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Consolidation therapy for primary CNS lymphoma (PCNSL) includes high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT), yet its efficacy compared with non-myeloablative chemoimmunotherapy remains uncertain. This study aimed to provide randomised comparative evidence on the efficacy and safety of thiotepa-based HCT-ASCT versus non-myeloablative R-DeVIC consolidation after uniform MATRix induction in newly diagnosed PCNSL. This open-label, randomised, phase 3 trial was conducted across 56 university and academic non-university hospitals with established transplantation facilities in five European countries. Eligible for inclusion were untreated, immunocompetent patients with B-cell PCNSL, aged 18-65 years regardless of Eastern Cooperative Oncology Group (ECOG) performance status, or 66-70 years with ECOG performance status 0-2. Pretreatment corticosteroids were permitted. Exclusion criteria included lymphoma manifestation outside the CNS, and congenital or acquired immunodeficiency. Patients received four cycles of MATRix induction (comprising rituximab, high-dose cytarabine, and thiotepa, in addition to high-dose methotrexate). Patients reaching at least partial response were randomly assigned (1:1) to two cycles of R-DeVIC (rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin) or HCT-ASCT with carmustine and thiotepa. The primary endpoint was progression-free survival, assessed in the full analysis set (excluding patients with major violations of entry criteria). The safety analysis set contained all randomised patients who initiated therapy. This study is registered with ClinicalTrials.gov (NCT02531841) and the EU Clinical Trials Register (EudraCT number 2012-000620-17). The study is completed. Between July 16, 2014, and Aug 31, 2019, 368 patients were enrolled. 346 (94%) patients started induction treatment, and 230 were randomly assigned; 229 patients were analysed (R-DeVIC group, n=115; HCT-ASCT group, n=114). After a median follow-up of 45·3 months, 3-year progression-free survival was significantly superior in the HCT-ASCT group (hazard ratio 0·43 [95% CI 0·27-0·68]; p=0·0003). The 3-year progression-free survival was 78% (95% CI 69-85) in the HCT-ASCT group compared with 51% (41-60) in the R-DeVIC group. The mean number of adverse events per patient was 9·3 (SD 4·4) in the R-DeVIC group and 14·6 (5·8) in the HCT-ASCT group. Fatal serious adverse events following consolidation treatment occurred in two patients in the R-DeVIC group (both acute myeloid leukaemia) and in five patients in the HCT-ASCT group (infections and infestations [n=4], pulmonary embolism [n=1]); all of these events apart from the pulmonary embolism were judged to be possibly related to treatment. In the largest randomised trial in untreated PCNSL to date, HCT-ASCT significantly improved progression-free and overall survival compared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients. German Federal Ministry of Research, Technology and Space; Swiss Cancer Research Foundation; and Riemser Pharma.
Zenagamtide (formerly amycretin) is a unimolecular peptide agonist of GLP-1, amylin, and calcitonin receptors. We aimed to investigate the dose-response relationship with respect to the efficacy and safety of once-daily oral zenagamtide compared with placebo in adults with type 2 diabetes. This 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was conducted at 83 hospital and clinic sites across 11 countries. The trial consisted of a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period. Adults (aged 18-75 years) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23·0 to <50·0 kg/m2 were randomly assigned (5:1) to oral zenagamtide or placebo using a randomisation and trial supplies management system, then further randomly assigned (1:1:1) to one of three dose groups (6, 25, or 50 mg). Participants assigned to placebo were similarly assigned to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA1c (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of oral zenagamtide was 1·5 mg, with dose escalations every 4 weeks until the maintenance dose was reached (6, 25, or 50 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA1c from baseline to week 36. The primary outcome was assessed in all randomly assigned participants using the efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all randomly assigned participants exposed to treatment. This trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 186 (20%) of 915 screened participants were randomly assigned to oral zenagamtide (54 participants to 6 mg, 51 participants to 25 mg, and 51 participants to 50 mg) or placebo (30 participants) and were included in the full analysis set. At week 36, from baseline (mean range 7·9-8·1%), estimated mean change in HbA1c was -0·9% with zenagamtide 6 mg (estimated treatment difference [ETD] vs placebo -0·5% [95% CI -1·04 to -0·04]; p=0·033), -1·3% with zenagamtide 25 mg (-0·99% [-1·49 to -0·49]; p=0·0001), and -1·4% with zenagamtide 50 mg (-1·09% [-1·59 to -0·59]; p<0·0001). The most common adverse events were gastrointestinal, occurring in 14 (26%) of 54 participants in the zenagamtide 6 mg group, 21 (41%) of 51 participants in the zenagamtide 25 mg group, 24 (47%) of 51 participants in the zenagamtide 50 mg group, and seven (23%) of 30 participants in the placebo group. Serious adverse events were reported in seven (4%) of 186 participants receiving zenagamtide: two in the 6 mg group, two in the 25 mg group, and three in 50 mg group. No serious adverse events were reported in the placebo group. No deaths occurred during the trial. In people with type 2 diabetes, once-daily oral zenagamtide showed clinically meaningful and significant improvements in HbA1c from baseline to week 36 compared with placebo at all three dose levels (6, 25, and 50 mg). The safety and tolerability of oral zenagamtide was consistent with other GLP-1 and amylin receptor agonists. Novo Nordisk.
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Coronary artery bypass grafting (CABG) is a common but invasive operation traditionally performed through a median sternotomy. Minimally invasive cardiac surgery (MICS) CABG via small thoracotomy might improve postoperative recovery, but randomised evidence has been scarce. We aimed to compare patient-reported recovery after MICS CABG versus sternotomy CABG in patients with multivessel coronary artery disease and to describe clinical and safety outcomes. MIST was an investigator-initiated, international, open-label, randomised controlled trial done at seven centres (four academic hospitals and three community hospitals) in Canada, India, China, Germany, the USA, and Japan. Patients referred to participating surgeons for CABG were eligible if they were aged 18 years or older; had angiographically confirmed multivessel coronary artery disease, defined as lesions of at least 70% stenosis in at least two major epicardial vessels and at least two separate coronary artery territories (left anterior descending artery, left circumflex artery, or right coronary artery) or left main coronary stenosis of 50% or more; and were suitable for coronary surgery both with sternotomy CABG and MICS CABG. Patients who were haemodynamically compromised, had contraindications to either approach, had had previous cardiac surgery, or required concomitant procedures were excluded. Eligible patients were randomly assigned (1:1) to MICS CABG or sternotomy CABG by a central, web-based system, stratified by centre, with block sizes of four and six. The primary endpoint was patient-reported physical recovery at 1 month, assessed by the 36-item Short Form Health Survey Physical Component Summary (SF-36 PCS) score. The primary analysis was by intention to treat; safety analyses were done according to treatment received. Missing 1-month questionnaire data were handled by multiple imputation. The trial was registered with ClinicalTrials.gov (NCT03447938), and is closed to recruitment. Between Aug 24, 2018, and Nov 26, 2024, 176 patients were enrolled, 170 of whom were randomly assigned to MICS CABG (n=86) or sternotomy CABG (n=84). The median age of patients was 67·0 years (IQR 61·0-72·0), 154 (91%) patients were male, and 16 (9%) were female. At 1 month after surgery, SF-36 PCS scores were significantly higher in the MICS CABG group than in the sternotomy CABG group (mean 45·1 [SD 8·0] vs 42·2 [9·1]; mean difference 2·9 [95% CI 0·3-5·5]; p=0·031). Clinical and safety follow-up at 1 month was complete in all patients; 12-month clinical and safety follow-up was complete in all except three patients in the sternotomy CABG group. Up to 12 months after surgery, there were no deaths or strokes in either group; one major adverse cardiac or cerebrovascular event occurred in the MICS CABG group before 1 month and none in the sternotomy CABG group. For selected patients with multivessel coronary artery disease, MICS CABG performed by experienced teams improved patient-reported physical recovery at 1 month compared with sternotomy CABG, with no apparent safety penalty through to 12 months. These findings support consideration of MICS CABG in appropriately selected patients treated by experienced teams, and further studies of implementation, recovery pathways, and long-term outcomes. Medtronic.
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Zenagamtide (formerly amycretin) is a unimolecular agonist of GLP-1, amylin, and calcitonin receptors. We aimed to investigate the dose-response relationship with respect to the efficacy and safety of once-weekly subcutaneous zenagamtide compared with placebo in adults with type 2 diabetes. This 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was conducted at 83 hospital and clinic sites across 11 countries. The trial consisted of a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period. Adults (aged 18-75 years) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23·0 to <50·0 kg/m2 were randomly assigned (6:1) to once-weekly subcutaneous zenagamtide or placebo using a randomisation and trial supplies management system, before being further randomly assigned to one of six dose groups (1:1:1:1:1:1; 0·4, 1·5, 5, 10, 20, or 40 mg). Participants assigned to placebo were similarly allocated to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA1c (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of subcutaneous zenagamtide was 0·2 mg, with dose escalations every 4 weeks until the maintenance dose was reached (0·4-40 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA1c from baseline to week 36. The primary outcome was assessed in all randomly assigned participants using the efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all randomly assigned participants exposed to treatment. The trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 262 (29%) of 915 screened individuals were randomly assigned to subcutaneous zenagamtide (n=225) or placebo (n=37). Participants were further randomly assigned (1:1:1:1:1:1) to one of six doses (38 participants to 0·4 mg, 36 participants to 1·5 mg, 37 participants to 5 mg, 38 participants to 10 mg, 38 participants to 20 mg, and 38 participants to 40 mg) or placebo (37 participants). 261 participants were exposed to treatment. At week 36, estimated change in HbA1c (mean across all groups at baseline 7·8% [SD 0·8]) ranged from -0·9% with zenagamtide 0·4 mg (estimated treatment difference vs placebo: -0·77% [95% CI -1·26 to -0·28]; p=0·0021) to -1·7% with zenagamtide 40 mg (-1·56% [-2·05 to -1·07]; p<0·0001). Most adverse events were gastrointestinal and mild to moderate in severity. 21 (8%) of 261 participants reported serious adverse events (four with zenagamtide 0·4 mg, three with 1·5 mg, two with 5 mg, five with 10 mg, three with 20 mg, one with 40 mg, and three with placebo). No deaths occurred. In people with type 2 diabetes, once-weekly subcutaneous zenagamtide 0·4-40 mg demonstrated clinically meaningful and significant improvements in change in HbA1c from baseline to week 36 compared with placebo, with a safety and tolerability profile consistent with that of other GLP-1-based and amylin-based therapies. Novo Nordisk.
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