaculatory latency time (IELT) measured by stopwatch. Safety and tolerability were assessed. All analyses were done on an intention-to-treat basis. The trials are registered at ClinicalTrials.gov, numbers NCT00211107 and NCT00211094. FINDINGS: 672, 676, and 610 patients completed in the placebo, 30 mg dapoxetine, and 60 mg dapoxetine groups, respectively. Dapoxetine significantly prolonged IELT (p<0.0001, all doses vs placebo). Mean IELT at baseline was 0.90 (SD 0.47) minute, 0.92 (0.50) minute, and 0.91 (0.48) minute, and at study endpoint (week 12 or final visit) was 1.75 (2.21) minutes for placebo, 2.78 (3.48) minutes for 30 mg dapoxetine, and 3.32 (3.68) minutes for 60 mg dapoxetine. Both dapoxetine doses were effective on the first dose. Common adverse events (30 mg and 60 mg dapoxetine, respectively) were nausea (8.7%, 20.1%), diarrhoea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%). INTERPRETATION: On-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation.


Assuntos
Benzilaminas/uso terapêutico , Ejaculação/efeitos dos fármacos , Naftalenos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Adulto , Idoso , Benzilaminas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Disfunções Sexuais Fisiológicas/psicologia , Fatores de Tempo , Resultado do Tratamento
6.
J Clin Sleep Med ; 11(4): 427-32, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25580605

RESUMO

STUDY OBJECTIVES: This post hoc analysis evaluated the time to response that can be expected with sodium oxybate (SXB) for treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy. METHODS: Data were from a 4-week, double-blind, randomized, placebo-controlled trial (GHB-2; N = 136) of oral SXB 3 g, 6 g, and 9 g nightly, and its 12-month open-label extension (GHB-3). Two response definitions were utilized: ≥ 20% improvement in Epworth Sleepiness Scale (ESS) score (EDS responders), and ≥ 50% reduction in weekly cataplexy attacks (cataplexy responders). These thresholds were previously determined to be clinically relevant based on analysis of the relationship of Clinical Global Impression of Change with ESS and number of cataplexy attacks. Kaplan-Meier curves and median times to first response, based on above criteria, and to maximum response were estimated. RESULTS: Among 86 patients randomized to SXB in GHB-2 and continued into GHB-3, 77.6% and 90.7% were EDS and cataplexy responders, respectively. The median (95% CI) times to first response were 37 (31-50) days for EDS and 25 (17-29) days for cataplexy, and median times to maximum response were 106 (85-164) days for EDS and 213 (94-279) days for cataplexy. GHB-3 results among 31 patients initially randomized to placebo were consistent with those treated with SXB throughout, but with longer times to maximum response. CONCLUSIONS: Response onset, assessed as clinically meaningful improvements in EDS and cataplexy, was observed in most patients within 2 months; a longer period is needed to achieve maximum response. Clinicians should recognize that time to initial and maximum response may take weeks to months.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Hipnóticos e Sedativos/uso terapêutico , Narcolepsia/tratamento farmacológico , Oxibato de Sódio/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento
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