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在季节性疟疾化学药物预防的基础上加用阿奇霉素的效应
Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention
摘 要
背景
通过阿奇霉素大规模用药控制沙眼使埃塞俄比亚儿童的全因死亡率持续下降。季节性疟疾化学药物预防应用的是磺胺多辛-乙胺嘧啶联合阿莫地喹每月用药,目前尚不明确在此基础上加用阿奇霉素可否降低非洲儿童的死亡率和发病率。
方法
我们以户为单位将布基纳法索和马里的3~59月龄儿童随机分组,在每年的疟疾传播季节,分别在磺胺多辛-乙胺嘧啶联合阿莫地喹的基础上加用阿奇霉素或加用安慰剂。联合用药的每个用药周期为3天,间隔期为1个月,每个传播季节用药4个周期,连续3个传播季节用药。主要终点是死亡或住院至少24小时,且住院原因并非创伤或择期手术。通过主动和被动监测的方式记录数据。
结果
2014年7月,共有19,578名儿童被随机分配接受季节性疟疾化学药物预防加用阿奇霉素(9735名儿童)或加用安慰剂(9843名儿童);每年,年满5岁的儿童退出试验,新的儿童被纳入试验。在意向治疗分析中,阿奇霉素组和安慰剂组在三个疟疾传播季节的死亡和住院总人数分别为250人和238人(有风险的每1000儿童-年的事件数,24.8 vs. 23.5;发生率比,1.1;95%置信区间[CI],0.88~1.3)。符合方案分析的结果相似。阿奇霉素组下列事件的发生率低于安慰剂组:胃肠道感染(1647 vs. 1985起;发生率比,0.85;95% CI,0.79~0.91)、上呼吸道感染(4893 vs. 5763起;发生率比,0.85;95% CI,0.81~0.90)以及疟疾以外的其他发热性疾病(1122 vs. 1424起;发生率比,0.79;95% CI,0.73~0.87)。两组的疟疾寄生虫血症患病率和不良事件发生率均相似。
结论
在布基纳法索和马里的儿童中,在季节性疟疾化学药物预防所使用的抗疟药物的基础上加用阿奇霉素与加用安慰剂相比,并未降低死亡或住院(原因并非创伤或手术)的发生率,但阿奇霉素组的疾病负担低于安慰剂组。(由全球联合健康试验计划[Joint Global Health Trials scheme]资助;在ClinicalTrials.gov number注册号为NCT02211729。)
Daniel Chandramohan, Alassane Dicko, Issaka Zongo, et al. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. DOI: 10.1056/NEJMoa1811400
阿奇霉素降低非洲儿童死亡率的更长期评估
Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa
摘 要
背景
MORDOR I试验(Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance)表明,在尼日尔,连续两年的每年两次阿奇霉素大规模用药与安慰剂相比,使新生儿期后的儿童死亡率降低了18%。这一获益是随着每次用药而增加还是由于抗生素耐药性而减少,我们目前尚不清楚。
方法
在MORDOR I试验的尼日尔部分,我们将594个社区随机分组,根据分组结果每年两次向1~59月龄儿童分发阿奇霉素或安慰剂,共分发4次。在MORDOR II试验中,我们再以开放标签方式向所有这些社区分发两次阿奇霉素。由不知晓参与者最初分组结果的人口普查工作者每年评估两次全因死亡率。
结果
在MORDOR II试验中,在首次接受每年两次阿奇霉素的社区(即在MORDOR I试验中接受了2年安慰剂)和第3年接受阿奇霉素的社区(即在MORDOR I试验中接受了2年阿奇霉素),阿奇霉素的平均(±SD)覆盖率分别为91.3±7.2%和92.0±6.6%。在MORDOR II试验中,在最初于第1年接受安慰剂的社区和最初于第1年接受阿奇霉素的社区,死亡率分别为24.0/1000人-年(95%置信区间[CI],22.1~26.3)和23.3/1000人-年(95% CI,21.4~25.5),两组无显著差异(P=0.55)。最初接受安慰剂的社区接受阿奇霉素之后,死亡率降低了13.3%(95% CI,5.8~20.2)(P=0.007)。在最初接受阿奇霉素并继续接受阿奇霉素一年的社区,第三年和前两年的死亡率差异不显著(-3.6%;95% CI,-12.3~4.5;P=0.50)。
结论
我们并无证据表明阿奇霉素大规模用药对尼日尔儿童死亡率的影响在第三年治疗中减小。最初接受安慰剂的社区接受阿奇霉素后,儿童死亡率下降。(由比尔和梅林达·盖茨基金会资助;在ClinicalTrials.gov注册号为NCT02047981。)
Jeremy D. Keenan, Ahmed M. Arzika, Ramatou Maliki, et al. Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa. DOI: 10.1056/NEJMoa1817213
2型糖尿病患者的强化血糖控制——15年随访
Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up
摘 要
背景
我们之前报告,经过总共10年的联合干预和观察性随访,在患2型糖尿病的1791名退伍军人中,与标准降糖治疗相比,中位5.6年的强化降糖治疗使主要心血管事件的风险显著降低(降幅17%)。我们在本文中报告全部15年的随访结果。
方法
完成最初的临床试验后,我们使用中央数据库确定心血管事件、住院治疗和死亡,从而对纳入的参与者(完整队列)进行观察性随访。我们还询问参与者是否愿意通过问卷调查和病历审核的方式提供更多数据(调查队列)。预设的主要结局是由主要心血管事件(包括非致死性心肌梗死、非致死性卒中、新发充血性心力衰竭或充血性心力衰竭恶化、因缺血性坏疽截肢和心血管原因死亡)构成的复合结局。全因死亡是预设的次要结局
结果
完整队列包括1655例参与者,调查队列包括1391例参与者。在本试验(最初纳入1791例参与者)期间,强化治疗组(892例参与者)和标准治疗组(899例参与者)的糖化血红蛋白曲线有平均1.5个百分点的分离,而到试验结束后3年时,这一差异减小至0.2~0.3个百分点。在15年随访(活性药治疗+试验后观察)期间,强化治疗组的主要心血管事件或死亡风险并未低于标准治疗组(主要结局的风险比,0.91;95%置信区间[CI],0.78~1.06;P=0.23;死亡的风险比,1.02;95% CI,0.88~1.18)。然而,在糖化血红蛋白曲线长时间分离期间,主要心血管疾病结局的风险降低(风险比,0.83;95% CI,0.70~0.99),但这一获益在糖化血红蛋白水平相等后未能持续(风险比,1.26;95% CI,0.90~1.75)。
结论
被随机分配接受5.6年强化血糖控制的2型糖尿病患者与接受标准治疗的患者相比,前者的心血管事件风险仅在糖化血红蛋白曲线长时间分离期间较低。并无证据表明强化血糖控制有遗留效应或生存获益。(由美国退伍军人事务部合作研究计划[VA Cooperative Studies Program]资助;VADT在ClinicalTrials.gov注册号为NCT00032487。)
Peter D. Reaven, Nicholas V. Emanuele, Wyndy L. Wiitala, et al. 10.1056/NEJMoa1806802. DOI: 10.1056/NEJMoa1806802
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维奈托克联合奥比妥珠单抗治疗有合并症的CLL患者
Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions
摘 要
背景
BCL2抑制剂维奈托克(venetoclax)已经对慢性淋巴细胞白血病(CLL)患者表现出活性,但维奈托克联合其他药物治疗有合并症的CLL患者的疗效尚不清楚。
方法
在这项开放标签的3期试验中,我们在未经治的有合并症CLL患者中研究了固定疗程的维奈托克联合奥比妥珠单抗治疗。疾病累计评分表(Cumulative Illness Rating Scale,评分范围为0~56分,较高评分表示器官系统功能受损较严重)评分大于6分或肌酐清除率计算值小于70 ml/min的患者被随机分组,分别接受维奈托克-奥比妥珠单抗或苯丁酸氮芥-奥比妥珠单抗治疗。主要终点是研究者判定的无进展生存期。我们还评价了各治疗方案的安全性。
结果
共有432例患者(中位年龄,72岁;中位疾病累计评分表评分,8分;中位肌酐清除率,66.4 ml/min)被随机分组,每组各216例患者。中位随访28.1个月后,维奈托克-奥比妥珠单抗组和苯丁酸氮芥-奥比妥珠单抗组分别发生了30和77起主要终点事件(疾病进展或死亡)(风险比,0.35;95%置信区间[CI],0.23~0.53;P<0.001)。维奈托克-奥比妥珠单抗组24个月时无进展生存率的Kaplan-Meier估计值显著高于苯丁酸氮芥-奥比妥珠单抗组:分别为88.2%(95% CI,83.7~92.6)和64.1%(95% CI,57.4~70.8)。这一获益也见于有TP53缺失、突变或两者同时存在的患者,以及免疫球蛋白重链基因无突变的患者。在维奈托克-奥比妥珠单抗组和苯丁酸氮芥-奥比妥珠单抗组中,3级或4级中性粒细胞减少的发生率分别为52.8%和48.1%,3级或4级感染的发生率分别为17.5%和15.0%。维奈托克-奥比妥珠单抗组和苯丁酸氮芥-奥比妥珠单抗组的全因死亡率分别为9.3%和7.9%。这些差异不显著。
结论
在未经治的有合并症CLL患者中,维奈托克-奥比妥珠单抗组的无进展生存期超过苯丁酸氮芥-奥比妥珠单抗组。(由罗氏制药和艾伯维资助;在ClinicalTrials.gov注册号为NCT02242942。)
Kirsten Fischer, Othman Al-Sawaf, Jasmin Bahlo, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. DOI: 10.1056/NEJMoa1815281
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Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention
在季节性疟疾化学药物预防的基础上加用阿奇霉素的效应
Abstract
Background
Mass administration of azithromycin for trachoma control led to a sustained reduction in all-cause mortality among Ethiopian children. Whether the addition of azithromycin to the monthly sulfadoxine–pyrimethamine plus amodiaquine used for seasonal malaria chemoprevention could reduce mortality and morbidity among African children was unclear.
Methods
We randomly assigned children 3 to 59 months of age, according to household, to receive either azithromycin or placebo, together with sulfadoxine–pyrimethamine plus amodiaquine, during the annual malaria-transmission season in Burkina Faso and Mali. The drug combinations were administered in four 3-day cycles, at monthly intervals, for three successive seasons. The primary end point was death or hospital admission for at least 24 hours that was not due to trauma or elective surgery. Data were recorded by means of active and passive surveillance.
Results
In July 2014, a total of 19,578 children were randomly assigned to receive seasonal malaria chemoprevention plus either azithromycin (9735 children) or placebo (9843 children); each year, children who reached 5 years of age exited the trial and new children were enrolled. In the intention-to-treat analysis, the overall number of deaths and hospital admissions during three malaria-transmission seasons was 250 in the azithromycin group and 238 in the placebo group (events per 1000 child-years at risk, 24.8 vs. 23.5; incidence rate ratio, 1.1; 95% confidence interval [CI], 0.88 to 1.3). Results were similar in the per-protocol analysis. The following events occurred less frequently with azithromycin than with placebo: gastrointestinal infections (1647 vs. 1985 episodes; incidence rate ratio, 0.85; 95% CI, 0.79 to 0.91), upper respiratory tract infections (4893 vs. 5763 episodes; incidence rate ratio, 0.85; 95% CI, 0.81 to 0.90), and nonmalarial febrile illnesses (1122 vs. 1424 episodes; incidence rate ratio, 0.79; 95% CI, 0.73 to 0.87). The prevalence of malaria parasitemia and incidence of adverse events were similar in the two groups.
Conclusion
Among children in Burkina Faso and Mali, the addition of azithromycin to the antimalarial agents used for seasonal malaria chemoprevention did not result in a lower incidence of death or hospital admission that was not due to trauma or surgery than antimalarial agents plus placebo, although a lower disease burden was noted with azithromycin than with placebo. (Funded by the Joint Global Health Trials scheme; ClinicalTrials.gov number, NCT02211729.)
Daniel Chandramohan, Alassane Dicko, Issaka Zongo, et al. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. DOI: 10.1056/NEJMoa1811400
Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa
阿奇霉素降低非洲儿童死亡率的更长期评估
Abstract
Background
The MORDOR I trial (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) showed that in Niger, mass administration of azithromycin twice a year for 2 years resulted in 18% lower postneonatal childhood mortality than administration of placebo. Whether this benefit could increase with each administration or wane owing to antibiotic resistance was unknown.
Methods
In the Niger component of the MORDOR I trial, we randomly assigned 594 communities to four twice-yearly distributions of either azithromycin or placebo to children 1 to 59 months of age. In MORDOR II, all these communities received two additional open-label azithromycin distributions. All-cause mortality was assessed twice yearly by census workers who were unaware of participants’ original assignments.
Results
In the MORDOR II trial, the mean (±SD) azithromycin coverage was 91.3±7.2% in the communities that received twice-yearly azithromycin for the first time (i.e., had received placebo for 2 years in MORDOR I) and 92.0±6.6% in communities that received azithromycin for the third year (i.e., had received azithromycin for 2 years in MORDOR I). In MORDOR II, mortality was 24.0 per 1000 person-years (95% confidence interval [CI], 22.1 to 26.3) in communities that had originally received placebo in the first year and 23.3 per 1000 person-years (95% CI, 21.4 to 25.5) in those that had originally received azithromycin in the first year, with no significant difference between groups (P=0.55). In communities that had originally received placebo, mortality decreased by 13.3% (95% CI, 5.8 to 20.2) when the communities received azithromycin (P=0.007). In communities that had originally received azithromycin and continued receiving it for an additional year, the difference in mortality between the third year and the first 2 years was not significant (−3.6%; 95% CI, −12.3 to 4.5; P=0.50).
Conclusion
We found no evidence that the effect of mass administration of azithromycin on childhood mortality in Niger waned in the third year of treatment. Childhood mortality decreased when communities that had originally received placebo received azithromycin. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02047981.)
Jeremy D. Keenan, Ahmed M. Arzika, Ramatou Maliki, et al. Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa. DOI: 10.1056/NEJMoa1817213
Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up
2型糖尿病患者的强化血糖控制——15年随访
Abstract
Background
We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.
Methods
We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.
Results
There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).
Conclusion
Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)
Peter D. Reaven, Nicholas V. Emanuele, Wyndy L. Wiitala, et al. 10.1056/NEJMoa1806802. DOI: 10.1056/NEJMoa1806802
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Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions
维奈托克联合奥比妥珠单抗治疗有合并症的CLL患者
Abstract
Background
The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.
Methods
In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax–obinutuzumab or chlorambucil–obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.
Results
In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax–obinutuzumab group and 77 had occurred in the chlorambucil–obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan–Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax–obinutuzumab group than in the chlorambucil–obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax–obinutuzumab group and in 48.1% of patients in the chlorambucil–obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax–obinutuzumab group and 7.9% in the chlorambucil–obinutuzumab group. These differences were not significant.
Conclusion
Among patients with untreated CLL and coexisting conditions, venetoclax–obinutuzumab was associated with longer progression-free survival than chlorambucil–obinutuzumab. (Funded by F. Hoffmann–La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.)
Kirsten Fischer, Othman Al-Sawaf, Jasmin Bahlo, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. DOI: 10.1056/NEJMoa1815281
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