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Ponsegromab for the
Treatment of Cancer Cachexia恶病质是癌症的常见并发症，与死亡风险增加相关。生长分化因子15（GDF-15）是一种循环细胞因子。癌性恶病质患者的GDF-15水平会升高。在一项对癌性恶病质患者进行的小型开放标签1b期研究中，抑制GDF-15的人源化单克隆抗体ponsegromab与患者体重、食欲和体力活动改善相关，并且与血清GDF-15水平降低相关。Cachexia is
a common complication of cancer and is associated with an increased risk of
death. The level of growth differentiation factor 15 (GDF-15), a circulating
cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b
study involving patients with cancer cachexia, ponsegromab, a humanized
monoclonal antibody inhibiting GDF-15, was associated with improved weight,
appetite, and physical activity, along with suppressed serum GDF-15 levels.在此项为期12周的2期、随机、双盲试验中，我们以1:1:1:1比例分配血清GDF-15水平升高（≥1500 pg/mL）的癌性恶病质患者接受100 mg、200 mg或400 mg剂量ponsegromab或安慰剂，每4周皮下注射一次，共注射3次。主要终点是12周时体重与基线相比的变化。关键次要终点是食欲和恶病质症状、体力活动的数字指标以及安全性。In this
phase 2, randomized, double-blind, 12-week trial, we assigned patients with
cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in
a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg
or to receive placebo, administered subcutaneously every 4 weeks for three
doses. The primary end point was the change from baseline in body weight at 12
weeks. Key secondary end points were appetite and cachexia symptoms, digital
measures of physical activity, and safety.共计187例患者接受随机分组。其中40%患非小细胞肺癌，32%患胰腺癌，29%患结直肠癌。12周时，ponsegromab组患者的体重增加幅度显著大于安慰剂组，100 mg组的中位组间差异为1.22 kg（95%可信区间，0.37~2.25），200
mg组为1.92 kg（95%可信区间，0.92~2.97），400 mg组为2.81
kg（95%可信区间，1.55~4.08）。与安慰剂组相比，400 mg ponsegromab组的食欲和恶病质症状以及体力活动指标均有所改善。据报告，ponsegromab组和安慰剂组的不良事件（任何原因）发生率分别为70%和80%。A total of
187 patients underwent randomization. Of these patients, 40% had non–small-cell
lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12
weeks, patients in the ponsegromab groups had significantly greater weight gain
than those in the placebo group, with a median between-group difference of 1.22
kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95%
credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible
interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across
measures of appetite and cachexia symptoms, along with physical activity, in the
400-mg ponsegromab group relative to placebo. Adverse events of any cause were
reported in 70% of the patients in the ponsegromab group and in 80% of those in
the placebo group.在GDF-15水平升高的癌性恶病质患者中，使用ponsegromab抑制GDF-15可增加体重和总体活动水平，减轻恶病质症状，这些发现证实GDF-15在恶病质中的驱动作用。（由辉瑞公司资助；在ClinicalTrials.gov注册号为NCT05546476。）Among
patients with cancer cachexia and elevated GDF-15 levels, the inhibition of
GDF-15 with ponsegromab resulted in increased weight gain and overall activity
level and reduced cachexia symptoms, findings that confirmed the role of GDF-15
as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.)Groarke
JD, Crawford J, Collins SM, et al. Ponsegromab for the Treatment of Cancer
Cachexia. DOI: 10.1056/NEJMoa2409515
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越南应用左氧氟沙星预防耐多药结核病
Levofloxacin for the Prevention
of Multidrug-Resistant Tuberculosis in Vietnam
预防耐药性结核病是全球卫生工作的重中之重。然而，对于耐药性结核病患者接触者的结核分枝杆菌感染治疗，目前仍缺乏评估治疗效果的试验。Prevention
of drug-resistant tuberculosis is a global health priority. However, trials
evaluating the effectiveness of treating Mycobacterium tuberculosis infection among contacts of persons with
drug-resistant tuberculosis are lacking.我们开展了一项双盲、随机、对照试验，目的是比较为期6个月的每日左氧氟沙星（按体重计算剂量）与安慰剂治疗对结核分枝杆菌感染的效果。试验人群包括越南经细菌学确诊的耐利福平或耐多药（MDR）结核病患者的家庭接触者。结核菌素皮肤测试呈阳性或有免疫损伤的接触者均符合纳入标准，不限年龄。主要终点是30个月内经细菌学确诊结核病。次要终点包括3级或4级不良事件、全因死亡和获得性耐药性。We
conducted a double-blind, randomized, controlled trial comparing 6 months of
daily levofloxacin (weight-based doses) with placebo to treat M. tuberculosis infection. The trial population comprised
household contacts of persons with bacteriologically confirmed rifampicin-resistant
or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with
a positive tuberculin skin test or immunologic impairment were eligible. The
primary end point was bacteriologically confirmed tuberculosis within 30 months.
Secondary end points included grade 3 or 4 adverse events, death from any
cause, and acquired drug resistance.在接受筛选的3948人中，61人（1.5%）同时患结核病（定义为在随机分组之前诊断出活动性结核病），2041人接受了随机分组。在这2041名参与者中，1995人（97.7%）完成了30个月随访、发生了主要终点事件或死亡。左氧氟沙星组6名参与者（0.6%）和安慰剂组11名参与者（1.1%）确诊为结核病（发病率比，0.55；95%置信区间[CI]，0.19~1.62）；这一差异并不显著。两组的3级或4级不良事件有很小差异（风险差异，1.0个百分点；95% CI，－0.3~2.4）。左氧氟沙星组306名参与者（31.9%）和安慰剂组125名参与者（13.0%）发生了不良事件（风险差异，18.9个百分点；95% CI，14.2~23.6）。未发现获得性氟喹诺酮耐药性。Of
3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis
(defined as active tuberculosis disease diagnosed before randomization) and
2041 underwent randomization. Of these 2041 participants, 1995 (97.7%)
completed 30 months of follow-up, had a primary end-point event, or died.
Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin
group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95%
confidence interval [CI], 0.19 to 1.62); this difference was not significant.
There was little difference in grade 3 or 4 adverse events between the two
groups (risk difference, 1.0 percentage point; 95% CI, −0.3 to 2.4). Adverse
events of any grade were reported in 306 participants (31.9%) taking
levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage
points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was
observed.虽然30个月时左氧氟沙星组的结核病发病率低于安慰剂组，但差异并不显著。（由澳大利亚国家健康与医学研究委员会[National Health and Medical Research Council of Australia]资助；VQUIN MDR在澳大利亚和新西兰临床试验注册系统[Australian New
Zealand Clinical Trials Registry]注册号为ACTRN12616000215426）。Although
the incidence of tuberculosis was lower in the levofloxacin group than in the
placebo group at 30 months, the difference was not significant. (Funded by the
National Health and Medical Research Council of Australia; VQUIN MDR Australia
New Zealand Clinical Trials Registry number, ACTRN12616000215426.)Fox
GJ, Nhung NV, Cam Binh N, et al. Levofloxacin for the Prevention of
Multidrug-Resistant Tuberculosis in Vietnam. DOI: 10.1056/NEJMoa2314325
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Levofloxacin Preventive Treatment
in Children Exposed to MDR Tuberculosis全世界约有200万15岁以下儿童感染耐多药（MDR）结核分枝杆菌，每年约有3万名儿童患耐多药结核病。目前仍缺乏对接触MDR结核病的人进行结核病预防性治疗的随机对照试验证据。Worldwide,
approximately 2 million children younger than 15 years of age are infected with
multidrug-resistant (MDR) Mycobacterium tuberculosis, with MDR tuberculosis developing in
approximately 30,000 annually. Evidence from randomized, controlled trials on
tuberculosis preventive treatment in persons exposed to MDR tuberculosis is
lacking.
在南非开展的此项基于社区的多中心、双盲、整群随机、安慰剂对照试验中，我们评估了对于与细菌学确诊MDR肺结核成人患者有家庭接触的儿童，作为预防性治疗药物的左氧氟沙星的疗效和安全性。对于5岁以下儿童，无论γ干扰素释放试验结果或人类免疫缺陷病毒（HIV）感染状况如何，均符合纳入标准；对于5~17岁儿童，如果γ干扰素释放试验结果呈阳性或感染HIV，则符合纳入标准。本试验以家庭为单位进行随机分组，家庭中的儿童每日一次接受左氧氟沙星或安慰剂，持续24周。主要疗效终点是随机分组后48周内的新发结核病，包括结核病导致死亡。主要安全性终点是治疗期间发生与试验治疗方案至少可能相关的3级或更高级别不良事件。In
this community-based, multisite, double-blind, cluster-randomized,
placebo-controlled trial in South Africa, we assessed the efficacy and safety
of levofloxacin as preventive treatment in children with household exposure to
an adult with bacteriologically confirmed MDR pulmonary tuberculosis. Children
younger than 5 years of age were eligible for inclusion regardless of
interferon-γ release assay result or human immunodeficiency virus (HIV) status,
and children 5 to 17 years of age were eligible if they had a positive
interferon-γ release assay or HIV infection. Households were randomly assigned
to a trial regimen, and children in the household received levofloxacin or
placebo once daily for 24 weeks. The primary efficacy end point was incident
tuberculosis, which included death from tuberculosis, by week 48 after
randomization. The primary safety end point was any adverse event of grade 3 or
higher during the treatment period that was at least possibly related to the
trial regimen.在来自497个家庭的922名参与者中，453人被分配接受左氧氟沙星，469人被分配接受安慰剂；91.0%的参与者为5岁以下儿童。每个试验组均有86%的参与者接受了至少80%的左氧氟沙星或安慰剂分配剂量。截至第48周，左氧氟沙星组5名参与者（1.1%）和安慰剂组12名参与者（2.6%）患上结核病（风险比，0.44；95%置信区间[CI]，0.15~1.25）。敏感性分析结果与主要分析结果一致。左氧氟沙星组4名参与者和安慰剂组8名参与者在治疗期间发生了与试验治疗方案至少可能相关的3级或更高级别不良事件（风险比，0.52；95% CI，0.16~1.71）。左氧氟沙星组1名儿童发生了2级肌腱炎。Of
922 participants from 497 households, 453 were assigned to receive levofloxacin
and 469 to placebo; 91.0% of the participants were younger than 5 years of age.
At least 80% of the assigned doses of levofloxacin or placebo were received by
86% of the participants in each trial group. By week 48, tuberculosis had
developed in 5 participants (1.1%) in the levofloxacin group and in 12
participants (2.6%) in the placebo group (hazard ratio, 0.44; 95% confidence
interval [CI], 0.15 to 1.25). The results of sensitivity analyses were
consistent with those of the primary analysis. Grade 3 or higher adverse events
during the treatment period that were considered to be at least possibly
related to the trial regimen occurred in 4 participants in the levofloxacin
group and in 8 participants in the placebo group (hazard ratio, 0.52; 95% CI,
0.16 to 1.71). Grade 2 tendonitis occurred in 1 child in the levofloxacin group.对于在家庭中接触MDR结核病的儿童，虽然与安慰剂相比，左氧氟沙星预防性治疗可降低结核病发病率，但差异并不显著。（由Unitaid等资助；TB-CHAMP在ISRCTN注册号为ISRCTN92634082）。Although preventive treatment with levofloxacin
led to a lower incidence of tuberculosis than placebo among children with
household exposure to MDR tuberculosis, the difference was not significant.
(Supported by Unitaid and others; TB-CHAMP ISRCTN Registry number, ISRCTN92634082.)Hesseling
AC, Purchase SE, Martinson NA, et al. Levofloxacin Preventive Treatment in
Children Exposed to MDR Tuberculosis. DOI: 10.1056/NEJMoa2314318
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DRC应用rVSV-ZEBOV-GP环围接种策略应对埃博拉疫情Ebola Outbreak Response in the
DRC with rVSV-ZEBOV-GP Ring Vaccination2018—2020年埃博拉病毒病（EVD）在刚果民主共和国（DRC）东部暴发之初，尚无任何疫苗获得许可。然而，2015年几内亚的整群随机试验证据表明，在新病例周围使用单剂rVSV-ZEBOV-GP活复制疫苗进行环围接种（针对接触者和次级接触者）可降低接种后10天之后的EVD发病率。因此，针对此次疫情的标准控制措施中增加了环围疫苗接种策略。At
the beginning of the 2018–2020 outbreak of Ebola virus disease (EVD) in eastern
Democratic Republic of Congo (DRC), no vaccine had been licensed. However,
cluster-randomized evidence from Guinea in 2015 had indicated that ring
vaccination around new cases (targeting contacts and contacts-of-contacts) with
the use of single-dose live-replicating rVSV-ZEBOV-GP vaccine reduced EVD rates
starting 10 days after vaccination. Thus, ring vaccination was added to the
standard control measures for that outbreak.在此项研究中，我们评估了接种疫苗后9天内（预计病例隔离或环围接种几乎不会起到保护作用）、第10~29天以及之后时间段的EVD发病率。在指示病例出现症状后21天内，我们在新病例或聚集病例周围确定了1853个环围，并为环围中的成员提供接种疫苗机会。我们一直监测疫苗接种者的EVD发病情况，直至疫情于2020年年中结束。In
this study, we evaluated the incidence of EVD within the first 9 days after
vaccination (when little protection was expected from case isolation or ring
vaccination), during days 10 to 29, and at later time periods. We established 1853 rings around new cases or clusters within 21 days after
symptom onset in the index case and offered vaccination to the ring members.
Vaccinees were monitored for EVD onset until the end of the outbreak in
mid-2020.从2018年8月8日至2020年1月14日，我们为265183名参与者接种了疫苗。在这些接种者中，有102,515人在第0天、第3天和第21天接受了安全性监测。在接触者和次级接触者中，确诊了434例EVD病例（每个环围0.2例），他们几乎全部是在接种疫苗后0~9天内（380例）或10~29天内（32例）确诊。另外22个病例是在第29天后的平均170天随访期间确诊。指示病例EVD发病后，越早启动控制措施（包括环围疫苗接种），接触者的EVD发病率越快下降。在每个亚组中，EVD发病率都在第10天左右突然下降。在第10天仍未患病的接触者和次级接触者中，第10~29天期间的EVD发病率为0.16‰（194,019名参与者中32人发病）。这一发病率远低于几内亚类似环围成员的4.64‰（4528名参与者中21人发病）。几内亚迅速启动了标准控制措施，但疫苗接种却推迟至确定环围后21天（发病率比，0.04；95%置信区间，0.02~0.06）。没有发现疫苗存在安全问题。From
August 8, 2018, to January 14, 2020, we vaccinated 265,183 participants. Of
these vaccinees, 102,515 were monitored on days 0, 3, and 21 for safety. Among
the contacts and contacts-of-contacts, 434 cases of EVD (0.2 per ring) were
diagnosed, almost all within 0 to 9 days (380 cases) or 10 to 29 days (32
cases) after vaccination. An additional 22 cases were diagnosed after day 29
during an average of 170 more days of follow-up. The sooner that control
measures (including ring vaccination) began after EVD onset in the index case,
the sooner EVD rates fell among contacts. In each subgroup, EVD rates fell
suddenly around day 10. Among the contacts and contacts-of-contacts who were
still disease-free at day 10, the EVD onset rate during days 10 to 29 was 0.16
per 1000 (in 32 of 194,019 participants). This rate was much lower than the
rate of 4.64 per 1000 (in 21 of 4528 participants) that had been seen among
similarly defined ring members in Guinea, in whom standard control measures had
been promptly initiated but vaccination was delayed until 21 days after ring
formation (rate ratio, 0.04; 95% confidence interval, 0.02 to 0.06). No safety
concerns with the vaccine were identified.在DRC东部，有关EVD标准控制措施联合环围疫苗接种的非随机研究证据证实了几内亚之前的随机试验证据，即接种疫苗对接种后10天或之后发病的EVD有预防效果。Nonrandomized
evidence regarding standard EVD control measures plus ring vaccination in
eastern DRC reinforces the earlier randomized evidence from Guinea of vaccine
efficacy against EVD onset 10 or more days after vaccination.Muyembe J-J, Pan H, Peto R, et al. for the Ebola
Ring Vaccination Team in the DRC. Ebola Outbreak Response in the DRC with
rVSV-ZEBOV-GP Ring Vaccination. DOI: 10.1056/NEJMoa1904387![]()
每年两次注射depemokimab治疗嗜酸性粒细胞表型重症哮喘
Twice-Yearly Depemokimab in Severe Asthma
with an Eosinophilic Phenotype
背景
depemokimab是一种与白介素-5具有较强结合亲和力的超长效生物疗法，可实现有效的6个月给药间隔。
Background
Depemokimab
is an ultra-long-acting biologic therapy with enhanced binding affinity for
interleukin-5 that may enable effective 6-month dosing intervals.在本文的两项3A期随机、安慰剂对照、验证试验中，我们评估了depemokimab对患嗜酸性粒细胞表型（特征是嗜酸性粒细胞计数较高[过去12个月中≥300/μL或筛选时≥150/μL]）重症哮喘，并且接受中剂量或大剂量吸入糖皮质激素治疗后仍有哮喘发作史的患者的疗效和安全性。以2:1比例将患者随机分成两组，两组均接受标准治疗，并且在第0周和第26周分别接受depemokimab（100
mg皮下注射）或安慰剂治疗。主要终点是52周时的年发作率。为了进行多重性校正，以分级方式分析次要终点，包括52周时的圣乔治呼吸问卷（SGRQ，St.
George’s Respiratory Questionnaire）评分、第一秒用力呼气量和哮喘症状报告与基线相比的变化。In these
phase 3A, randomized, placebo-controlled replicate trials, we evaluated the
efficacy and safety of depemokimab in patients with severe asthma and an
eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per
microliter in the previous 12 months or ≥150 cells per microliter at screening)
and a history of exacerbations despite the receipt of medium- or high-dose
inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to
receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at
weeks 0 and 26, plus standard care. The primary end point was the annualized
rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in
a hierarchical manner to adjust for multiplicity, included the change from
baseline in the score on the St. George’s Respiratory Questionnaire (SGRQ), the
forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks.在这两项试验中，792例患者接受了随机分组，762例患者被纳入全分析人群；502例患者被分配接受depemokimab治疗，260例患者被分配接受安慰剂治疗。在SWIFT-1中，depemokimab组的年发作率为0.46（95%置信区间[CI]，0.36~0.58），安慰剂组为1.11（95% CI，0.86~1.43）（率比，0.42；95% CI，0.30~0.59；P<0.001）；在SWIFT-2中，depemokimab组为0.56（95%
CI，0.44~0.70），安慰剂组为1.08（95% CI，0.83~1.41）（率比，0.52；95% CI，0.36~0.73；P<0.001）。在这两项试验中，SGRQ评分与基线相比的变化均无显著组间差异，因此未对后续次要终点进行统计学推断。在两项试验中，两组的不良事件发生率均相似。Across the
two trials, 792 patients underwent randomization and 762 were included in the
full analysis; 502 were assigned to receive depemokimab and 260 to receive
placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval
[CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with
placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and
0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41)
with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2.
No significant between-group difference in the change from baseline in the SGRQ
score was observed in either trial, so no statistical inference was drawn on
subsequent secondary end points. The proportion of patients with any adverse
event was similar in the two groups in both trials.depemokimab降低了嗜酸性粒细胞表型重症哮喘患者的年发作率。（由GSK资助；SWIFT-1和SWIFT-2在ClinicalTrials.gov注册号为NCT04719832和NCT04718103）。Depemokimab reduced the annualized rate of
exacerbations among patients with severe asthma with an eosinophilic phenotype.
(Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and
NCT04718103.)Jackson DJ, Wechsler ME, Jackson DJ, et al. for the SWIFT-1 and
SWIFT-2 Investigators. Twice-Yearly
Depemokimab in Severe Asthma with an Eosinophilic Phenotype. DOI: 10.1056/NEJMoa2406673
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