附表: SARS-CoV-2 之藥物使用實證摘要 (2022.9.7)
1.
疫情初期,
SARS-CoV-2治療相關證據主要來自同為冠狀病毒的
SARS-CoV-1與
MERS-CoV之治療經驗、臨床與體外試驗結果,與針對
SARS-CoV-2患者的小規模臨床研究。曾被用於治療的藥物包括多種抗病毒藥物(
ribavirin, lopinavir/ritonavir, remdesivir)、免疫調節劑、病患恢復期血清與單株
/多株抗體等
[1, 2]。
2.
許多
SARS-CoV-2治療的相關臨床試驗已有結果或正在進行中,大規模隨機對照試驗包括由英國牛津大學主導的
RECOVERY trial,與
WHO主導之
SOLIDARITY trial
。
RECOVERY trial治療組最初包括
lopinavir/ritonavir、
dexamethasone、
hydroxychloroquine與
azithromycin四種藥物。
SOLIDARITYtrial
則包括
remdesivir、
lopinavir/ritonavir、
lopinavir/ritonavir加
interferon-β與
chloroquine或
hydroxychloroquine四組。兩試驗平台後續均有加入 許多候選藥物試驗。
3.
由於藥物治療試驗眾多且證據力不一,為使臨床醫師獲得證據力較高之實證資訊,自
2021年
6月
28日更新版起,「實證摘要表格」將僅新增經 大規模隨機對照試驗
(randomized controlled trial, RCT)評估之藥物結果。目前針對
SARS-CoV-2之藥物依主要作用機轉分類為抗病毒藥物、免疫調節
劑、抗
SARS-CoV-2單株抗體與其他藥物,實證簡列如下表
(紅字表示本版更新內容
)。另自本版起,單株抗體體外試驗部分將合併至
SARS-CoV-2感
染臨床處置指引內容,請參見表五「單株抗體對
SARS-CoV-2變異株效果實證」 :
一、抗病毒藥物
藥物名稱 證據等級 目前實證摘要
Lopinavir/Ritonavir ± interferon 體外試驗 ⚫ 藥物接受器模擬研究顯示lopinavir/ritonavir對SARS-CoV-2可能有療效[3]。
隨機對照試驗 ⚫ 99名使用lopinavir/ritonavir之嚴重肺炎(SpO2<94%)成人(>18歲)患者與100名接受標準治療者相比,兩組達臨 床改善天數與28天死亡率均無統計顯著差異,lopinavir/ritonavir治療組中有13.8%因副作用而停止用藥[4]。
⚫ 86名接受lopinavir/ritonavir合併ribavirin與IFN-β1b的輕症患者,相較於41名僅接受lopinavir/ritonavir者,較早清 除病毒(陰轉天數中位數7 vs 12天)與達症狀緩解[5]。
⚫ RECOVERY trial:1616名使用lopinavir/ritonavir之COVID-19住院病患,相較於3424名對照組,28天死亡率並無統 計顯著差異(23% vs 22 %)[6]。
⚫ SOLIDARITY trial:1399名使用lopinavir/ritonavir之COVID-19住院病患,相較於對照組,28天時住院死亡率並無統 計顯著差異(9.7% vs 10.3%)[7]。
Remdesivir@* 體外試驗 ⚫ 體外試驗顯示有抑制病毒效果[8]。
個案報告 ⚫ 個案報告顯示患者於入院第七天起使用remdesivir,隔日起病況改善[9]。
⚫ 恩慈療法結果顯示,53名用藥患者中,68%用藥後氧氣需求下降,插管與非插管病患追蹤18天死亡率分別為18%
與5%[10]。
觀察性研究 ⚫ 570名病患之匹配病例對照研究顯示,使用remdesivir治療者相較於未用藥者較快達臨床改善(5 vs 7天),但兩組病 患28天死亡率差異並未達統計顯著(7.7% vs 14%)。本研究同時也比較184 名同時使用remdesivir與
corticosteroids,與158名僅使用remdesivir之病患,併用corticosteroids者較慢達臨床改善(aHR 0.77),但兩組28天 死亡率並無差異(8.2% vs 6.3%) [11]。
⚫ 352名於住院兩天內使用remdesivir治療之病患,與1347名未用藥者匹配後,治療組14天時死亡率較低(4.3% vs 6.7%, HR 0.58, CI 0.34-0.99),且Ct值≧ 35之比例較高(40.6% vs 28.1%)。治療組與對照組分別有79.3%與83.3%病患於 收案時並未使用氧氣[12]。
目前已不建議使用
⚫ 28855名於住院兩天內使用remdesivir治療之病患,經與16687名未用藥者匹配後,治療組14天(10.6% vs 15.4%, HR 0.76, CI 0.70-0.83)與28天(15.4% vs 19.1%, HR 0.89, CI 0.82-0.96)死亡率均較低。同時在住院時未用氧、使用低/高流量 氧氣與插管或使用ECMO之病患均有統計顯著差異[13]。
隨機對照試驗 ⚫ 158名接受remdesivir治療的嚴重肺炎病患,相較於接受標準治療者,兩組達臨床改善或病毒清除天數均無顯著差 異[14]。
⚫ ACTT-1 trial : 538名接受remdesivir治療的嚴重肺炎病患,相較於521名接受安慰劑者,較快達臨床改善(臨床改善 天數中位數11 vs 15天)[15]。
⚫ 397名接受五天或十天remdesivir治療的嚴重肺炎病患,校正收案時疾病嚴重度後,臨床改善率並無統計差異[16]。
⚫ SOLIDARITY trial interim:2743名接受remdesivir治療的COVID-19住院病患,相較於對照組,28天時住院死亡率未 有統計顯著差異(12.5% vs 12.7%)[7]。
⚫ PINETREE:279名發病七日內具重症風險因子COVID-19門診病患,接受三天remdesivir治療,相較於283名接受安 慰劑者,28天時因COVID-19住院或全死因死亡率下降87%(0.7% vs 5.3%, p=0.008),因COVID-19就診與全死因死亡 率亦下降81% (1.6% vs 8.6%, p=0.002),但兩組第七天時鼻咽病毒量並無顯著差異[17, 18]。
⚫ Interferon beta-1a plus remdesivir:487名X光片顯示肺炎或需使用氧氣之COVID-19住院病患,接受remdesivir與四 劑IFN beta-1a治療,相較於482名接受remdesivir與安慰劑者,28天死亡率並無差異(5% vs 3%,p=0.39),且兩組達 臨床恢復天數均為五天[19]。
⚫ CMAJ:634名病患接受10天remdesivir治療,相較於648名接受標準治療者,兩組住院死亡率(18.7 vs 22.6%)與60 天死亡率(24.8 vs 28.2%)無統計顯著差異。但對於收案時尚未插管病患,remdesivir組插管率顯著較低(8 vs 15%, RR 0.53), 28天內不需用氧天數亦較低(15.9 vs 14.2, p=0.006) [20]。
⚫ SOLIDARITY trial final:4146名接受remdesivir十天療程之病患,相較於4129名接受標準治療之對照組,住院中死 亡率並無統計顯著差異(14.5 vs 15.6%, p=0.12)。對收案時已插管病患,remdesivir無法降低死亡率 (42.1 vs 38.6%, p=0.32),但對收案時用氧且尚未插管病患,remdesivir可降低死亡率(14.6 vs 16.3%, RR 0.87, p=0.03)[21]。
(Hydroxy)chloroquine +/- 體外試驗 ⚫ 體外試驗顯示chloroquine與hydroxychloroquine均有抑制病毒與免疫調節(immune modulation)效果,且 hydroxychloroquine用於暴露後預防亦可達有效抑菌濃度[8, 22, 23]。
azithromycin 觀察性研究 ⚫ 小規模非隨機對照試驗顯示,接受hydroxychloroquine與azithromycin治療之輕症患者較早清除病毒[24, 25]。
⚫ 大規模回溯性研究顯示接受hydroxychloroquine(+/- azithromycin)治療並無顯著降低重症或死亡率,且增加產生心 律不整之風險[26-29]。
⚫ 接受高劑量chloroquine或合併azithromycin治療之患者,有較高比例出現QT延長之副作用[30]。 隨機對照試驗
(治療)
⚫ 對輕症病患於發病早期給予hydroxychloroquine,並未加速症狀改善或病毒清除[31, 32]。
⚫ RECOVERY trial:1561名接受hydroxychloroquine治療的COVID-19住院病患,相較於3155名對照組,28天內全死 因死亡率未有統計顯著差異(27% vs 25%)[33]。
⚫ SOLIDARITY trial:947名接受hydroxychloroquine治療的COVID-19住院病患,相較於對照組,28天時住院死亡率未 有統計顯著差異(10.2% vs 8.9%)[7]。
隨機對照試驗 (預防)
⚫ 暴露後
(1) 家戶內或職場確定病例接觸者於暴露後接受hydroxychloroquine預防性投藥,並未降低14天內COVID-19症狀發 生率[34]。
(2) 家戶內或醫護確定病例接觸者於暴露後接受hydroxychloroquine預防性投藥,並未降低14天內COVID-19確診 率;對收案時SARS-CoV-2 PCR陽性之無症狀接觸者,亦未降低症狀發生率[35]。
⚫ 暴露前:對高風險醫護工作者給予每周一或兩次hydroxychloroquine預防性投藥,連續12周,相較於安慰劑組,用 藥並未降低確診或臨床症狀相符之SARS-CoV-2感染發生率[36]。
統合分析 (預防)
⚫ WHO統合分析顯示,在共計有6059名參與者的臨床試驗中,高強度證據顯示預防性給予hydroxychloroquine並無 法降低死亡率、住院率與確診率,並可能增加不良事件發生機率,並建議將投注於hydroxychloroquine的研發資源 轉向其他藥物[37]。
Ivermectin 隨機對照試驗 ⚫ 200名使用ivermectin發病七天內輕症病患,相較於200名使用安慰劑者,達症狀改善天數中位數並無差異(10 vs 12
天,p=0.53)[38]。
⚫ WHO的統合分析納入共有2407名病患參與的16個臨床試驗,結論顯示ivermectin對死亡、插管、病毒清除或住院 的效果均不確定,且試驗存在嚴重偏差,不建議在臨床試驗之外情境使用ivermectin[39]。
⚫ I-TECH:50歲以上具潛在疾病之輕中症病患於發病一周內隨機分配接受五天ivermectin (n=241)或標準治療(n=241), 28天時分別有21.6%與17.3%病患進展為重症(p=0.25),顯示ivermectin對治療並無效果[40]。
目前已不建議使用
目前已不建議使用
⚫ TOGETHER:679名發病七天內病患接受ivermectin治療(400ug/kg/day),相較於679名接受安慰劑者,28天時住院 或急診比率並無統計顯著差異(14.7 vs 16.3)[41]。
⚫ IVERCOR-COVID19:250名發病48小時內門診病患接受ivermectin治療,相較於251名接受安慰劑者,住院率分別 為5.6%與8.4%,差距未達統計顯著[42]。
統合分析 ⚫ 分析10個隨機對照試驗,對照組為安慰劑或標準治療,其中8個收案對象為輕症,共1173名病患統合分析結果。
Ivermectin無法降低病患全死因死亡率(RR 0.37, 0.12-1.13)或住院天數(差距0.72天,-0.86-2.29)[43]。
⚫ Cochrane:分析14個隨機對照試驗,1478名住院、門診病患或預防性用藥者,28天死亡率(RR 0.60, CI 0.14-2.51)、 插管率(0.55, CI 0.11-2.59)、住院天數(-0.10, CU -2.43-2.23)差異均未達統計顯著[44]。
Molnupiravir (MK-4822) @# 動物試驗 ⚫ 倉鼠實驗顯示,於暴露SARS-CoV-2前或後12小時給予MK-4822,可抑制病毒複製[45]。
隨機對照試驗 ⚫ 發病七天內門診病患,隨機分配給予molnupiravir 200mg (n=23)、400mg (n=62)、800mg (n=55)每日兩次共五天或安 慰劑(n=62),第三天時800mg組PCR陽性率顯著低於安慰劑組(1.9% vs 16.7%, p=0.02);第五天時安慰劑組仍有 11.1%培養陽性,400mg與800mg組檢體則均已無法分離出病毒[46]。
⚫ MOVe-OUT Phase III (interim):已達收案目標90%的第三期臨床試驗期中分析結果顯示,385名發病五天內,至少具 一個重症風險因子之門診病患接受口服molnupiravir治療,相較於377 名接受安慰劑者,29天時住院或死亡率顯著 較低(7.3% vs 14.1% ,p=0.0012),其中治療組無人死亡,安慰劑組則有8人死亡。病毒定序結果顯示molnupiravir對 Gamma、Delta與Mu變異株均有效果[47]。
⚫ MOVe-OUT Phase III (final):完整研究報告顯示716名發病五天內,至少具一個重症風險因子且未接種COVID-19疫 苗之門診病患口服molnupiravir 800mg治療,相較於717 名接受安慰劑者,29天時住院或死亡率顯著較低(6.8% vs 9.7%, 下降31%)。病毒定序結果顯示molnupiravir對Gamma、Delta與Mu變異株均有效果,但分層分析顯示 molnupiravir對anti-SARS-CoV-2抗體陽性、病毒量低與糖尿病者效果可能較不顯著[48]。
⚫ MOVe-OUT Phase III (secondary analysis):701名發病五天內,至少具一個重症風險因子且未接種COVID-19疫苗之門 診病患接受molnupiravir治療,相較於701名接受安慰劑者,第三天時CRP與血氧濃度有顯著改善[49]。
Paxlovid@#
(Nirmatrelvir+Ritonavir)
隨機對照試驗 ⚫ EPIC-HR:1039名發病五天內,至少具一個重症風險因子且未接種COVID-19疫苗之門診病患口服
nirmatrelvir/ritonavir 300 mg/100 mg,相較於1046名接受安慰劑者,28天時COVID-19相關住院或死亡率下降88%
(0.8 vs 6.3%)[50, 51]。
觀察性研究 ⚫ 以色列於Omicron變異株疫情期間回溯性統計研究,比較3902名接受nirmatrelvir/ritonavir治療與105352名未接受
治療之40歲以上COVID-19確診病患,用回歸模型校正人口學變項、潛在疾病與疫苗接種狀態後統計兩組因COVID-
19住院或死亡率差異。結果顯示年齡≥65歲之治療組因COVID-19住院率較對照組下降73% (14.7 vs 58.9 每十萬人 年,aHR 0.27),死亡率下降79% (aHR 0.21),但在40-64歲族群之住院或死亡率則無顯著差異[52]。
⚫ 香港於Omicron BA.2變異株疫情期間回溯性統計所有於發病三日內住院之18歲以上COVID-19確診病患,以
propensity score matching方法比較1856名接受nirmatrelvir/ritonavir者、890接受molnupiravir治療者與匹配之對照 組。結果顯示接受nirmatrelvir/ritonavir治療可降低全死因死亡率64% (10.28 vs 26.47每十萬人年, HR 0.34),接受 molnupiravir治療則可降低52% (19.98 vs 38.07 每十萬人年,HR 0.48)[53]。
二、免疫調節劑
藥物名稱 證據等級 目前實證摘要
IL-6 inhibitor
(tocilizumab#/siltuximab/
sarilumab)
觀察性研究 ⚫ 小規模觀察性研究顯示,患者接受IL-6 inhibitor(siltuximab)治療後CRP明顯下降,但僅約三成臨床改善[54]。
⚫ 回溯性世代研究統計179名嚴重肺炎患者使用tocilizumab(皮下或靜脈注射),相較於365名接受標準治療者,死亡 率較低且達統計顯著(13% vs 20%)[55]。
⚫ 世代研究顯示419名於入住加護病房兩天內使用tocilizumab的患者,相較於3492名未用藥者,27天時的死亡風險 下降29% (HR 0.71, CI 0.56-0.92)[23]。
隨機對照試驗 ⚫ 60名使用tocilizumab確診住院病患與接受標準治療者相比,14天時插管入住加護病房或死亡比率未達統計顯著差 異(Rate ratio 1.05, CI 0.59-1.86)[56]。
⚫ 63名需用氧氣但未插管確診病患接受tocilizumab治療,與接受標準治療者相比,14天時需使用氧氣或死亡的比率 較低(24% vs 36%, HR 0.58, CI 0.33-1.00)[57]。相同病患追蹤至90天,接受tocilizumab治療者90天死亡率較低 (11%
vs 18%, aHR 0.64, CI 0.25-1.65)。而若病患CRP≧15mg/dL,則14天時需使用氧氣或死亡之風險可下降82% (18% vs 57%, HR 0.18, CI 0.06-0.59),90天時死亡風險亦可下降82% (9% vs 35%, HR 0.18, CI 0.04-0.89)[58]。
⚫ 161名需用氧氣或有肺炎確診病患接受tocilizumab治療,與接受安慰劑者相比,28天時插管或死亡比例並無顯著差 異(10.6% vs 12.5%)[59]。
⚫ REMAP-CAP:401名入住ICU之確診病患,於入住ICU 24小時內接受tocilizumab 或sarilumab治療,相較於402名 接受標準治療者,21天時無器官衰竭之天數顯著較長(10 vs 11天vs 0天),住院死亡率也較低(28% vs 22% vs 35.8%)[60]。
⚫ COVACTA:294名接受tocilizumab治療之嚴重肺炎程度以上病患,與144名安慰劑組相比,28天死亡率並無差異
(19.7% vs 19.4%)[61]。
⚫ 65名接受tocilizumab治療之需用氧氣確診病患,與64名接受標準治療者相比,15天時死亡風險顯著較高(OR 6.42,
1.59-43.2),試驗也因此提前終止[62]。
⚫ RECOVERY trial:2022名需用氧氣確診病患接受tocilizumab治療,2094名接受標準治療,兩組共有82%同時接受 dexamethasone治療。Tocilizumab組相較於標準治療組,28天死亡率較低(RR 0.86, CI 0.77-0.96),且存活出院率較高 (RR 1.23, CI 1.12-1.34)[63]。
⚫ WHO meta-analysis:WHO團隊統計27個隨機對照試驗,共10930名病患。結果顯示使用IL-6抑制劑
(tocilizumab/siltuximab/sarilumab)者,相較於僅使用包括類固醇在內之標準治療,28天死亡率下降(22% vs 25%, OR 0.86, CI 0.79-0.95),且使用呼吸器比例較低(OR 0.72, CI 0.57-0.90)[64]。
⚫ REMDACTA:需用氧且>6L/min之嚴重肺炎病患,隨機分配接受tocilizumab(n=434)或安慰劑(n=251),同時併用 remdesivir。兩組自收案至出院天數並無差異(14 vs 16天,p=0.74),死亡率亦無差異(18.2 vs 19.7%)[65]。
JAK inhibitor
(Baricitinib#, tofacitinib, ruxolitinib)
隨機對照試驗 ⚫ ACTT-2 trial:相較於僅使用remdesivir者(n=518),對確診住院病患(n=515)併用baricitinib,可加速臨床改善約一天(7 vs 8 天,=0.03),且第15天時臨床改善機率增加30% (OR 1.3, 1.0-1.6)。分層分析顯示在收案時使用非侵襲性呼吸器 或高流量氧氣者,效果最顯著,可加速臨床改善八天(10 vs 18天)[66]。
⚫ COV-BARRIER:未插管住院病患隨機分配接受baricitinib(n=764)或安慰劑(n=761),並接受含dexamethasone在內的標 準治療,28天全死因死亡率下降38.2%(8.1% vs 13.1%),且效果在收案時使用高流量氧氣或非侵襲性呼吸器之病患最 顯著(HR 0.52, p=0.007)[67]。
⚫ COV-BARRIER:插管或使用ECMO之重症病患除標準治療外,隨機分配接受baricitinib(n=51)或安慰劑(n=50)治療,治 療組28天全死因死亡率下降46%(39.2 vs 58.0%, p=0.03),60天死亡率亦下降(45.1 vs 62.0%, p=0.027)[68]。
⚫ STOP-COVID trial:18歲以上住院確診病患,未使用非侵襲性呼吸器或插管者,住院三天內隨機分配接受口服 tofacitinib(n=144)或標準治療(n=145),治療組28天時死亡或插管率下降37% (18% vs 29%, RR=0.63),但死亡率無顯著 差異(2.8% vs 5.5%, HR 0.49, CI 0.15-1.63)[69]。
⚫ RECOVERY:8156名確診病患隨機分配接受barticinib與標準治療,相較於4148名僅接受標準治療者,28天時死亡 率下降13% (12 vs 14%, aRR 0.87),使用呼吸器或死亡率則下降11% (aRR 0.89)。依收案時使用氧氣狀況之分層分析顯 示,僅對於收案時使用非侵襲性呼吸器之病患效果達統計顯著(aRR 0.75)。病患可使用之標準治療包括
corticosteroids(95%)、remdesivir(20%)、tocilizumab(23%)[70]。
Corticosteroids 隨機對照試驗 ⚫ RECOVERY trial:2104名使用dexamethasone病患與4321接受標準治療組相比,對收案時需使用氧氣或插管者,使
用dexamethasone 6mg十天可分別降低28天全死因死亡風險18%與36%,但對收案時不需使用氧氣者,用藥與未
用藥死亡率差異未達統計顯著[71]。
⚫ MetCOVID:194名使用methylprednisolone (0.5mg/kg)之住院病患與199名接受安慰劑者相比,28天死亡率差異未 達統計顯著[72]。
⚫ CAPE COVID:76名使用hydrocortisone 200mg之入住加護病房病患與73名接受安慰劑者相比,21天治療失敗率差 異未達統計顯著[73]。
⚫ CODEX:151名使用dexamethasone 20mg五天與10mg五天之插管病患與148名標準治療組相比,28天時可脫離呼 吸器天數較多(6.6 vs 4.0天, p=0.04)[74]。
⚫ REMAP-CAP:比較使用固定劑量(hydrocortisone 50或100mg q6h共七天、休克劑量(50mg q6h,臨床休克時使用)與
未使用hydrocortisone之加護病房住院病患,21天時不需插管或其他器官支持療法天數與死亡率差異未達統計顯著
[75]。
⚫ DEXA-COVID-19:7名使用dexamethasone 20mg五天與10mg五天與12名未使用之插管病患,28天死亡率差異未 達統計顯著[76]。
⚫ COVID STEROID 2:497名使用dexamethasone 12mg十天,與485名使用6 mg十天之需使用10L/min以上濃度氧氣 或插管病患,兩組在第28天時不需器官支持天數中位數並無差異(22 vs 20.5天,p=0.07),死亡率亦無統計顯著差異 (27.1% vs 32.3%)[77]。
Interferon 隨機對照試驗 ⚫ SOLIDARITY trial:2050名使用interferon病患與接受標準治療者相比,28天住院死亡率並無差異(12.9% vs 11.0%)[7]。
GM-CSF inhibitors (Otilimab, lenzilumab, mavrilimumab)
隨機對照試驗 ⚫ OSCAR trial:403名使用高流量氧氣、非侵襲性呼吸器或插管的確診病患使用otilimab,相較於403名使用安慰劑 者,28天時存活且未插管率(71 vs 67%)與全死因死亡率(17 vs 19%)均無差異,但70歲以上病患28天時存活且未插 管率顯著改善(66 vs46%)[78]。
⚫ LIVE-AIR trial:261名使用氧氣但未插管病患接受lenzilumab治療,相較於259名使用安慰劑者,28天時不需呼吸 器且存活之機率增加54% (HR: 1.54, CI: 1.02-2.31)[79]。
⚫ MASH-COVID:21名需使用氧氣且CRP>5 mg/dL之確診病患接受mavrilimumab治療,相較於19名使用安慰劑者,
14天時存活且不需使用氧氣之比例並未達統計顯著差異(57 vs 47%)[80]。
⚫ 236名需使用氧氣但未插管病患接受三劑lenzilumab治療,相較於243名接受安慰劑者,28天時不需用氧存活率分 別為84%與78% (p<0.04)。94%病患同時接受steroids,72%同時接受remdeivir治療,包括69%同時使用steroids及 remdesivir [93]。
三、抗
SARS-CoV-2單株抗體
藥物名稱 證據等級 目前實證摘要
Bamlanivimab±etesevimab
(LY-CoV555)@
觀察性試驗 (治療)
⚫ 接受bamlanivimab治療的232名具重症風險因子門診病患,與1160名未接受治療者相比,經校正可能干擾因子
後,bamlanivimab組28天住院或死亡率下降60% (OR=0.4, CI 0.4-0.69),且效果對65歲以上族群更加顯著。但須注 意研究進行期間,美國當地B.1.1.7變異株盛行率仍低[81]。
⚫ 回溯型研究顯示,至少具一個重症風險因子之成人病患,於發病10天內接受bamlanivimab (n=2747)或casirivimab + imdevimab (b=849)治療,28天住院率分別為4.34%與2.83%,差異達統計顯著(p=0.05),但若校正收案時風險因子後 則無顯著差異。另28天COVID-19相關住院率為2.84 vs 1.65%,無統計顯著差異[82]。
隨機對照試驗 (治療)
⚫ BLAZE-1, monotherapy:接受bamlanivimab治療的309名門診病患與接受安慰劑者相比,病毒量下降較快、29天時 住院率較低且症狀較快緩解[83]。
⚫ ACTIV-3:接受bamlanivimab治療的163名住院病患與接受安慰劑者相比,臨床改善比率並無差異[84]。
目前已不建議使用
⚫ BLAZE-1, combination:接受bamlanivimab(309名)、bamlanivimab + etesevimab(112名)與安慰劑(156名)之門診病患 相比,bamlanivimab + etesevimab組在第十一天時病毒量較低[85]。
⚫ BLAZE-1, phase 3:接受bamlanivimab + etesevimab治療的511名具重症風險因子之輕中度確診病患,相較於258名 安慰劑組,住院率下降87%[86]。
隨機對照試驗 (預防)
⚫ BLAZE-2:965名長照機構住民與工作人員,曾暴露於機構中確診者但收案時SARS-CoV-2血清抗體與PCR均陰性。
隨機接受bamlanivimab(n=484)或安慰劑(n=482)預防性投藥,用藥組八周內發生COVID-19有症狀感染風險較低(OR 0.43, p=0.00021)。接受預防性用藥的住民感染風險可下降80% (OR 0.20)。但須注意研究進行期間,美國當地B.1.1.7 變異株盛行率仍低[87, 88]。
Casirivimab + Imdevimab (REGN-CoV2)@
隨機對照試驗 (治療)
⚫ 接受casirivimab與imdevimab合併療法的533名門診病患與接受安慰劑者相比,病毒量下降較快且28天時住院或
前往急診比率較低[89]。
⚫ 275名門診病患接受不同劑量casirivimab + imdevimab或安慰劑,用藥組第七天時病毒量下降較多,且若接受治療時 病毒量較高,或為SARS-CoV-2血清陰性(seronegative),治療效果更顯著[90]。
⚫ 具重症風險因子門診病患,接受1200mg(n=736)或2400mg(n=1355) casirivimab + imdevimab治療,相較於接受安慰 劑者(n=748, 1341),28天死亡或住院率分別下降70.4% (p<0.001)與71.3% (p<0.001),且均可提早四天達症狀改善(10 vs 14天,p<0.0001)。治療組收案時有24%為血清抗體陽性,亦顯示相同治療效果[91, 92]。
⚫ 803名門診病患接受不同劑量靜脈或皮下注射casirivimab + imdevimab (IV: 2400/1200/600mg, SC 1200/600mg),相較 於接受安慰劑者,第七天時均可加速病毒清除[93]。
⚫ RECOVERY trial:4839名住院病患接受casirivimab + imdevimab (IV 4000+4000mg)或安慰劑(n=4946),收案時血清陰性 者,28天死亡率可下降20% (24% vs 30%, RR=0.8),但對收案時血清陽性及所有病患,效果則未達統計顯著[94]。 隨機對照試驗
(預防)
⚫ 753名確診病患之家戶接觸者,年齡≧12歲,收案時PCR陰性且無症狀,於暴露四天內接受casirivimab +
imdevimab (SC 1200mg),另752名安慰劑組,兩組於收案後均持續與確診家屬同住。治療組28天時有症狀確診率
下降81.4% (1.5 vs 7.8%p<0.0001),有症狀確診者症狀持續時間較短(1.2 vs 3.2週),且病毒量較低[95, 96]。追蹤結果 顯示治療組在用藥2-8個月後確診率仍可下降81.6% (p<0.0001),且無人因COVID-19而住院。治療組與對照組分別 有34.5%與35.2%於追蹤期間曾接種COVID-19疫苗[97]。
目前已不建議使用
Sotrovimab 隨機對照試驗 (治療)
⚫ COMET-ICE:291名具重症風險因子門診病患於發病五天內接受sotrovimab治療,相較於292名接受安慰劑組,第
29天時住院或死亡率下降85% (1% vs 7%),且治療組無人入住ICU[98, 99]。
Regdanvimab 隨機對照試驗
(治療)
⚫ 204名門診病患接受40或80mg ragdanvimab治療,相較於103名接受安慰劑者,28時須用氧/住院或死亡率較低
(4.4 vs 8.7%)。具重症風險因子病患分組分析亦顯示相同結果(5.5 vs 12.7%),且治療組第七天鼻咽拭子病毒量較治療
組下降39%[100]。 Tixagevimab + cilgavimab
(EVUSHELD)#@
隨機對照試驗 (預防)
⚫ PROVENT:3441名18歲以上至少具一個重症風險因子,或有感染風險者接受一劑300mg tixagevimab+cilgavimab肌 肉注射做為暴露前預防,相較於1731名接受安慰劑者,追蹤至183天時PCR確診有症狀SARS-CoV-2感染機率下降 77%(0.2 vs 1.0%, p<0.001)[101, 102]。
⚫ STORM-CHASER:749名18歲以上成人在與SARS-CoV-2確診病患接觸後八天內接受一劑300mg
tixagevimab+cilgavimab做為暴露後預防,相較於372名接受安慰劑者,追蹤至183天時PCR確診有症狀SARS-CoV-2 感染機率並無統計顯著差異(3.1 vs 4.6%, CI: -26-65)[101]。
隨機對照試驗 (治療)
⚫ TACKLE:452名18歲以上未曾接種COVID-19疫苗之輕中症門診病患於發病七天內接受600mg tixagevimab+cilavimab 一劑,相較於451名接受安慰劑者,28天時重症或死亡率降低50.5%,且發病後越早給予治療,效果越顯著[103]。
⚫ ACTIV-3 :710名成年中症住院病患於發病十二天內接受600mg tixagevimab+cilavimab一劑,相較於707名接受安慰 劑者,90天恢復率兩組沒有顯著差異,但死亡率降低30%,且發病後越早給予治療,效果越顯著[104]。
Bebtelovimab# 隨機對照試驗
(治療)
⚫ BLAZE-4 (low-risk):無任何重症風險因子之輕中症門診病患於確診三天內隨機分配接受bebtelovimab(n=125)、 bebtelovimab+bamlanivimab+etesivimab(n=127)或安慰劑(n=128),第七天時病毒量與第29天時住院率並無統計顯著 差異(1.6 vs 2.4 vs 1.6%),但bebtelovimab組可較早達症狀改善(6 vs 7 vs 8天,p=0.003)[105]。
⚫ BLAZE-4 (high-risk):具重症風險因子之輕中症門診病患於確診三天內隨機分配接受bebtelovimab(n=100)或
bebtelovimab+bamlanivimab+etesivimab(n=50),第三/五/七/十一天時病毒量與第29天時住院率並無統計顯著差異(3 vs 4 %)[105]。
四、其他藥物
藥物名稱 證據等級 目前實證摘要
Aspirin 隨機對照試驗 ⚫ RECOVERY trial:7351名使用aspirin之住院病患,與7541名標準治療組相比,28天死亡或呼吸器使用率並無差
異。Aspirin組血栓發生風險較低(4.6% vs 5.3%),但嚴重出血事件發生率較高(1.6% vs 1.0%)。研究結果不支持對 COVID-19住院病患除LMWH外常規給予aspirin[106]。
Colchicine 隨機對照試驗 ⚫ COLCORONA trial:40歲以上PCR或症狀確診門診病患,具有至少一個研究中所定義之風險因子者,隨機分配給與
colchicine(0.5mg每日兩次x3天,每日一次x27天)或安慰劑。兩組各2253名病患中,死亡或住院率並無差異(4.7%
vs 5.8%),但colchicine治療組PCR確診患者之死亡或住院率較低(4.6% vs 6.0%, OR=0.75, CI 0.57-0.99)。治療組腹瀉比 例較高(13.7% vs 7.3%, p<0.001),且肺栓塞發生率較高(0.5% vs 0.1%, p=0.01)[107]。
⚫ RECOVERY trial:11162名住院病患隨機分配接受colchicine或標準治療,初步結果顯示兩組28天死亡率並無差異 (20% vs 19%, p=0.63),試驗也因此提前結束收案[108, 109]。
⚫ COLCOVID:1279名住院病患隨機分配接受colchicine或標準治療,兩組在第28天時死亡率(HR0.88; CI 0.70–1.12)與 使用呼吸器或死亡率(HR 0.83; CI, 0.67–1.02)均無統計顯著差異[110]。
Fluvoxamine 隨機對照試驗 ⚫ TOGETHER trial:741名具重症風險門診病患接受fluvoxamine十天治療,相較於756名接受安慰劑者,28天內前往
急診或住院機率較低(11% vs 16%, RR 0.52-0.88),且兩組副作用比例並無差異[111]。
⚫ COVID-OUT:發病七天內之30-85歲過重或肥胖之確診病患,經隨機分配後接受metformin(n=630)、
fluvoxamine(n=343)、ivermecti(n=410)或安慰劑。14天內發生缺氧(SpO2≤93%)、至急診就醫、住院或死亡之風險與 使用安慰劑者並無統計顯著差異[112]。
統合分析 ⚫ 統合分析三個隨機臨床試驗,共2196名輕症病患,使用fluvoxamine組住院風險為0.78 (0.58-1.08),根據不同預設 條件,fluvoxamine可降低住院風險的可能性為94.1-98.6[113]。
恢復期血清 隨機對照試驗 ⚫ 228名接受恢復期血清治療之病患,相較於105名安慰劑組,雖治療兩天後體內SARS-CoV-2抗體濃度較高,但30 天時達臨床改善比例與死亡率(10.96% vs 11.43%)並無差異[114]。
目前已不建議使用
目前已不建議使用
⚫ 80名於發病72小時內接受恢復期血清治療之65歲以上病患,相較於80名安慰劑組,第15天時進展至嚴重肺炎比 例較低(16% vs 31, RR=0.52, p=0.03),且抗體濃度越高,治療效果越好[115]。
⚫ PLACID:235名接受恢復期血清治療之嚴重肺炎以上程度病患,相較於229名接受標準治療者,28天死亡率並無差
異(19% vs 18%) [116]。
⚫ 55名接受恢復期血清治療之嚴重肺炎以上程度病患,相較於51名接受標準治療者,28天時臨床改善率(51.9% vs 43.1%, p=0.26)與死亡率(15.7% vs 24.0%, p=0.30)均無差異 [117]
⚫ RECOVERY trial:5795名使用恢復期血清治療之住院病患,相較於5763名使用標準治療者,28天死亡率並無差異
(24% vs 24%, RR 1.00, p=0.95)。病患收案時嚴重程度以須用氧氣但未插管最多(87%)[37]。
⚫ C3PO:257名於發病七天內使用恢復期血清,且具重症風險因子之門診病患,相較於257名使用安慰劑者,收案第 15天時病情惡化至住院、急診就醫或死亡之比率並無差異(30.0 vs 31.9%)[118]。
⚫ REMAP-CAP:1084名入住加護病房之重症病患,於收案48小時內使用恢復期血清,相較於916名接受標準治療
者,第21天時不需器官支持天數並無統計顯著差異(0天 vs 3天,OR 0.97,0.82-1.14);住院死亡率亦無差異(37.3 vs 38.4%)[119]。
⚫ CONTAIN-COVID:468名使用氧氣或非侵襲性呼吸器病患,於發病七天或住院三天內使用恢復期血清,相較於473
名對照組,第14天時臨床改善率並未達統計顯著差異(cOR 0.94, 0.75-1.18),28天亦未達統計顯著(cOR 0.72, 0.46- 1.13)[120]。
⚫ 592名發病八天內成人門診病患接受高效價(≥1:320 anti-S antibody)恢復期血清約250mL,相較於589名接受安慰劑 血清者,28天時住院率下降54% (2.9 vs 6.3%)[121, 122]。
⚫ 188名發病七天內50歲以上成人病患(97%為輕症)接受高效價(EUROIMMUN ratio≥6)恢復期血清治療,相較於188名 接受安慰劑者,28天時住院率並無統計顯著差異(12 vs 11%),第七天時病毒量亦無統計顯著差異。依病患收案時血 清抗體陽性情形,或發病至收案天數分層分析亦顯示相同結果[123]。
統合分析 ⚫ 統合分析十個隨機對照試驗,共11782名病患使用結果,恢復期血清無法降低病患死亡風險(RR 1.02, 0.92-1.12)[87]。
⚫ Cochrane review:統合分析13 個隨機對照試驗,共48509名病患資料顯示,對中重度COVID-19病患,恢復期血清 無助於降低病患死亡率或改善呼吸狀況,但對輕症或無症狀病患,恢復期血清效果尚無明確證據[124]。
@已於我國專案輸入 *已取得美國FDA藥證 #目前有美國FDA緊急使用授權(EUA)
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