反義寡核苷酸tofersen治療SOD1突變所致肌萎縮側索硬化的1-2期試驗
Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
背景
tofersen是一種反義寡核苷酸，介導超氧化物歧化酶1（SOD1）信使RNA的降解，從而減少SOD1蛋白的合成。目前正在研究tofersen鞘內給藥治療SOD1突變所致的肌萎縮側索硬化（ALS）。
Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.方法
我們開展了一項1-2期劑量遞增試驗，目的是評估tofersen在SOD1突變所致ALS成人患者中的作用。在各劑量組（20、40、60或100 mg）中，我們以3:1的比例將參與者隨機分組，分別接受為期12周的5劑tofersen或安慰劑鞘內給藥。主要結局是安全性和藥代動力學。次要結局是第85日的腦脊液（CSF）SOD1濃度相對於基線的變化。我們還測定了臨床功能和肺活量。
We conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.結果
共計50例參與者被隨機分組，並被納入分析；48例參與者接受了計劃的全部5劑治療。大多數參與者發生了與腰椎穿刺相關的不良事件。在接受tofersen治療的參與者中，分別有4例和5例報告了不良事件CSF白細胞計數增加和蛋白升高。在接受tofersen治療的參與者中，1例於第137日死於肺栓塞，1例於第152日死於呼吸衰竭；安慰劑組1例參與者於第52日死於呼吸衰竭。對於20 mg劑量、40 mg劑量、60 mg劑量和100 mg劑量，在tofersen組和安慰劑組之間，第85日的CSF SOD1濃度相對於基線的變化的差異分別為2個百分點（95%置信區間[CI]，-18~27）、-25個百分點（95% CI，-40~-5）、-19個百分點（95% CI，-35~2）和-33個百分點（95% CI，-47~-16）。
Result
A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture–related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose.
結論
在SOD1突變所致的ALS成人患者中，在12周期間，最高濃度tofersen鞘內給藥後，CSF SOD1濃度降低。一些接受tofersen治療的參與者出現了CSF腦脊液細胞增多。大多數參與者發生了與腰椎穿刺相關的不良事件。（由渤健公司資助；在ClinicalTrials.gov註冊號為NCT02623699；在EudraCT註冊號為2015-004098-33。）
Conclusions
In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.)
本周五 中午十二點 app和官網發布全文中譯
COVID-19患者的肺血管內皮炎、血栓形成和血管生成
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
背景
進行性呼吸衰竭是2019冠狀病毒病（COVID-19）大流行中患者的主要死亡原因。雖然人們廣泛關注該病的病理生理學，但對死於COVID-19的患者外周肺的相關形態和分子變化卻知之甚少。
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.方法
我們檢查了死於COVID-19的患者屍檢時獲得的7個肺，並與死於甲型H1N1流感繼發性急性呼吸窘迫症候群（ARDS）的患者屍檢時獲得的7個肺和10個年齡匹配的未感染對照肺進行了比較。我們利用七色免疫組化分析、顯微計算機斷層成像、掃描電子顯微鏡、腐蝕鑄型和直接多重（multiplexed）基因表達測定對肺部進行了檢查。
We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.
結果
在死於COVID-19相關呼吸衰竭或流感相關呼吸衰竭的患者中，外周肺的組織學形態均為瀰漫性肺泡損傷伴血管周圍T細胞浸潤。COVID-19患者的肺部還表現出獨特的血管特徵，包括與細胞內病毒相關的重度內皮損傷和細胞膜破裂。COVID-19患者肺血管的組織學分析結果顯示廣泛血栓形成和微血管病變。肺泡毛細血管微血栓在COVID-19患者中的發生率是流感患者的9倍（P<0.001）。COVID-19患者肺部的新血管生長量（主要通過套疊式血管生成機制）是流感患者肺部的2.7倍（P<0.001）。
Result
In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).結論
在這一小型病例系列中，血管生成使COVID-19患者的肺部病理學有別於同樣嚴重的流感病毒感染患者。本研究中觀察結果的普遍性和臨床意義有待進一步研究來確定。（由美國國立衛生研究院等資助。）
Conclusions
In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)Maximilian Ackermann, Stijn E. Verleden, Mark Kuehnel, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. DOI:10.1056/NEJMoa2015432
用於預防嚴重跌傷的多方面策略的隨機試驗
A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries
背景
跌倒所致損傷是老年人出現併發症和死亡的主要原因。雖然來自效果試驗的證據表明許多跌倒是可以避免的，但導致損傷的跌倒發生率卻並未下降。
Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined.方法
我們開展了一項實效性、整群隨機試驗，目的是評價由接受過專門培訓的護士實施，包括風險評估和個體化計劃的多方面幹預方案在預防跌傷方面的效果。我們將10個醫療系統的總共86個初級診療機構隨機分組，分別採用幹預措施或加強常規護理（對照）（每組43個初級診療機構）。參與者是居住在社區，跌傷風險較高的≥70歲成人。在至事件發生的時間分析中進行評估的主要結局是第一次嚴重跌傷（根據參與者報告、電子病歷和保險理賠數據做出裁定）。我們假設幹預組的事件發生率比對照組低20%。
We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group.結果
幹預組（2802例參與者）和對照組（2649例參與者）參與者的人口統計學和基線特徵相似；平均年齡為80歲，62.0%的參與者為女性。在至第一起事件發生的時間分析中，兩組中經過裁定的第一起嚴重跌傷的發生率無顯著差異（每100人-年隨訪的事件數量，幹預組4.9起和對照組5.3起；風險比，0.92；95%置信區間[CI]，0.80~1.06；P=0.25）。在幹預組和對照組中，第一起參與者報告的跌傷發生率分別為25.6起事件/100人-年隨訪和28.6起事件/100人-年隨訪（風險比，0.90；95% CI，0.83~0.99；P=0.004）。兩組的住院或死亡發生率相似。
Result
The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P=0.004). The rates of hospitalization or death were similar in the two groups.
結論
與加強常規護理相比，由護士實施的多方面幹預措施未能降低經過裁定的第一起嚴重跌傷的發生率。（由以患者為中心的結局研究所[Patient-Centered Outcomes Research Institute]等資助；STRIDE在ClinicalTrials.gov註冊號為NCT02475850。）
Conclusions
A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.)nemolizumab並用外用藥治療特應性皮炎伴瘙癢的試驗
Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus背景
nemolizumab是皮下注射的抗白介素-31受體A的人源化單克隆抗體，而白介素-31受體A與特應性皮炎的瘙癢和炎症相關。在2期研究中，nemolizumab減輕了特應性皮炎的嚴重程度。
Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis.方法
在一項為期16周的雙盲3期試驗中，我們將有中度至重度瘙癢且對外用藥應答不足的日本特應性皮炎患者以2:1的比例隨機分組，兩組分別每4周接受一次nemolizumab（60 mg）或安慰劑皮下注射，直到第16周，而且並用外用藥。主要終點是瘙癢的視覺模擬量表（VAS）評分（範圍，0~100，評分較高表示瘙癢較嚴重）從基線至第16周的平均變化百分比。次要終點包括截至第4周時瘙癢VAS評分變化情況的時間過程，溼疹面積和嚴重程度指數（Eczema Area and Severity Index，EASI）評分（範圍，0~72，評分較高表示較嚴重）的變化，皮膚病學生活質量指數（Dermatology Life Quality Index，DLQI）評分（範圍，0~30，評分較高表示對日常生活的影響較大）≤4分，失眠嚴重程度指數（Insomnia Severity Index，ISI）評分（範圍，0~28，評分較高表示較嚴重）≤7分和安全性。
In a 16-week, double-blind, phase 3 trial, we randomly assigned Japanese patients with atopic dermatitis and moderate-to-severe pruritus and an inadequate response to topical agents in a 2:1 ratio to receive subcutaneous nemolizumab (60 mg) or placebo every 4 weeks until week 16, with concomitant topical agents. The primary end point was the mean percent change in the visual-analogue scale (VAS) score for pruritus (range, 0 to 100, with higher scores indicating worse pruritus) from baseline to week 16. Secondary end points included the time course of change in the VAS score for pruritus up to week 4, the change in the Eczema Area and Severity Index (EASI) score (range, 0 to 72, with higher scores indicating greater severity), a score of 4 or less on the Dermatology Life Quality Index (DLQI; range, 0 to 30, with higher scores indicating a greater effect on daily life), a score of 7 or less on the Insomnia Severity Index (ISI; range, 0 to 28, with higher scores indicating greater severity), and safety.結果
共計143例患者被隨機分配接受nemolizumab治療，72例患者被隨機分配接受安慰劑治療。基線時瘙癢的中位VAS評分為75分。第16周時，nemolizumab組和安慰劑組VAS評分的平均變化百分比分別為-42.8%和-21.4%（差異，-21.5個百分點；95%置信區間，-30.2~-12.7；P<0.001）。nemolizumab組和安慰劑組EASI評分的平均變化百分比分別為-45.9%和-33.2%。nemolizumab組和安慰劑組DLQI評分≤4分的患者百分比分別為40%和22%；ISI評分≤7分的患者百分比分別為55%和21%。nemolizumab組和安慰劑組的注射相關反應發生率分別為8%和3%。
Result
A total of 143 patients were randomly assigned to receive nemolizumab and 72 to receive placebo. The median VAS score for pruritus at baseline was 75. At week 16, the mean percent change in the VAS score was −42.8% in the nemolizumab group and −21.4% in the placebo group (difference, −21.5 percentage points; 95% confidence interval, −30.2 to −12.7; P<0.001). The mean percent change in the EASI score was −45.9% with nemolizumab and −33.2% with placebo. The percentage of patients with a DLQI score of 4 or less was 40% in the nemolizumab group and 22% in the placebo group; the percentage of patients with an ISI score of 7 or less was 55% and 21%, respectively. The incidence of injection-related reactions was 8% with nemolizumab and 3% with placebo.
結論
在這項為期16周的試驗中，與特應性皮炎外用藥並用安慰劑相比，外用藥並用nemolizumab皮下注射更大幅減輕了患者瘙癢。nemolizumab的注射部位反應發生率高於安慰劑。我們有必要通過更長時間、更大規模的試驗來確定nemolizumab對特應性皮炎是否具有持久療效以及是否安全。（由Maruho資助；在JapicCTI註冊號為173740。）
Conclusions
In this 16-week trial, the use of subcutaneous nemolizumab in addition to topical agents for atopic dermatitis resulted in a greater reduction in pruritus than placebo plus topical agents. The incidence of injection-site reactions was greater with nemolizumab than with placebo. Longer and larger trials are necessary to determine whether nemolizumab has a durable effect and is safe for atopic dermatitis. (Funded by Maruho; JapicCTI number, 173740.)本周五 中午十二點 app和官網發布全文中譯
利用腺相關病毒和微RNA抑制SOD1治療家族性肌萎縮側索硬化
SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS有超氧化物歧化酶1編碼基因（SOD1）突變的兩例家族性肌萎縮側索硬化（ALS）患者接受了腺相關病毒單次鞘內輸入治療，該腺相關病毒編碼靶向SOD1的微RNA。患者1在屍檢時測定的脊髓組織SOD1水平低於未接受治療的SOD1 ALS患者和健康對照的相應水平。患者1的腦脊液SOD1水平只是一過性地略微降低，而患者2的腦脊液SOD1水平未受影響。患者1接受輸入給藥後發生了腦膜神經根炎；患者2預先接受了免疫抑制藥物治療，該患者未出現這一併發症。患者1的右腿力量有一過性改善（這一指標在該患者的病程中保持相對穩定），但肺活量無變化。患者2的ALS功能綜合指標評分和肺活量在12個月期間保持穩定。本研究表明，微RNA鞘內給藥有可能成為SOD1介導的ALS的治療方案。
Christian Mueller, James D. Berry, Diane M. McKenna-Yasek, et al. SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS. DOI:10.1056/NEJMoa2005056
本周五 中午十二點 app和官網發布全文中譯
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