Confidential

ラゲブリオカプセルに関する費用対効果評価 [第 1.0 版]
MSD 株式会社
2023 年 5 月 2 日

本資料の無断転載はご遠慮頂きたくお願い申し上げますConfidential【目次】

0. 要旨 ...................................................................................................8
1. 対象となる医薬品･医療機器の性質 ............................................................. 13
1.1 名称 ............................................................................................ 13
1.2 保険償還価格 ................................................................................. 13
1.3 治療効果のメカニズム ........................................................................ 13
1.4 対象疾患 ....................................................................................... 14
1.5 使用方法等 .................................................................................... 15
1.6 対象疾患の治療における当該医薬品･医療機器の位置づけ ............................. 16
1.7 主な有害事象 .................................................................................. 17
1.8 他国の医療技術評価機関における評価結果 ............................................... 18
2. 費用効果分析における分析条件の設定............................................................................ 20
2.1 分析対象とする集団 .......................................................................... 20
2.2 比較対照 ....................................................................................... 20
2.3 分析の立場と費用の範囲 .................................................................... 20
2.4 効果指標 ....................................................................................... 20
2.5 分析期間 ....................................................................................... 20
2.6 割引率.......................................................................................... 21
2.7 分析条件の設定の要約 ...................................................................... 21
3. 追加的有用性................................................................................................................... 23
3.1 クリニカルクエスチョン ........................................................................ 23
3.2 システマティックレビュー ...................................................................... 24
3.2.1 組み入れ基準と除外基準 ............................................................... 24
3.2.2 使用したデータベース ................................................................... 27
3.2.3 システマティックレビューの実施 ........................................................ 28
3.2.4 検索結果 ................................................................................. 28
3.3 クリニカルクエスチョン(異なる比較対照あるいは単群試験) [該当する場合のみ] ..... 50
3.4 システマティックレビュー (異なる比較対照あるいは単群試験) [該当する場合のみ].. 50
3.5 既存データの再解析 .......................................................................... 50
3.6 メタアナリシスの詳細 [該当する場合のみ] ............................................... 50
3.7 間接比較やネットワークメタアナリシスの結果 [該当する場合のみ] ..................... 50
3.8 追加的有用性の有無に関する評価 ......................................................... 51
4. 分析方法の詳細 ............................................................................................................... 55
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4.1 分析方法 ....................................................................................... 55
4.1.1 費用対効果の算出方法 ................................................................. 55
4.1.2 モデルで使用した仮定 .................................................................. 56
4.2 分析で使用したパラメータ .................................................................... 57
4.2.1 有効性･安全性等のパラメータの詳細 ................................................. 60
4.2.2 QOL 値の詳細 ........................................................................... 61
4.2.3 費用のパラメータの詳細 ................................................................ 62
5. 分析結果 .......................................................................................................................... 65
5.1 基本分析(費用対効果評価専門組織で決定された分析枠組みによる分析)の結果 .... 65
5.1.1 基本分析の増分費用、増分効果、増分費用効果比 .................................. 65
5.1.2 感度分析 ................................................................................. 66
5.1.3 分析の妥当性の検討 .................................................................... 71
5.1.4 分析結果の解釈 ......................................................................... 74
5.1.5 価格調整率の重み [該当する場合のみ] ............................................. 75
5.1.6 価格の引き上げ [該当する場合のみ] ................................................ 75
5.2 公的介護費用や生産性損失を含めた分析 [該当する場合のみ] ........................ 75
5.3 その他の分析 [該当する場合のみ] ........................................................ 75
6. 再分析用のデータ ................................................................................. 76
7. 実施体制 ........................................................................................... 77
8. 参考文献 ........................................................................................... 78
Appendix .............................................................................................. 91
別添 1： SLR1 に用いた検索式 ..................................................................... 92
別添 2： SLR2 に用いた検索式 ................................................................... 100
別添 3： SLR3 に用いた検索式 ................................................................... 107
別添 4： SLR4 に用いた検索式 ................................................................... 116
別添 5： 同定した臨床研究(論文)の詳細 ........................................................ 125
別添 6： QOL 値の詳細............................................................................ 234

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略語
略語

正式表記

AE

Adverse Events

ATS

American Thoracic Society

BMJ

British Medical Journal

CADTH

Canadian Agency for Drugs and. Technologies in Health

COVID-19

Coronavirus disease 2019

CROI

Conference on Retroviruses and Opportunistic Infections

CTRI

Clinical Trial Registry of India

DSA

Deterministic sensitivity analysis

ECCMID

European Congress of Clinical Microbiology and Infectious
Diseases

ECMO

Extracorporeal Membrane Oxygenation

ED

Emergency Department

EMBASE

Excerpta Medica Database

HAS

Haute Autorité de Santé

ICER

Incremental Cost-Effectiveness Ratio

ICU

Intensive Care UnitIDSA

US Infectious Diseases Society of America

ICTRP

International Clinical Trials Registry Platform

IQWiG

Instituts für Qualität und Wirtschaftlichkeit im
Gesundheitswesen

MAGIC

Mutant-Assisted Gene Identification and Characterization

MEDLINE

Medical Literature Analysis and Retrieval System Online

MERS

Middle East Respiratory Syndrome

MTA

Multi Technology Appraisal

MV

Mechanical ventilation

NHC

β-d-N-hydroxycytidine/N-ヒドロキシシチジン

NHC-TP

Triphosphate β-d-N-hydroxycytidine/N-ヒドロキシシチジン三リン酸

NICE

National Institute for Health and Care Excellence

NIH

National Institutes of Health

NMA

Network meta-analysis

NR

Not reported
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PBAC

Pharmaceutical Benefits Advisory Committee

PMC

NIH PubMed Central

PRISMA

Preferred Reporting Items for Systematic Reviews and MetaAnalyses

PSA

Probabilistic Sensitivity Analysis

QOL

Quality of Life

RCT

Randomized Controlled Trial

RdRp

RNA-dependent RNA polymerase/RNA 依存性 RNA ポリメラーゼ

RNA

Ribonucleic acid

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2SEStandard Error

SMC

Scottish Medicines Consortium

SMR

Standardized Mortality Ratio

UPMC

University of Pittsburgh Medical Center

WHO

World Health Organization

WTP

Willingness-to-pay

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図一覧
図 1 治療効果のメカニズム .......................................................................... 13
図 2 NHC の SARS-CoV-2 の変異株に対する抗ウイルス作用 ................................ 14
図 3 SARS-CoV-2 による感染者数の推移 ....................................................... 15
図 4 COVID-19 の重症度分類 .................................................................... 16
図 5 重症度別マネジメント ........................................................................... 17
図 6 PRISMA フロー図 .............................................................................. 29
図 7 分析モデルの構造 .............................................................................. 55
図 8 一次元感度分析 ................................................................................ 69
図 9 費用効果平面上の散布図 ..................................................................... 69
図 10 費用効果受容曲線 ............................................................................ 70

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表一覧
表 1 主要国における評価の一覧表 ................................................................. 18
表 2 評価の有無の一覧.............................................................................. 18
表 3 評価結果の詳細 ................................................................................ 18
表 4 分析条件の設定の要約 ........................................................................ 21
表 5 システマティックレビューのクリニカルクエスチョン ........................................... 23
表 6 臨床研究の組み入れ基準と除外基準 ........................................................ 24
表 7 検索データベースおよび検索期間 ............................................................ 28
表 8 同定した臨床研究(論文)の一覧表 ........................................................... 30
表 9 MOVe-OUT 試験（第Ⅲ相パート）の詳細表 ................................................. 46
表 10 追加的有用性の有無に関する主な報告の概要,,........................................... 53
表 11 SARS-CoV-2 による感染症（COVID-19）患者における追加的有用性 ................ 54
表 12 MDV データベース調査の概要 .............................................................. 57
表 13 ベースラインの患者特性および疾患特性 ................................................... 59
表 14 その他のパラメータ ........................................................................... 60
表 15 MOVe-OUT 試験に基づくモルヌピラビルの有効性 ....................................... 60
表 16 COVID-19 による死亡率.................................................................... 61
表 17 COVID-19 患者における QOL 値.......................................................... 62
表 18 治療費用の推計方法 ......................................................................... 63
表 19 治療の費用 .................................................................................... 64
表 20 年齢階級別 1 日あたりの平均賃金 ......................................................... 64
表 21 基本分析の結果............................................................................... 65
表 22 費用の内訳 .................................................................................... 65
表 23 パラメータの設定 .............................................................................. 66
表 24 MOVe-OUT 試験（全集団）の患者特性および疾患特性による分析 ..................... 70
表 25 MOVe-OUT 試験（軽症患者サブ集団）の患者特性および疾患特性による分析 ....... 71
表 26 MOVe-OUT 試験（60 歳以下サブ集団）の患者特性および疾患特性による分析 ...... 71
表 27 基本分析の設定における社会の立場での分析 ............................................ 71
表 28 分析結果の解釈............................................................................... 74

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0. 要旨
分析対象技術名 [1.1 節]

ラゲブリオ（モルヌピラビル）

他国の医療技術評価機関•

イギリス（National Institute for Health and Care
Excellence, NICE）： Multi Technology Appraisal

における評価結果 [1.8 節]（MTA）実施中•

イギリス（Scottish Medicines Consortium, SMC）：該
当なし•

フランス（Haute Autorité de Santé, HAS)：該当なし•

ドイツ（Instituts für Qualität und
Wirtschaftlichkeit im Gesundheitswesen,
IQWiG)：該当なし•

カナダ（Canadian Agency for Drugs andTechnologies in Health, CADTH）：該当なし•

オーストラリア（Pharmaceutical Benefits Advisory
Committee, PBAC）：評価中対象とする疾患･集団 [2.1 節]重症化リスク因子を有する SARS-CoV-2 による感染症（COVID-19）患者（18 歳以上）
但し、有効性が確立していないため、重症度*の高い
COVID-19 患者を除く。
*重症度の定義は新型コロナウイルス感染症（COVID-19）
診療の手引き・第 8.1 版に準ずる。

比較対照技術名 [2.2 節]

標準治療分析の立場と費用の範囲

公的医療の立場[2.3 節]公的医療費のみ

使用する効果指標 [2.4 節]質調整生存年(Quality-adjusted life-year, QALY）

設定した分析期間 [2.5 節]

生涯割引率 [2.6 節]

費用、効果ともに年率 2%

システマティックレビューの介入

クリニカルクエスチョン[3.1/3.3 節]••

ラゲブリオ/モルヌピラビル
ロナプリーブ/カシリビマブ＋イムデビマブ

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システマティックレビューの対象集団

クリニカルクエスチョン•

COVID-19 患者（外来のみ）[3.1/3.3 節]•••

ゼビュディ/ソトロビマブ/VIR-7831
ベクルリー/レムデシビル/GS-5734
パキロビッド/ニルマトレルビル+リトナビル/PF07321332
Levovir/Revovir/clevudine/クレブジン
Arbidol/umifenovir/ウミフェノビル
Kineret/anakinra
Lenzilumab/レンジルマブ
Bebtelovimab/ベブテロビマブ
AT-527/RO7496998
Tixagevimab + cilgavimab/(AZD7442 or
AZD8895) and AZD1061
Bamlanivimab/LY-CoV555/バムラニビマブ
Bamlanivimab + etesevimab/LY CoV555 +LY-CoV016/バムラニビマブ ＋ エテセビマブ
パルミコート/ブデソニド
フオイパン/カモスタットメシル酸塩
コルヒチン
Regdanvimab/CT-P59
アビガン/ファビピラビル
ヒドロコルチゾン
メチルプレドニゾロン
Nitazoxanide/ニタゾキサニド
ペグインターフェロンラムダ-1
プレドニゾン
ADG20
オルミエント/バリシチニブ
Ensovibep/MP0420
ファモチジン
フルボキサミン
MP-0423
ゾコーバ/エンシトレルビル/S-217622

（続き）

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比較対照
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ラゲブリオ/モルヌピラビルを除く上述の治療

アウトカム
•

有効性：外来患者の治療経過に関連するアウトカム（以下を含むが、これに限定しない。）- 悪化までの期間- 持続的回復までの期間- COVID-19 の徴候及び症状の持続期間- ウイルス学的治癒/ウイルスクリアランスを達成するまでの期間及び達成した患者の割合- ウイルス量／ウイルス排出量9Confidential

システマティックレビューのクリニカルクエスチョン[3.1/3.3 節]（続き）•- （下記の測定方法による）症状の重症度及びフォローアップ時の疾患の進行度〇Pulmonary or pulmonary + score〇National Early Warning Score〇WHO 11-point outcomes score- フォローアップ時の臨床的改善度（WHO 臨床的改善度カテゴリースケール、または臨床/実験データ/CT スキャン/ウイルス消失率によるもの）- 全生存（人数/割合/率）- 全死因死亡（人数/割合/率）- COVID-19 関連死亡（人数/割合/率）- 入院（人数/割合/率）- 入院までの期間- ICU または一般病棟に入院した患者（人数/割合/率）
安全性- 治療に関連する有害事象- グレード 3 および 4 の有害事象- 重篤な有害事象- 治療の中止（有害事象によるものなど）

研究デザイン•

第 II 相または第 III 相の無作為化比較試験

検索期間•

英語：2020/01/01～2022/12/06•

日本語：2020/01/01～2022/12/06

システマティックレビュー結果の上述のクリニカルクエスチョンに従って、システマティックレビュ

概要 [3.2/3.4 節]ーを実施した。分析ガイドラインには、文献検索終了時点について「分析枠組みが決定された後から製造販売業者による分析提出までの一時点に決める」の規定に沿って、既に 2021
年 5 月から 2022 年 5 月の間に 3 回実施していたシステマ
ティックレビューに加えて、2022 年 12 月に和文文献検索を含めたシステマティックレビューの更新を実施した。（2021 年
9 月、2022 年 5 月、2022 年 12 月までの間に 3 回更新した）。
関連する論文を特定するために、文献データベースは、
Embase, Medline を使用し、第４回では医中誌を追加し文献検索を実施した。また、その他の情報源として、臨床試験のデータベースや学会抄録の検索も行った。更新を含めた計 4回の検索で同定された文献数は下記の通りである。

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システマティックレビュー結果の概要 [3.2/3.4 節]（続き）

件数
文献データベース

52

その他の情報源

34

合計

86（60 試験）

間接比較の結果 [3.7 節]

該当なし

追加的有用性の有無 [3.8 節]■ 追加的有用性あり □ 「追加的有用性なし」あるいは「あるとは判断できない」

費用対効果の分析方法の概要

本分析では、COVID-19 の発症から急性期治療終了までの[4.1.1 項、4.2 節等]

分析期間（30 日）に決定木モデルを用い、その後の分析期間（生涯：死亡又は 100 歳まで）には 1 サイクルを 1 年（但し、初年は急性期を除いた 11 か月）に設定したマルコフモデルを用いた。決定木モデルでは外来治療（非入院）から開始され、COVID-19 の重症化に伴い、最終的に外来から入院へ移行する可能性を想定した。また、入院中に到達しうる最高レベルのケアセッティングとして 3 レベル（一般病棟、ICU、体外式

膜型人工肺（ECMO）又は人工呼吸器（MV）の使用を伴うICU）を想定し、入院後の患者の転帰として、完全に回復する
ケース、長期の後遺症を伴って回復するケース、入院中に死亡するケースを想定した。入院後の生存患者では、再入院を経験することも想定した。有害事象（Adverse Events, AE）
または治療上緊急を要する有害事象は、非入院 COVID-19
患者を対象とした MOVe-OUT 試験で安全性及び忍容性が良好であり、特段の安全性上の懸念が認められなかったため、本分析では想定しない。
基本分析に加えて、一次元感度分析、確率的感度分析、シナリオ分析を実施した。有効性や安全性のパラメータにはデータ
ベース調査および自社試験結果、QOL 値には文献値および海外における調査結果の日本人換算値、費用のデータには
データベース調査の結果を主に使用した。

結果の概要 [5.1 節]重症化リスク因子を有する SARS-CoV-2 による感染症(COVID-19)患者において、モルヌピラビル＋標準治療に対11Confidential

する標準治療の（Incremental Cost-EffectivenessRatio、ICER） は 1,930,637 円/QALY であり、「医薬品及び医療機器の費用対効果評価に係る分析結果の記載様式と手引」に記載の価格調整の閾値「500 万円以下 (750 万円
以下) 」の区分に相当すると考える。実施した PSA においてICER が基準値の 500 万円を下回る確率は 100%、250 万円を下回る確率は 93%であり、さらに公的医療の立場でのシナリオ分析全てにおいて ICER が基準値の 500 万円を下回
り、基本分析と同様の結果が示された。
ICER の所属する確率が最も高い□ 費用削減あるいはドミナントと考える区間■ 500 万円以下 (750 万円以下)□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125
万円以下)□ 750 万円超 (1125 万円超)かつ 1000 万円以下
(1500 万円以下)□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い

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1. 対象となる医薬品･医療機器の性質
1.1 名称
販売名

ラゲブリオカプセル 200mg

一般名

和名：モルヌピラビル
洋名：Molnupiravir

1.2 保険償還価格
薬価

200mg 1 カプセル 2,357.80 円 （2023 年 4 月時点）

算定方式

類似薬効比較方式（I）

加算率

有用性加算（II）（A=10%）

1.3 治療効果のメカニズム
ラゲブリオ（一般名：モルヌピラビル）は、ウイルスでのエラーカタストロフの誘導により抗ウイルス作用を示す。モルヌピラビルの活性本体である N-ヒドロキシシチジン三リン酸（β-d-Nhydroxycytidine Triphosphate, NHC-TP）がウイルス由来 RNA 依存性 RNA ポリメラーゼ（RNA-dependent RNA polymerase, RdRp）によりウイルス RNA に取り込まれた結果、ウ
イルス RNA の複製エラーが増加し、ウイルスの増殖が阻害される（図 1）。
図 1 治療効果のメカニズム

NHC：N-ヒドロキシシチジン、NHC-TP：N-ヒドロキシシチジン三リン酸、RdRp：RNA 依存性 RNA ポリメラーゼ
出典：ラゲブリオカプセル 200mg インタビューフォーム（2023 年 4 月改訂、第 3 版）

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モルヌピラビルの主要代謝物である NHC は、SARS-CoV-2 の従来株（USA-WA1/2020株）、並びにその変異株である B.1.1.7 系統（アルファ株）、B.1.351 系統（ベータ株）、P.1 系統（ガンマ株）、B.1.617.2 系統（デルタ株）、C.37 系統（ラムダ株）、B.1.621 系統（ミュー株）および B.1.1.529/BA.1、BA1.1、BA.2、BA.4、BA.5（オミクロン株）に対して同程度の抗ウイルス作用を示した（図 2）。さらに、Kawaoka らのグループにより、より新しい BQ.1.1 系統[1]、XBB.1.5 系統[2]等に対しても同程度の抗ウイルス作用が報告されている。
図 2 NHC の SARS-CoV-2 の変異株に対する抗ウイルス作用

出典：ラゲブリオカプセル 200mg 添付文書（2023 年 4 月改訂、第 5 版）

1.4 対象疾患
ラゲブリオカプセルの保険適用となっている効能・効果は、「SARS-CoV-2 による感染症」（新型コロナウイルス感染症（COVID-19））である[3]。病原体である SARS-CoV-2 は、SARS やMERS の病原体と同じβコロナウイルス属に分類される動物由来コロナウイルスと判明したが宿主動物はまだ分かっていない。現在はヒト-ヒト感染によって流行が世界的に広がっている状況である。感染経路は、感染者（無症状病原体保有者を含む）から咳、くしゃみ、会話などの際に排出されるウイルスを含んだ飛沫・エアロゾル（飛沫よりさらに小さな水分を含んだ状態の粒子）の吸入が主要感染経路と考えられる。潜伏期・感染可能期間については、潜伏期は 1 ～14 日間で14

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あり、曝露から 5 日程度で発症することが多い。ただし、オミクロン株は潜伏期が 2～3 日、曝露から 7 日以内に発症する者が大部分であるとの報告がある。発症前から感染性があり、発症から間もない時期の感染性が高いことが市中感染の原因となっており、SARS や MERS と異なる特徴である[4]。2023 年 4 月 17 日現在、国内 COVID-19 の陽性者数は累計約 3,360 万人、累計死亡者数は約 7.4 万人である[5]。
図 3 SARS-CoV-2 による感染者数の推移

出典：厚生労働省第 121 回新型コロナウイルス感染症対策アドバイザリーボード（令和 5 年 4 月 19 日）

1.5 使用方法等
投与経路
投与量・投与頻度

経口
通常、18歳以上の患者には、モルヌピラビルとして1回800mg
を 1 日 2 回、5 日間経口投与する。
• 臨床試験における主な投与経験を踏まえ、SARS-CoV-2による感染症の重症化リスク因子を有する等、本剤の投与が必要と考えられる患者に投与すること。また、本剤の投与対象につ効能又は効果に関連する注意

いては最新のガイドライン*も参考にすること。
• 重症度の高いSARS-CoV-2による感染症患者に対する有効性は確立していない。
* 新型コロナウイルス感染症（COVID-19） 診療の手引き など

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SARS-CoV-2 による感染症の症状が発現してから速やかに投用法及び用量に関連する注意

与を開始すること。臨床試験において、症状発現から 6 日目以降に投与を開始した患者における有効性を裏付けるデータは得られていない。

平均的な投与期間(あるいはサイクル数)
平均投与量

5 日間1600mg/日

出典：ラゲブリオカプセル 200mg 添付文書（2023 年 4 月改訂、第 5 版）

1.6 対象疾患の治療における当該医薬品･医療機器の位置づけ
2023 年 3 月現在、国内 COVID-19 の陽性者数は累計約 3,348 万人、累計死亡者数は約7.4 万人である[5]。COVID-19 の重症度は図 4 の通り 4 段階に分類されている[4]。
図 4 COVID-19 の重症度分類

出典：新型コロナウイルス感染症（COVID-19） 診療の手引き 第 9.0 版

モルヌピラビルは新型コロナウイルス感染症（COVID-19） 診療の手引き[4]の 4.重症度分類とマネジメントの中で軽症及び中等症Ⅰの患者への投与が推奨されている（図 5）。
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図 5 重症度別マネジメント

出典：新型コロナウイルス感染症（COVID-19） 診療の手引き 第 9.0 版

1.7 主な有害事象
臨床試験において認められた主な副作用は下痢、悪心、浮動性めまい、頭痛（1%以上5%未満）であった[6]。これらの副作用について観察を十分に行い、異常が認められた場合には投与を中止するなど適切な処置を行うこととされている[3]。なお、「日本人患者へ投与時の安全性を可能な限り承認後早期に確認し、検討すること、及び有効性についても副次的に確認すること」を目的とした特定使用成績調査の中間解析（回収数：1,064例）では、副作用発現割合は72/1,061例（6.79%）であり、4例以上で発現した副作用は下痢が26例（2.45%）、発疹が6例（0.57%）、
浮動性めまいが5例（0.47%）、軟便が4例（0.38%）であった。重篤な副作用の発現は4例（0.38%）であり、発疹、肝機能異常、COVID-19（増悪）、間質性肺疾患（増悪）であった[7]。

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1.8 他国の医療技術評価機関における評価結果
表 1 主要国における評価の一覧表
国名評価結果 (記載例)

機関名

リスト価格
(現地通貨建)

NICE

イギリス

･ 推奨/非推奨/条件つき推奨(具体的に:)/その他 （MTA 実施中）･ 評価ステータス: 最終ガイダンス/ドラフト/その他
(

)

SMC

該当なし

フランス

HAS

該当なし

ドイツ

IQWiG

該当なし

カナダ

CADT

該当なし

H
オーストラリア

PBAC･ 推奨/非推奨/条件つき推奨(具体的に:)/その他(評価中)

表 2 評価の有無の一覧
国名

機関名

評価結果の有無

イギリス

NICE

あり/ なし/ 評価中(ドラフトあり/なし)/不明

SMCあり/ なし/ 評価中/不明

フランス

HAS

あり/ なし/ 評価中/不明

カナダ

CADTH

あり/ なし/ 評価中/不明

オーストラリアPBACあり/ なし/ 評価中/不明

表 3 評価結果の詳細
国名

イギリス

機関名

NICE

評価結果の URL など
評価対象技術https://www.nice.org.uk/guidance/indevelopment/GIDTA11297
モルヌピラビル

評価結果

N/A（MTA 評価中）

条件付き推奨の場合は、N/A（MTA 評価中）

その条件の詳細18Confidential

評価対象疾患SARS-CoV-2 による感染症

使用方法 (※)

通常、18 歳以上の患者には、モルヌピラビルとして 1 回 800mg
を 1 日 2 回、5 日間経口投与する。

比較対照
主要な増分費用効果比

標準治療
N/A（MTA 評価中）の値

国名オーストラリア

機関名

PBAC

評価結果の URL など

評価対象技術評価結果

https://www.pbs.gov.au/industry/listing/elements/pbacmeetings/pbac-outcomes/2022-11/covid-19-oraltreatments-outcome-nov-2022.pdf
モルヌピラビル推奨

条件付き推奨の場合以下に該当する場合推奨

は、その条件の詳細- 70 歳以上（無症状陽性者を含む）- 50 歳以上で複数の重症化リスク因子を有する軽症者- 30 歳以上の先住民で複数の重症化リスク因子を有する軽症者- 18 歳以上で中等度～重度の免疫抑制状態の軽症者

評価対象疾患SARS-CoV-2 による感染症

使用方法 (※)

通常、18 歳以上の患者には、モルヌピラビルとして 1 回 800mg
を 1 日 2 回、5 日間経口投与する。

比較対照
主要な増分費用効果比

標準治療
N/A（評価中）の値

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2. 費用効果分析における分析条件の設定
2.1 分析対象とする集団
重症化リスク因子を有する SARS-CoV-2 による感染症（COVID-19）患者（18 歳以上） 但し、有効性が確立していないため、重症度*の高い COVID-19 患者を除く、とする。
*重症度の定義は新型コロナウイルス感染症（COVID-19） 診療の手引き・第 8.1 版[8]に準ずる。

2.2 比較対照
ラゲブリオカプセル（以下モルヌピラビル）の保険適用となっている効能効果は「SARS-CoV-2 による感染症」であり、本剤と同様に重症化リスク因子を有する軽症又は中等症Ⅰの患者に推奨される抗ウイルス薬としてレムデシビルおよびニルマトレルビル/リトナビルも薬価収載品目として使用されている。レムデシビルは臨床専門家の意見聴取等から入院外診療において幅広くは使用されておらず、主に入院外で用いる経口薬のモルヌピラビルによっては代替されないと考えられた。一方、ニルマトレルビル/リトナビルはモルヌピラビルと同様、主に重症化リスク因子を有する
入院外の軽症患者で使用される経口薬であり、治療上の位置づけが類似している（併用禁忌・併用注意薬が多い点や腎機能又は肝機能障害の患者で投与量の減量を要する点はモルヌピラビ
ルとは異なる）。従って、本来のところニルマトレルビル/リトナビルが比較対照技術として適当と考えられるものの、ニルマトレルビル/リトナビルは分析枠組み決定の時点で薬価未収載であり薬剤価格が不明だったため、分析の実施が困難であった。
よって、その他に公的医療保険で使用が認められ代替されると想定されるものが存在しないことから、比較対照技術は、「標準治療**（評価対象技術：モルヌピラビル＋標準治療） 」として、
2022 年 11 月 25 日に開催された中央社会保険医療協議会の費用対効果評価専門組織より了承を得た。**COVID-19 に対して治療の適応がある薬剤を除く、対症療法
なお、その後エンシトレルビルが薬価収載され、重症化リスク因子のない軽症例で使用されるが、当該対象患者はモルヌピラビルとは異なる。
2.3 分析の立場と費用の範囲
分析ガイドライン[9]に則り、分析の立場は「公的医療の立場」とした。また、費用の範囲は公的医療の立場において考慮すべき公的医療費（直接医療費）の範囲とした。
2.4 効果指標
分析ガイドラインに則り、評価指標は質調整生存年（QALY）とした。
2.5 分析期間
分析ガイドラインに則り、評価対象技術の費用や効果におよぼす影響を評価するのに十分に長20Confidential

い分析期間を設けるため、分析期間は一生涯（死亡もしくは 100 歳のいずれか早いほう）とした。
2.6 割引率
分析ガイドラインに則り、費用および効果ともに年率 2%で現在価値に割引換算して計算した。
2.7 分析条件の設定の要約
本分析における分析条件の設定の要約を表 4 に示す。
表 4 分析条件の設定の要約
設定
分析対象とする集団項目
重症化リスク因子を有する SARS-CoV-2 による感染症（COVID19）患者（18 歳以上）
但し、有効性が確立していないため、重症度*の高い COVID-19
患者を除く。
*重症度の定義は新型コロナウイルス感染症（COVID-19）診療の手引き・第 8.1 版に準ずる。

比較対照

標準治療*（評価対象技術：モルヌピラビル＋標準治療）*COVID19 に対して治療の適応がある薬剤 中和抗体、その他の抗ウイルス薬等 を除く、対症療法

比較対照を選定した理由

2022 年 8 月の本剤評価品目選定時点では、臨床において抗ウイルス薬としてモルヌピラビルの他に、レムデシビルやニルマトレルビ
ル/リトナビルが政府確保品目もしくは薬価収載後の一般流通品目として使用されている。レムデシビルは臨床専門家の意見聴取等から、入院外診療において幅広くは使用されておらず、主に入院外で用いる経口薬のモルヌピラビルによっては代替されない。一方で、ニルマトレルビル/リトナビルはモルヌピラビルと同様の経口薬であり、治療上の位置づけが類似している。したがって、本来のところニルマ
トレルビル/リトナビルが比較対照技術として適当と考えられるものの、ニルマトレルビル/リトナビルは薬価未収載で薬剤価格が不明なため、分析の実施が困難と考えられた。よって、その他に公的医療保険で使用が認められ代替されると想定されるものが存在しないことから、比較対照技術は標準治療（評価対象技術：モルヌピラビル＋標準治療）とすることが適当である。

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分析の立場と費用の範囲

公的医療の立場
公的医療費のみ

効果指標

質調整生存年（QALY）

分析期間

生涯

割引率

費用･効果ともに年率 2%

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3. 追加的有用性
3.1 クリニカルクエスチョン
対象集団における追加的有効性･安全性を検討するためのクリニカルクエスチョンを表 5 に示す。
表 5 システマティックレビューのクリニカルクエスチョン
項目
対象集団

内容
COVID-19 患者（外来のみ）
以下の治療法のうちいずれかを含む
•
•
•
•
•
•
•
•
•
•
•
•
•
•

介入

比較対照

•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

ラゲブリオ/モルヌピラビル
ロナプリーブ/カシリビマブ＋イムデビマブ
ゼビュディ/ソトロビマブ/VIR-7831
ベクルリー/レムデシビル/GS-5734
パキロビッド/ニルマトレルビル+リトナビル/PF-07321332
Levovir/Revovir/clevudine/クレブジン
Arbidol/umifenovir/ウミフェノビル
Kineret/anakinra
Lenzilumab/レンジルマブ
Bebtelovimab/ベブテロビマブ
AT-527/RO7496998
Tixagevimab + cilgavimab/(AZD7442 or AZD8895) and
AZD1061
Bamlanivimab/LY-CoV555/バムラニビマブ
Bamlanivimab + etesevimab/LY CoV555 + LY-CoV016/バム
ラニビマブ ＋ エテセビマブ
パルミコート/ブデソニド
フオイパン/カモスタットメシル酸塩
コルヒチン
Regdanvimab/CT-P59
アビガン/ファビピラビル
ヒドロコルチゾン
メチルプレドニゾロン
Nitazoxanide/ニタゾキサニド
ペグインターフェロンラムダ-1
プレドニゾン
ADG20
オルミエント/バリシチニブ
Ensovibep/MP0420
ファモチジン
フルボキサミン
MP-0423
ゾコーバ/エンシトレルビル/S-217622

ラゲブリオ/モルヌピラビルを除く上述の治療

23Confidential【有効性】
外来患者の治療経過に関連するアウトカム（以下を含むが、これに限定しない。）

アウトカム- 悪化までの期間- 持続的回復までの期間- COVID-19 の徴候及び症状の持続期間- ウイルス学的治癒/ウイルスクリアランスを達成するまでの期間及び達成した患者の割合- ウイルス量／ウイルス排出量- （下記の測定方法による）症状の重症度及びフォローアップ時の疾患の進行度〇Pulmonary or pulmonary+ score〇National Early Warning Score〇WHO 11-point outcomes score- フォローアップ時の臨床的改善度（WHO 臨床的改善度カテゴリースケール、または臨床/実験データ/CT スキャン/ウイルス消失率によるもの）- 全生存（人数/割合/率）- 全死因死亡（人数/割合/率）- COVID-19 関連死亡（人数/割合/率）- 入院（人数/割合/率）- 入院までの期間- ICU または一般病棟に入院した患者（人数/割合/率）【安全性】- 治療に関連する有害事象- グレード 3 および 4 の有害事象- 重篤な有害事象- 治療の中止（有害事象によるものなど）

研究デザイン
検索対象期間

第 II 相または第 III 相の無作為化比較試験
英語：2020/01/01～2022/12/06
日本語：2020/01/01～2022/12/06

3.2 システマティックレビュー
定義したクリニカルクエスチョンに基づき、システマティックレビューを実施した。詳細を下記に示す。
3.2.1 組み入れ基準と除外基準
以下に組み入れ基準と除外基準をまとめた。

表 6 臨床研究の組み入れ基準と除外基準
項目
対象患者

組み入れ基準COVID-19 患者*（外来のみ）**

除外基準
COVID-19 患者（入院）**
COVID-19 以外の患者

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項目
介入

組み入れ基準以下の治療法のうちいずれかを含む
•
•
•
•
•
•
•
•
•
•
•
•
•
•

•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

ラゲブリオ/モルヌピラビル
ロナプリーブ/カシリビマブ＋イムデビ
マブ
ゼビュディ/ソトロビマブ/VIR-7831
ベクルリー/レムデシビル/GS-5734
パキロビッド/ニルマトレルビル+リトナ
ビル/PF-07321332
Levovir/Revovir/clevudine/クレブ
ジン
Arbidol/umifenovir/ウミフェノビル
Kineret/anakinra
Lenzilumab/レンジルマブ
Bebtelovimab/ベブテロビマブ
AT-527/RO7496998
Tixagevimab +cilgavimab/(AZD7442 or
AZD8895) and AZD1061
Bamlanivimab/LY-CoV555/バム
ラニビマブ
Bamlanivimab + etesevimab/LY
CoV555 + LY-CoV016/バムラニビ
マブ ＋ エテセビマブ
パルミコート/ブデソニド
フオイパン/カモスタットメシル酸塩
コルヒチン
Regdanvimab/CT-P59
アビガン/ファビピラビル
ヒドロコルチゾン
メチルプレドニゾロン
Nitazoxanide/ニタゾキサニド
ペグインターフェロンラムダ-1
プレドニゾン
ADG20
オルミエント/バリシチニブ
Ensovibep/MP0420
ファモチジン
フルボキサミン
MP-0423
ゾコーバ/エンシトレルビル/S217622

除外基準• 組み入れ基準に記載されていない薬物的治療、および入院患者のみに使用される治療（以下を含む）。
o インターフェロンβo クロロキン/ヒドロキシク
ロロキン
o ロピナビル／リトナビル
o アジスロマイシン• 以下のような非薬物的治療。
o 回復期患者血漿o 漢方薬
o 植物性の生薬• 予防が目的の介入

比較対照

ラゲブリオ/モルヌピラビル を除く上述の治療介入で定義されていない治療

アウトカム

【有効性】

***

外来患者の治療経過に関連するアウトカム（以• 組み入れ基準に記載されていない臨床的な安全性または有効性のアウトカム• その他すべての非臨床試験
結果

下を含むが、これに限定しない。）- 悪化までの期間- 持続的回復までの期間

25

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項目

組み入れ基準アウトカム- COVID-19 の徴候及び症状の持続期間- ウイルス学的治癒/ウイルスクリアランスを達成するまでの期間及び達成した患者の割合- ウイルス量／ウイルス排出量- （下記の測定方法による）症状の重症度及びフォローアップ時の疾患の進行度〇Pulmonary or pulmonary+ score〇National Early Warning Score〇WHO 11-point outcomes score- フォローアップ時の臨床的改善度（WHO 臨
床的改善度カテゴリースケール、または臨床/
実験データ/CT スキャン/ウイルス消失率によるもの）- 全生存（人数/割合/率）- 全死因死亡（人数/割合/率）- COVID-19 関連死亡（人数/割合/率）- 入院（人数/割合/率）- 入院までの期間- ICU または一般病棟に入院した患者（人数/
割合/率）

***
（続き）

除外基準

【安全性】
- 治療に関連する有害事象- グレード 3 および 4 の有害事象- 重篤な有害事象- 治療の中止（有害事象によるものなど）
検索期間

2020 年 1 月から 2022 年 12 月まで****2020 年 1 月より前に発表された論文

第 II 相または第 III 相の無作為化比較試験• 無作為化試験でない試験• 初期段階の試験（第 II 相ま
たは第 III 相試験以前）• 組み入れ患者が 20 名未満の試験*****

国・地域

制限なし

制限なし

言語

英語および日本語

左記以外の言語研究
デザイン*COVID-19 の確定例（PCR、診断コードなどによる）および疑い例（症状や X 線検査結果などによる）を含む。論文中で治験責任医師が「外来患者」「軽症 COVID-19 患者」（入院の記載なし）と表現した患者を含み、「入院患者」「重症／重篤 COVID19 患者」（治験の基準に従って）と表現した患者は除外とした。検索に使用した検索式については、別添 1、別添 2、別添 3、別添 4 を参照。
**外来患者に対する有効性・安全性データが単独で提供されている場合は、入院患者及び外来患者を含む無作為化比較試験を含めることとした。外来患者については、試験中に入院した場合の解析が可能であるため、入院患者の転帰を含めることとした。
***文献から得られたアウトカムの統計的比較は本レビューの結果から行わず、記述的統計の比較のみとした。
****2022 年 5 月に実施した検索期間：2021 年 5 月～現在、新たな比較対象は 2020 年～現在（結果を網羅するため）2022 年 12 月に実施した更新の検索期間：2022 年 5 月～現在（医中誌データベースでは 2020 年 1 月～現在）
また、重複を避けるため、オリジナルと更新の検索結果に対して、研究の重複を排除した。
***** 20 人以上の患者を含むランダム化比較試験（RCT）のサブグループ解析で 20 人未満の患者を評価した場合は対象とした。

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3.2.2 使用したデータベース
上記で定義したクリニカルクエスチョンに基づき、以下のデータベースを用いて検索を行った。検索式は別添 1、別添 2、別添 3、別添 4 に記載した。
論文については下記のデータベースでの検索を実施した。
• Medical Literature Analysis and Retrieval System Online (MEDLINE)• Excerpta Medica Database (EMBASE)• 医中誌 web
上述の論文検索を補完するために、下記のデータベースにおいても同様に検索を実施した。
• “Living” network meta-analyses (NMAs) published by academic andgovernment bodies:o The BMJ-MAGIC-WHO26 (as of 14th June 2022)
o Cochrane-WHO27 (as of 14th June 2022)• Guidelines on treatment of COVID-19 published by academic andgovernment bodies:o The BMJ28 (as of 14th June 2022)
o US Infectious Diseases Society of America (IDSA)29 (as of 14th June2022)
o US National Institutes of Health (NIH)30 (as of 14th June 2022)• Conference proceedings:
o American Thoracic Society (ATS) International Conference 2021, 2022
o Conference on Retroviruses and Opportunistic Infections (CROI) 2020,
2021, and 2022
o European Congress of Clinical Microbiology and Infectious Diseases(ECCMID) 2020, 2021, and 2022
o Infectious Disease (ID) Week (IDSA) 2020, 2021 and 2022
• Clinical trial registries:o clinicaltrials.gov (as of 28th December 2022)
o WHO International Clinical Trials Registry Platform (ICTRP) (as of 14th
June 2022)• Pre-print database:o NIH PubMed Central (PMC) preprints (as of 14th June 2022)• Japanese websites:o KAKEN database (as of 16th December 2022)27

Confidential

o The Japanese Association for Infectious Diseases (日本感染症学会) (as of
16th December 2022)
o National Institute of Infectious Diseases (国立感染症研究所) (as of 16th
December 2022)
o The Japanese Respiratory Society (日本呼吸器学会) (as of 16th December
2022)
3.2.3 システマティックレビューの実施
上述のクリニカルクエスチョンに従って、アブストラクトレビューおよびフルテキストレビュー、デー
タ抽出、バイアスリスクの評価の順に実施した。すべての論文について、「3.1 クリニカルクエス
チョン」で定義した基準に従って、2 名が独立してレビューを行い、Preferred Reporting Items
for Systematic Reviews and Meta-Analyses（PRISMA）のフローチャートを用いて結果を示した。初回のシステマティックレビューを 2021 年 5 月に実施し（SLR 1）、以後 2022 年 12月までの間に 3 回更新した（SLR 2: 2021 年 9 月、SLR 3: 2022 年 5 月、SLR 4: 2022 年
12 月）。SLR4 の実施時点は分析ガイドライン[9]に基づき決定した。
表 7 検索データベースおよび検索期間
使用データベース

実施時期

検索対象期間SLR 1

MEDLINE, EMBASE

2021 年 5 月

2020 年 1 月～2021 年 5 月

SLR 2

MEDLINE, EMBASE

2021 年 9 月

2020 年 1 月～2021 年 9 月

SLR 3

MEDLINE, EMBASE

2022 年 5 月

2021 年 5 月～2022 年 5 月

SLR 4

MEDLINE, EMBASE

2022 年 12 月

2022 年 5 月～2022 年 12 月

医中誌 web

2022 年 12 月

2020 年 1 月～2022 年 12 月

3.2.4 検索結果
データベース及びその他の情報を含めて合計 6,174 件が検出され、スクリーニングの結果、86件が同定された。図 6 に PRISMA フロー図を用いてプロセスと結果を示す。

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図 6 PRISMA フロー図

*2021 年 9 月以前にイベルメクチンに関する試験報告 1 件を同定し、データを抽出した[10]。しかし、COVID-19 におけるイベ
ルメクチンの定期的な使用は現在 WHO[11]、欧州医薬品庁[12]、米国国立衛生研究所[13]および食品医薬品局[14]によって推奨されておらず、イベルメクチン使用を裏付ける主要試験データは撤回されているため[15]、Mahmud らの試験のデータ[10]は、
本報告書には含まれていない。
†
補足検索として、PubMed および medRxiv のターゲット検索を行った。
‡
抄録は各検索で重複を排除し、過去の検索結果（初回、1 回目の更新、2 回目の更新）と比較した。

論文およびその他の検索より、86 件（60 試験）の文献が同定された（表 8 参照、詳細は別添
5）が、その中で本剤と他剤を直接比較している臨床試験が同定されなかったこと、比較対照技術
が標準治療であることから、自社試験「MOVe-OUT」のデータ（表 9 に詳細を記載）を用いて追加的有用性を検討した（3.8 追加的有用性の有無に関する評価に記載）。

29

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表 8 同定した臨床研究(論文)の一覧表
Author
Sourceand year
Antiviral therapies
Adhikari
OVID
et al.
2021[ 16]

Bernal etal.
2022[ 17]OVID

Strizki etal.
2022[ 18]

ECCMID
2022

Guan etal.
2022[ 19]

ECCMID
2022

Johnsonet al.
2022a[20]

ECCMID
2022

Johnsonet al.
2022b[21]

OVID

Title

Reporttype

Trialidentifier(s)Phase

Efficacy of
Favipiravir intreatment of mild &moderate COVID-19
infection in Nepal: amulticenter,randomized, openlabelled, phase III
clinical trial
Molnupiravir for oral
treatment of
COVID-19 in
non-hospitalized
patients
Virologic outcomesfrom MOVe-OUT, arandomized,
controlled phase III
trial evaluating
molnupiravir fortreatment of
COVID-19 in nonhospitalized adults
Impact ofmolnupiravir
treatment onpatient-reported
COVID-19
symptoms in the
MOVe-OUT study
Molnupiravir fortreatment of
COVID-19 in
immunocompromised patients: efficacy,
safety, and virology
results from thephase III MOVeOUT trial
Effect ofMolnupiravir on
Biomarkers,
Respiratory
Interventions, andMedical Services in
COVID-19: A
Randomized,
Placebo-Controlled
Trial

Conferenceabstract

Adhikari et al.
2021
favipiravir

3

JournalarticleMOVe-OUT
NCT04575597

3

Conferenceabstract

ConferenceposterConferenceposter

Journalarticle30

Confidential

Authorand year
Bosaeedet al.
2022[ 22]

SourceOVID

Hammond et al.
2022[ 23]OVID

EPIC-SR2022[ 24]

PfizerHolubar
et al.
2022[ 25]

OVID

Gottliebet al.
2022[ 26]

OVID

Webb etal.
2022[ 27]

CROI
2022

Title
Efficacy offavipiravir in adults
with mild COVID19: a randomized,
double-blind,multicenter,
placebo-controlled
clinical trial
Oral nirmatrelvir for
high-Risk,
non-hospitalized
adults with
COVID-19
Pfizer Announces
Additional Phase
2/3 Study Results
Confirming Robust
Efficacy of Novel
COVID-19 Oral
Antiviral Treatment
Candidate in
Reducing Risk of
Hospitalization or
Death
Favipiravir fortreatment of
outpatients withasymptomatic or
uncomplicated
COVID-19: adouble-blind
randomized,
placebo-controlled,phase 2 trial
Early remdesivir toprevent progression
to severe COVID-19
in outpatients
Safety of remdesivir
vs placebo in nonhospitalized
patients with
Covid-19

Reporttype
JournalarticleTrial
identifier(s)Bosaeed et al.
2022
favipiravir

Phase

JournalarticleEPIC-HR
NCT04960202

2/3

Press
releaseEPIC-SR
NCT05011513

2/3

JournalarticleHolubar et al.
2022
favipiravir
NCT04346628

2

JournalarticlePINETREE
NCT04501952

3

NR

Conferenceabstract31

Confidential

Authorand year
Paredes
et al.
2022[ 28]

SourceTitle

ECCMID2022

Outpatient
remdesivir prevents
COVID-19
progression in highrisk patients when
randomized withinseven days fromsymptom onset:
sub-analyses from aphase III trial
PHASE III trial ofmolnupiravir in
adults with mild
SARS-CoV-2
Infection in India
Reduction in
infectious
SARS-CoV-2 intreatment study of
COVID-19 withmolnupiravir
Molnupiravir, an
Oral Antiviral
Treatment for
COVID-19 (preprint)
A phase 2a clinical
trial of molnupiravir
in patients with
COVID-19 shows
accelerated
SARS-CoV-2 RNA
clearance andelimination of
infectious virus(Published)
Favipiravir,
lopinavir-ritonavir
or combination
therapy (FLARE): a
randomized,
double-blind, 2x2
factorial placebocontrolled trial ofearly antiviraltherapy in COVID19

Kumarasamy etal.
2022[ 29]

CROI
2022

Painter
et al.
2021[ 30]

OVID

Fischer
et al.
2021[ 31]clinicaltri
als.gov

Fischer
et al.
2022[ 32]OVID

Lowe etal.
2022a[33]medRxiv

Reporttype
ConferenceposterTrialidentifier(s)PhaseConferenceabstract

Kumarasamy
et al. 2022
molnupiravir

3

Conferenceabstract

Painter et al.
2021
molnupiravir

2

Journalarticle(preprint)

Fischer et al.
2021
molnupiravir[later portionof trial]
NCT04405570

2a

FLARE
NCT04499677

2

Journalarticle(published)

Journalarticle(preprint)

32

Confidential

Authorand year
Lowe etal.
2022b[34]SourceOVID

MOONSONG 2021[authorNR][ 35]

Atea
Pharmaceuticals

Ramachandran etal.
2022[ 36]

Clinical
Trial
Registryof India(CTRI)

Ruzhents
ova et al.
20201,2[37]The
BMJMAGICWHO

Yotsuyanagi et al.
2022[ 38]

ECCMID
2022

Title
Favipiravir,
lopinavir-ritonavir
or combination
therapy (FLARE): a
randomized, double
blind, 2x2 factorial
placebo-controlled
trial of early
antiviral therapy in
COVID-19
Atea
Pharmaceuticals
Provides Update
and Topline Resultsfor Phase 2
MOONSONG Trial
Evaluating AT-527
in the Outpatient
SettingPhase III,
Randomized,
Double-blind,
Placebo-controlled
trial of Efficacy,
Safety andTolerability of
Antiviral drug
Umifenovir vsStandard care oftherapy in nonsevere COVID-19
patients
Phase 3 Trial ofCoronavir(Favipiravir) inpatients with mild
to moderate
COVID-19
Results from Ph1
and Ph2a studies of
S-217622 a novel
3C-like proteaseinhibitor as once
daily oral treatment
for SARS-CoV-2
infection

Reporttype
JournalarticleTrial
identifier(s)

Phase

Press
releaseMOONSONG

2

JournalarticleRamachandran et al. 2022
umifenovir
CTRI/2020/09/027535

3

Journalarticle(preprint1
andpublished2)
Conferenceabstract

Ruzhentsova
et al. 2021
favipiravir
NCT04501783

3

Yotsuyanagi
et al. 2022 S217622

2a33

Confidential

Authorand year
Zhao etal.
2021[ 39]

SourceOVID

Khoo etal.
2022[ 40]OVID

Golan etal.
2022[ 41]

OVID

Zhao etal.
2022[ 42]OVID

McMahonet al.
2022[ 43]

OVID

Sirijatup
hat et al.
2022[ 44]

OVID

Title
Favipiravir in thetreatment ofpatients with
SARS-CoV-2 RNA
recurrent positive
after discharge: A
multicenter,
open-label,randomized trial
Molnupiravir versus
placebo in
unvaccinated andvaccinated patientswith early SARSCoV-2 infection in
the UK (AGILE CST2): a randomized,
placebo-controlled,
double-blind, phase2 trialFavipiravir inpatients with early
mild-to-moderate
COVID-19: arandomized
controlled trial
A trial of arbidolhydrochloride in
adults with COVID19
Favipiravir in early
symptomatic
COVID-19, arandomized
placebo-controlled
trial
Early treatment of
Favipiravir in
COVID-19 patients
without pneumonia:
a multicenter,
open-labelled,
randomized control
study

Reporttype
JournalarticleTrial
identifier(s)Zhao et al.
2021
favipiravir
NCT04333589

JournalarticleAGILE CST-2
NCT04746183

2

JournalarticlePRESECO
NCT04600895

3

JournalarticleZhao et al.
2022 arbidolhydrochloride
NCT04260594
VIRCO
NCT04445467

4

Sirijatuphat etal. 2022
favipiravir
TCTR2020051
4001

NR

JournalarticleJournalarticle

Phase
NR

2

34

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Authorand year
Zou et al.
2022[ 45]

Source
OVID

Title

Reporttype
JournalarticleAntiviral Efficacy
and Safety of
Molnupiravir
Against Omicron
Variant Infection: A
Randomized
Controlled Clinical
Trial
Neutralizing antibodies (See section 3.2.21.1.1)
Weinreic The
REGN-COV2, a
Journalh et al.
BMJNeutralizing
article2020[ 46]
MAGICAntibody Cocktail,WHO
in Outpatients with
COVID-19
Weinreic Identifie
REGEN-COV
Journalh et al.
d byAntibody Cocktail
article2021a[47] research Clinical Outcomes(preers,
Study in COVID-19
print)
outsideOutpatientsof thesearches
specifiedinsection 2
Weinreic Identifie
REGEN-COV
Journalh et al.
d byAntibody Cocktail
article(publish2021a[47] research Clinical Outcomesers,
Study in COVID-19
ed)outsideOutpatientsof thesearches
specifiedinsection 2
Weinreic OVID
REGEN-COV
Journalh et al.
Antibody
article2021b[48]Combination and(publishOutcomes ined)Outpatients with
COVID-19
Gupta et
NIH
Early COVID-19
Journalal.
guideline Treatment With
article
[ 49]
2021
(pres
SARS-CoV-2
print)
Neutralizing
Antibody
Sotrovimab

Trialidentifier(s)Zou et al.
2022
molnupiravir
ChiCTR22000
56817

REGEN-COV
NCT04425629

Phase
NR

2

3

COMET-ICE
NCT04545060

335

Confidential

Authorand year
Gupta etal.
2022a[50]SourceOVID

Gupta etal.
2022b[51]

CROI
2022

Shapiroet al.
2022[ 52]

CROI
2022

Gupta etal.
2022c[ 53]

Decemb
er ID
Week
2022

Chen etal.
2020[ 54]

OVID

Gottliebet al.
2021[ 55]

OVID

Title
Effect of
Sotrovimab on
Hospitalization or
Death Among Highrisk Patients withMild to Moderate
COVID-19
Effect of serostatuson the efficacy ofsotrovimab inpreventing Covid19 progression
Intramuscularsotrovimab is
noninferior to
intravenous
sotrovimab for
COVID-19
Safety, Tolerability,
and Viral
Pharmacodynamics
of the IgG
Monoclonal
Antibody
Sotrovimab
Administered via
Intramuscular
Injection for theTreatment of Early
Mild-to-Moderate
COVID-19
SARS-CoV-2
Neutralizing
Antibody LYCoV555 in
outpatients with
COVID-19
Effect of
Bamlanivimab as
Monotherapy or in
Combination with
Etesevimab on Viral
Load in Patientswith Mild toModerate COVID19: a Randomized
Clinical Trial

Reporttype
Journalarticle(published)

Trialidentifier(s)PhaseConferenceabstract

COMET-TAIL
NCT04913675

3

Conferenceabstract

COMET-PEAK(Parts B andC)
NCT04779879

2

JournalarticleBLAZE-1
NCT04427501

2

Conferenceabstract

Journalarticle36

Confidential

Authorand year
Douganet al.
2021a[56]SourceOVID

Douganet al.
2021b[57]OVID

Upadhya
ya et al.
2022[ 58]

CROI
2022

Douganet al.
2022[ 59]

OVID

Chen etal.
2022[ 60]

Clinicaltr
ials.gov

Title
Bamlanivimab +etesevimab fortreatment of
COVID-19 in highrisk ambulatory
patients
Bamlanivimab plus
Etesevimab in Mildor Moderate
COVID-19
Bamlanivimab plus
etesevimab for thetreatment of Covid19 in pediatricpatients
A Randomized,
Placebo-Controlled
Clinical Trial of
Bamlanivimab andEtesevimab
Together in HighRisk Ambulatory
Patients With
COVID-19 andValidation of the
Prognostic Value of
Persistently High
Viral Load
Bamlanivimab andEtesevimab
Improve Symptoms
and Associated
Outcomes inAmbulatory Patientsat Increased Risk
for SevereCoronavirus Disease
2019: Results fromthe PlaceboControlled DoubleBlind Phase 3
BLAZE-1 Trial

Reporttype
Conferenceabstract

Trial
identifier(s)

Phase
3

JournalarticleConferencepresenta
tion
JournalarticleJournalarticle2/3(Results from
phase
3)

37

Confidential

Authorand year
Williams
et al.
2022[ 61]

SourceATS20212022

Davis etal.
2022[ 62]

OVID

Huang etal.
2021[ 63]

OVID

Chew etal.
2021[ 64]

OVID

Chew etal.
2022[ 65]

OVID

Title
Bebtelovimab,
Alone and Together
with Bamlanivimab
and Etesevimab, as
a Broadly
Neutralizing
Monoclonal
Antibody Treatment
and a Slow
Intravenous Push
Option for
Ambulatory
COVID-19
Pharmacokinetics
andpharmacodynamics
of casirivimab andimdevimab in adose-ranging study
in outpatients with
COVID-19
Effectiveness ofcasirivimab andimdevimab, andsotrovimab during
Delta variant surge:
a prospective
cohort study andcomparative
effectivenessrandomized trial

Bamlanivimab
reduces
nasopharyngeal
SARS-CoV-2 RNA
levels but not
symptom durationin non-hospitalized
adults with
COVID-19
Antiviral and clinicalactivity ofbamlanivimab in arandomized trial of
non-hospitalized
adults with COVID19

Reporttype
Conferenceabstract

Trial
identifier(s)BLAZE-4
NCT4634409

Conferenceabstract

Davis et al.
2022
casirivimab/im
devimab
NCT04666441

2

Journalarticle(preprint)

UPMC Quality
Improvement
ReviewCommittee
Project ID
3282.
University ofPittsburgh
Institutional
Review Board
STUDY210220
179
NCT04790786
ACTIV2/A5401
NCT04518410

4*

Journalarticle(preprint)

Phase
2

2

Journalarticle38

Confidential

Authorand year
Boucauet al.
2022[ 66]

SourceOVID

Kumarasamy etal.
2022[ 67]

CROI
2022

StreinuCercel etal.
2022[ 68]

OVID

Montgomery et al.
2022a[69]

ECCMID
2022

Montgomery et al.
2022b[70]Clinicaltr
ials.gov

Title
Monoclonal
antibody treatment
drives rapid culture
conversion in SARSCoV-2 infection
Interim results fromthe randomized,
controlled EMPATHY
phase II/III study
evaluating ofcasirivimab andimdevimab, a DARP
in therapeutic, inpatients with mild
to moderate
COVID-19
Efficacy and Safetyof Regdanvimab(CT-P59): A Phase
2/3 Randomized,
Double-Blind,
Placebo-Controlled
Trial in Outpatientswith Mild toModerate
Coronavirus Disease2019
Efficacy and safety
of intramuscularadministration of
AZD7442(tixagevimab/cilgavimab) for early
outpatient
treatment of
COVID-19: theTACKLE phase III
trial
Efficacy and safety
of intramuscularadministration of
tixagevimab–
cilgavimab for early
outpatient
treatment of
COVID-19(TACKLE): a phase3, randomized,
double-blind,placebo-controlled
trial

Reporttype
JournalarticleTrial
identifier(s)PhaseConferenceabstract

EMPATHY
NCT04828161

2/3

JournalarticleCT-P59
NCT04602000

2/3(Results fromphase
2)

Conferenceabstract

TACKLE
NCT04723394

3

2/3

Journalarticle39

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Authorand yearHobbs etal.
2022[ 71]

SourceTitle

Decemb
er ID
Week
2022

Outpatient
Treatment With the
SARS-CoV-2–
Neutralizing
Antibody
Combination
AZD7442(Tixagevimab/Cilga
vimab) for
Preventing COVID19 Hospitalizationsin the Phase 3
TACKLE Trial
Adagio Therapeutics
Announces ADG20(adintrevimab) is
the First Monoclonal
Antibody to Meet
Primary Endpoints
with Statistical
Significance AcrossPre- and
Post-exposure
Prophylaxis andTreatment for
COVID-19 andPlans to Seek US
Emergency Use
Authorization
Effect of
Subcutaneous
Casirivimab and
Imdevimab
Antibody
Combination vsPlacebo on
Development ofSymptomatic
COVID-19 in Early
Asymptomatic
SARS-CoV-2
Infection: A
Randomized Clinical
Trial
Exploratory data on
the clinical efficacy
of monoclonal
antibodies against
SARS-CoV-2
Omicron variant ofconcernSTAMP
2022[ 72]

AdagioTherapeutics
2022

O’Brienet al.
2022[ 73]

OVID

Mazzaferri et al.
2022[ 74]

OVID

Reporttype
Conferenceabstract

Trial
identifier(s)

Phase

Press
release

STAMP

2/3

JournalarticleO’Brien et al.
2022
casirivimab/im
devimab
NCT04452318

3

JournalarticleMANTICO
NCT05205759

3

40

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Authorand year
PortalCelhay etal.
2022[ 75]

Source
OVID

Title

Virologic Efficacy of
Casirivimab and
Imdevimab COVID19 Antibody
Combination in
Outpatients With
SARS-CoV-2
Infection A Phase 2
Dose-Ranging
Randomized ClinicalTrial
Kim etOVID
A Randomizedal.
Clinical Trial of2022[ 76]
Regdanvimab in
High-Risk Patientswith Mild-toModerate
Coronavirus Disease
2019
Schilling
OVID
Pharmacometric
et al.
assessment of the2022[ 77]
in vivo antiviral
activity ofivermectin in early
symptomatic
COVID-19
Interferon (See section 3.2.3)
Feld etThe
Peginterferonal.
BMJlambda for the2021[ 78]
MAGICtreatment ofWHOoutpatients with
COVID-19: a phase2, placebocontrolled
randomized trial
Jagannat The
Peginterferon
han et al. BMJLambda-1a for2021[ 79]
MAGICtreatment ofWHOoutpatients with
uncomplicated
COVID-19: arandomized
placebo-controlled
trial

Reporttype
JournalarticleTrial
identifier(s)Portal-Celhay
et al. 2022
casirivimab/im
devimab
NCT04666441

Phase

JournalarticleKim et al.
2022
regdanvimab
NCT04602000

3

Journalarticle(preprint)

PLATCOV
NCT05041907

2

JournalarticleFeld et al.
2021
peginterferon
LambdaNCT04354259

2

JournalarticleJagannathan
et al. 2021
peginterferon
Lambda-1a
NCT04331899

2

2

41

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Author
Source
Title
ReportTrial
and year
type
identifier(s)H2 antagonist (See section 3.2.4)
Brennan
OVID
Oral famotidine
JournalBrennan et al.
et al.
versus placebo inarticle2022
2022[ 80]
non-hospitalized
famotidine
NCT04724720
patients with
COVID-19: arandomized,
double-blind,
data-intense, phase2 clinical trial
Steroid (See section 3.2.5)
Ramakri
OVID
Inhaled budesonide Journal
STOIC
shnan etin the treatment ofarticleNCT04416399
al.
early COVID-19
2021[ 81](STOIC): a phase 2,
open-label,randomized
controlled trial
Yu et al.
NIH
Inhaled budesonide Journal
PRINCIPLE
2021a[82] guideline for COVID-19 inarticleISRCTN86534(prespeople at higher
580
print)
risk of adverse
outcomes in thecommunity: interim
analyses from the
PRINCIPLE trial
Yu et al.
OVID
Inhaled budesonide Journal
2021b[83]for COVID-19 inarticlepeople at high risk
(publishof complications ined)the community in
the UK(PRINCIPLE): a
randomized,
controlled,
open-label,
adaptive platform
trial
Selective serotonin reuptake inhibitor (See section 3.2.6)
Lenze etOVID
Fluvoxamine vsJournalSTOP COVID
al.
Placebo and Clinical article
NCT04342663
2020[ 84]
Deterioration in
Outpatients with
Symptomatic
COVID-19

Phase
2

2

NR

2

42

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Authorand year
Seo et al.
2022[ 85]

Source
OVID

Title

Reporttype
JournalarticleFluvoxamine
Treatment ofPatients with
Symptomatic
COVID-19 in a
Community
Treatment Center:
A Preliminary Resultof Randomized
Controlled Trial
Reis etOVID
Effect of early
Journalal. 2022
treatment witharticle3,
fluvoxamine on risk
4[86],[87]of emergency careand hospitalization
among patientswith COVID-19: theTOGETHER
randomized,
platform clinical
trial
Bramant
OVID
Randomized Trial of Journal
e et al.
Metformin,
article2022[ 88]
Ivermectin, andFluvoxamine for
Covid-19
McCarthy OVID
Fluvoxamine for
Journal
et al.
Outpatient
article2022[ 89]
Treatment of(preCOVID-19: A
print)
Decentralized,
Placebo-controlled,
Randomized,
Platform Clinical
Trial
Serine protease inhibitors (See section 3.2.7)
Chupp et OVID
A Phase 2
Journalal.
Randomized,
article2022[ 90]
Double-Blind,
Placebo-controlled
Trial of Oral
Camostat Mesylate
for Early Treatmentof COVID-19
Outpatients Showed
Shorter Illness
Course andAttenuation of Lossof Smell and Taste

Trialidentifier(s)Seo et al.
2022
fluvoxamine
NCT04711863

Phase
2

TOGETHER
NCT04727424

3

COVID-OUT
NCT04510194

3

ACTIV-6
NCT04885530

3

Chupp et al.
2022
camostatmesylate
NCT04724720

2

43

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Authorand year
Jilg et al.
2022a[91]Source
CROI
2022

Title

A randomized
controlled trial of
camostat in
outpatients with
COVID-19
Jilg et al. CROI
Camostat is not
[92]
2022b
2022
effective for mildmoderate COVID-19
in a phase 2
Trial of ACTIV-2
Tobback
OVID
Efficacy and safety
et al.
of camostat
2022[ 93]mesylate in early
COVID-19 diseasein an ambulatory
setting: arandomized
placebo-controlled
phase II trial
Anti-inflammatory (See section 3.2.8)
DorwardOVID
Colchicine foret al.
COVID-19 in the
[ 94]
2022
community(PRINCIPLE): a
randomized,
controlled, adaptive
platform trial
Tardif et
OVID
Colchicine foral.
community-treated2021[ 95]
patients with
COVID-19(COLCORONA): a
phase 3,
randomized,
double-blinded,
adaptive, placebocontrolled,
multicenter trial
Audemar OVID
Efficacy and safety
d-Vergerof anakinra in
et al.
adults presenting
2022[ 96]
deteriorating
respiratory
symptoms fromCOVID-19: A
randomized
controlled trial

Reporttype
Conferenceabstract

Trial
identifier(s)CAMELOT
NCT04583592

Phase

Conferenceabstract

ACTIV2/A5401
NCT04518410

2

JournalarticleTobback et al.
2022
camostatmesylate
NCT04625114

2

Journalarticle

PRINCIPLE
ISRCTN86534
580 [trial does
not appear on
clinicaltrials.g
ov]

NR

JournalarticleCOLCORONA
NCT04322682

3

JournalarticleANACONDA
NCT04364009

3

2

44

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Author
SourceTitle
and year
Antiparasitic (See section 3.2.9)
Rocco etOVID
Early use ofal.
nitazoxanide in mild
2021[ 97]
COVID-19 disease:randomized,
placebo-controlled
trial
Rossigno clinicaltri Early treatmentl et al.
als.gov
with nitazoxanide
2021[ 98]
prevents worseningof mild andmoderate COVID-19
and subsequenthospitalization
Rossignol et al.
2022[ 99]

OVID

Mehdatet al.
2022[ 100]OVID

A randomized
double-blind
placebo-controlled
clinical trial ofnitazoxanide fortreatment of mild or
moderate COVID-19
Sofosbuvir/ledipasvi
r in combination or
nitazoxanide alone
are safe andefficient treatments
for COVID-19
infection: A
randomized
controlled trial for
repurposing
antivirals

Reporttype

Trialidentifier(s)PhaseJournalarticleRocco et al.
2021
nitazoxanide
NCT04552483

2

Journalarticle(preprint)

Rossignol etal. 2021
nitazoxanide
NCT04486313

3

Journalarticle(published)

JournalarticleRossignol etal. 2022
nitazoxanide
NCT04486313

Mehdat et al.
2022
nitazoxanide
andsofobuvir/ledi
pasvir
NCT04498936

4*Please note that this is described as a phase 4 (post-marketing) trial; however, patients wererandomized to treatment, rather than assigned according to physician's discretion.
BMJ: British Medical Journal; CROI: Conference on Retroviruses and Opportunistic Infections; CTRI:
Clinical Trial Registry of India; ECCMID: European Congress of Clinical Microbiology and Infectious
Diseases; MAGIC: Mutant-Assisted Gene Identification and Characterization; NIH: National Institutes of
Health; NR: not reported; RCT: randomized controlled trial; RNA: ribonucleic acid;
UPMC: University of Pittsburgh Medical Center; WHO: World Health Organization.

45

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表 9 MOVe-OUT 試験（第Ⅲ相パート）の詳細表 17
項目

内容

試験を実施した場所

日本、米国等 20 カ国

参加者の組入れ期間

2021 年 5 月から 10 月

対象集団

18 歳以上の非入院 COVID-19 患者

主な選択基準

1. SARS-CoV-2 陽性（無作為化前 5 日以内に採取された検体を用いた PCR 検査等により確認）
2. SARS-CoV-2 による感染症の症状 a）発現が無作為化前 5 日以
内であり、かつ無作為化時点において SARS-CoV-2 による感染症に関連する症状 b）が 1 つ以上認められる
3. 以下の定義における、軽症患者又は中等症患者
SARS-CoV-2 による感染症の重症度の判断に用いられた定義は以下のとおり。
【軽症】①及び②を満たす①次のすべてが認められる呼吸数が 20 回/分未満、心拍数が 90 回/分未満、SpO2 が 93%超
c）

②次のいずれも認められない
安静時又は労作時の息切れ、呼吸不全 d）、ショック状態 e）、多臓器機能不全 f）【中等症】①～③をすべて満たす① 次のうち、1 つ以上が認められる
労作時の息切れ、呼吸数が 20 回/分以上 30 回/分未満、心拍数が90 回/分以上 125 回/分未満
4. 次の SARS-CoV-2 による感染症の重症化リスク因子を少なくとも一つ有する･ 61 歳以上･ 活動性のがん［免疫抑制や高い死亡率を伴わないがん（例：基底細胞がん）は除く］･ 慢性腎臓病･ 慢性閉塞性肺疾患･ 肥満（BMI 30 kg/m2 以上）･ 重篤な心疾患（心不全、冠動脈疾患又は心筋症）
･ 糖尿病

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項目
主な選択基準（続き）

内容
5. 治験薬投与終了後少なくとも 4 日間避妊が可能な男性又は妊娠しておらず治験薬投与終了後少なくとも 4 日間避妊が可能な女性a）具体的な症状の規定なしb）咳、咽頭痛、鼻閉、鼻水、労作時の息切れ又は呼吸困難、筋肉又は体の痛み、疲労、発熱（38.0ºC 超）、悪寒、頭痛、悪心、嘔吐、下痢、嗅覚消失、味覚消失c）室内気又は SARS-CoV-2 による感染症以外の理由で酸素投与されており SARSCoV-2 による感染症の症状発現以降に酸素量が増量されていない状態における数値d）＜呼吸不全＞次の①～④を 1 つ以上要する場合：①気管内挿管及び人工呼吸器、②鼻カニューレを用いた高流量酸素療法（流量 20 L/min 超、酸素割合 0.5 以上）、③
非侵襲的陽圧換気、④ECMOe）＜ショック状態＞昇圧剤を要する場合と定義
f）＜多臓器不全＞呼吸器、循環器、腎臓、血液、肝臓又は中枢神経系の 1 つ以上に不全又は障害が認められる急性期の患者と治験担当医師が判断した場合と定義

主な除外基準1. 入院中又は無作為化後 48 時間以内に SARS-CoV-2 による感染症のために入院が必要となることが想定される患者
2. 透析中又は eGFR が 30 mL/min/1.73 m2 未満
3. 直近の HIV RNA 量が 50 copies/mL 超又は過去 6 カ月において HIV の指標疾患が認められた患者
4. 好中球数 500/mm3 未満の患者
5. HBV 又は HCV の既往を有し、肝硬変、末期肝疾患、肝細胞がん又はスクリーニング時の AST 若しくは ALT が基準値上限の 3 倍超の患者
6. 血小板数が 100,000/μL 未満又は無作為化前 5 日以内に血小板輸血を受けた患者
7. SARS-CoV-2 による感染症に対するワクチンの接種歴を有する患者
8. 本試験への組入れ理由となった今回の SARS-CoV-2 感染に対するモノクローナル抗体による治療歴を有する患者

介入方法の詳細比較対照の詳細標準治療に加えて1回800mgを1日2回、5日間経口投与する
プラセボ＋標準治療

試験デザイン

ランダム化比較試験

盲検化法

二重盲検法

主要評価項目• 有効性：無作為化 29 日目までの理由を問わないすべての入院又は死亡• 安全性：有害事象、投与中止に至った有害事象47Confidential項目
主な副次評価項目内容• 無作為化 29 日目までにおける特定の COVID-19 の徴候/症状（患者報告）の持続的な回復又は改善注 1）までの期間及び悪化注 2）までの期間• 各時点における WHO11-point ordinal scale の改善のオッズ
注 1）

無作為割付け時点で症状の報告がなかった被験者は除外

注 2）

無作為割付け時点で症状を「重度」と報告した被験者は除外

統計解析手法

• 有効性：主要評価項目である無作為化 29 日目までに入院又は死亡した被験者の割合の差（モルヌピラビル群－プラセボ群）は、SARS-CoV-2 による感染症の症状発現から無作為割付け日までの期間（3 日間以下／3 日間超）を層別因子とした層別
Miettinen and Nurminen 法により算出された調整済みリスク差及び 95%信頼区間を用いて、Cochran–Mantel–Haenszel 重
み付けにより解析した。重要な副次評価項目である無作為化 29 日
目までにおける特定の COVID-19 の徴候や症状（患者報告）の持続的な回復又は改善までの期間及び悪化までの期間については、
モルヌピラビル群とプラセボ群の比較には層別ログランク検定を用い、ハザード比の推定には Cox 比例ハザードモデルを用いた。
WHO 11-point ordinal scale スコアについては、累積ロジット関
数と比例オッズモデルを用いた McCullagh の方法を用いて、群間差を評価するための共通のオッズ比を推定した。投与群に加え、層別因子もモデルに加える。WHO11-point ordinal scale は
eCRF で収集した関連データに基づいて決定される。
• 安全性：群間の有害事象の割合の差について、Tier1（注目すべき事象）については P 値および 95%信頼区間、Tier2（有害事象）については 95%信頼区間を層で調整しない Miettinen andNurminen の方法を用いて算出する。

サンプルサイズ

モルヌピラビル群: n=716、プラセボ群: n =717

フォローアップ期間

7 か月

対象者の主な背景要因

年齢：平均 43.0 歳
性別：男性 48.7％

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項目
主要評価項目の結果

内容【有効性】 事前に計画された中間解析*• 無作為化 29 日目までに入院又は死亡した割合は、モルヌピラビル
群 7.3％（385 例中 28 例、死亡例なし）、プラセボ群 14.1％（377
例中 53 例、うち死亡 8 例）であり、群間差は-6.8（95%信頼区間:-11.3, -2.4）、p=0.001 であった。
なお、無作為化された全例を対象とした補足的な解析で、29 日目までに入院又は死亡した被験者の割合は、モルヌピラビル群が 6.8％（709 例中 48 例）、プラセボ群が 9.7％（699 例中 68 例）でモルヌ
ピラビル群がプラセボ群より低かった（群間差-3.0、95％信頼区間：5.9～-0.1）。29 日目までの死亡例は、モルヌピラビル群で 1 例、プラセボ群で 9 例であった。

【安全性】 全例における解析• 本剤群の 710 例及びプラセボ群の 701 例が少なくとも 1 回の治験薬を投与され、解析対象集団に含まれた。
• 有害事象が発現した被験者の割合は、モルヌピラビル群 30.4％（710 例中 216 例）、プラセボ群 33.0％（701 例中 231 例）で両群で同程度であった。
• 有害事象による投与中止は、モルヌピラビル群 1.4％（710 例中10 例）、プラセボ群 2.9％（701 例中 20 例）であった。
• 死亡例はモルヌピラビル群で 2 例、プラセボ群で 12 例に認められたが、いずれの事象も治験薬との因果関係は否定された。

*中間解析において早期の有効性の基準を満たしたことから、外部データモニタリング委員会により本剤の有効性が示されたとの勧告がなされ、2021 年 10 月 2 日以降の新規組入れは中止された。第Ⅲ相パート（パート 2）の予定組入れ被験者数の合計は約 1550 例であったが、早期終了となったため、第Ⅲ相パートの全体集団には、1433
例［中間解析時点の 775 例及び中間解析後に組み入れられた追加の 658 例］が含まれた。
事前に計画された中間解析において早期有効中止となったことから、本試験の成功の可否を判定する上での主たる結果は中間解析の主
要評価項目の結果となる。

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項目

内容

主な副次評価項目の結果• COVID-19 の徴候及び症状（患者報告）のほとんどで、持続的な回復又は改善の可能性はプラセボの投与を受けた被験者よりもモルヌピラビル投与を受けた被験者で高かった。また、COVID-19 の徴候及び症状（患者報告）のほとんどで、進行（悪化）の可能性は、プ
ラセボの投与を受けた被験者よりもモルヌピラビル投与を受けた被験者で低かった。
• WHO 11-point ordinal scale による不良な転帰を示す被験者の割合は、プラセボ群よりもモルヌピラビル群で低く、Day 10 及びDay 15 時の差が最も大きかった。WHO 11-point ordinalscale をカテゴリー別［0（感染していない）、1～3（歩行可能、軽主な副次評価項目の結果

症）、4～5（入院、中等症）、6～9（入院、重症）、10（死亡）］に分類（続き）

すると、Day 10 の転帰改善のオッズは、プラセボ群と比較してモルヌピラビル群で 1.58 倍高かった。

試験の限界• COVID-19 のワクチンを接種していない被検者のみ含まれている。
• 入院の習慣や病院のキャパシティが国によって異なるため、入院に関するアウトカムに影響を与えた可能性がある。

3.3 クリニカルクエスチョン(異なる比較対照あるいは単群試験) [該当する場合のみ]
該当なし
3.4 システマティックレビュー (異なる比較対照あるいは単群試験) [該当する場合のみ]該当なし
3.5 既存データの再解析
該当なし
3.6 メタアナリシスの詳細 [該当する場合のみ]
該当なし
3.7 間接比較やネットワークメタアナリシスの結果 [該当する場合のみ]
該当なし

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3.8 追加的有用性の有無に関する評価
3.2 システマティックレビューで示した通り、本剤と他剤を直接比較している臨床試験は同定されず、プラセボ（標準治療）を対照としたランダム化比較試験（RCT）である MOVe-OUT 試験が追加的有用性の根拠として適切と考えられた。MOVe-OUT 試験第Ⅲ相パートの主要な解析である
中間解析で、主要評価項目である無作為化 29 日目までの理由を問わないすべての入院又は死亡した被験者の割合において、モルヌピラビル群で 7.3%（385 例中 28 例）及びプラセボ群で14.1%（377 例中 53 例）、割合の群間差は-6.8%（95%信頼区間：-11.3, -2.4）であり、プラセボ群に対するモルヌピラビル群の優越性が検証された。また、少なくとも 1 つの有害事象が発生した患者の割合は、モルヌピラビル群とプラセボ群で、それぞれ 30.4%（710 例中 216 例）、
33.0%（701 例中 231 例）と両群で同程度であった。有害事象による投与中止は、モルヌピラビ
ル群 1.4%（710 例中 10 例）、プラセボ群 2.9%（701 例中 20 例）であった。
3.2 システマティックレビューの終了後、英国のリアルワールドにおけるモルヌピラビルの有効性・安全性の検証を目的とした非盲検ランダム化プラグマティック試験である PANORAMIC 試験に関する論文が新たに発表された[101]。本試験では、ワクチン接種が進展しオミクロン株を主体とした変異株が流行していた 2021 年 12 月～2022 年 4 月に患者組み入れが行われた（適格25,708 例中 SARS-CoV-2 ワクチン 3 回以上接種済 94%）。主要評価項目であるランダム化
後 28 日以内の理由を問わないすべての非待機的入院又は死亡した被験者の割合は、モルヌピ
ラビル＋標準治療群で 1%（12,529 例中 105 例）及び標準治療群でも 1%（12,525 例中 98
例）といずれも低く、両群間の差が見られなかった。一方、副次的評価項目に関しては、標準治療群に比べモルヌピラビル＋標準治療群で症状改善までの日数が有意に短い、非緊急医療電話相談（NHS111）や在宅急性期治療プログラム（Hospital at home for COVID-19）の利用割合が低い、プライマリ医受診割合が有意に低いなどの結果が報告された。
MOVe-OUT 試験と PANORAMIC 試験における入院又は死亡に関するアウトカムが異なった原因に関し、対象集団の重症化リスク保有割合が後者において明らかに低かったことが大きく影響した可能性が指摘されている（1 つ以上の重症化リスク因子を有する患者の割合：99% vs.
69%）。そのほか、ワクチン接種の有無、主たる変異株の病原性の違い（デルタ株 vs. オミクロ
ン株）、実施時期や地域の違いに起因する標準治療（ガイドライン等）の違いなども影響した可能性が考えられる。また、その他の重要な相違点として PANORAMIC 試験では入院又は死亡のリスクが著しく高い患者において中和抗体（使用割合 1％未満）やレムデシビル（使用割合不明）の使用が許容されていた点なども挙げられる。これらに代表される両試験間の相違を背景に、
PANORAMIC 試験の Day28 における標準治療群の死亡率（0.04%）及び入院率（1%）は、
MOVe-OUT 試験第Ⅲ相パートの Day29 における標準治療群の死亡率（2.1%）及び入院率（13.8%）に比べ顕著に低く、入院又は死亡リスクに関して標準治療に対するモルヌピラビルの51Confidential

優越性を示すことは著しく困難であったと考えられる。

重症化リスクを有する患者の入院又は死亡に対する有効性の検証を主要目的としたモルヌピラビ
ルの RCT が MOVe-OUT 試験と PANORAMIC 試験の 2 試験に限られること、加えて両者の明示的かつ著しい異質性や例数の偏りも考慮すれば、これら 2 試験のアウトカムをランダム効果
モデル等で統合する手法によってモルヌピラビルの追加的有用性を推定することは科学的妥当性の面から適切でないと考えられた。よって、本分析では追加的有用性のパラメータとして単一
RCT のデータを用いることとし、その選択にあたっては当該パラメータがリアルワールドにおける観察研究のアウトカムによっても支持される必要があると考えた。観察研究を対象とした追加的な PubMed 文献検索（2023 年 3 月実施）を行った結果、モルヌピラビルの COVID-19 関連入院又は死亡に対する有効性を支持する複数の観察研究が同定されたが[102],[103]、1 つ以上の重症化リスク因子を有する外来患者のみを対象とした観察研究としては、米国退役軍人保険の医療情報データベースを用いた Target Trial Emulation 法による COVID-19 外来患者におけるモルヌピラビルの有効性評価に関する論文（Xie, et al. 2023、表 10）が唯一同定された[104]。同研究における傾向スコアマッチング後の主要評価項目（基準日+30 日目までの入院又は死亡）の発現割合はモルヌピラビル使用患者で 2.7%、無治療患者で 3.8%であり、無治療群に対するモルヌピラビル群の相対リスクは 0.72（95%CI：0.64, 0.79）と、MOVe-OUT 試験の主要評価項目に関する time-to-event 解析で示されたハザード比 0.69（95%CI：0.48,
1.01）[17]と数値的に近く、オミクロン株流行下（2022 年 1 月～2022 年 9 月）のリアルワールド
においてもモルヌピラビルの使用が入院又は死亡リスクの低減と関連することが示された。また、本研究の対象集団は 1 つ以上の重症化リスクを有する非入院の COVID-19 患者であり、2.1
分析対象とする集団に示す分析対象集団との類似性を有する。また対照群が無治療であることは、我が国の外来標準治療において中和抗体薬、ステロイド、レムデシビル等の使用が基本的に想定されないことや、2.2 比較対照に示す比較対象技術「標準治療（COVID-19 に対して治療の適応がある薬剤を除く、対症療法）」で想定する標準治療との共通性がある。

以上より、MOVe-OUT 試験における有効性と安全性のデータを対象集団における追加的有用性の根拠とすることは現時点で利用可能なエビデンスの選択として最も妥当と考えられ、無作為化 29 日目までの理由を問わないすべての入院又は死亡した被験者の割合を指標とした標準治療との比較に基づきモルヌピラビルの追加的有用性ありと判断した（表 11）

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表 10 追加的有用性の有無に関する主な報告の概要
Xie et al. [104]Study population

People eligible formolnupiravir

Intervention intreatmentgroup

Received
molnupiravir as
the only outpatient
COVID-19
treatmentIntervention incontrol group

No outpatient
COVID-19
treatment

Hospitalization ordeath rate incontrol group
Death rate incontrol groupAge (years)
Baseline
cardiovasculardiseaseBaseline diabetes

3.8% at 30 days

PANORAMIC
trial [101]People eligible formolnupiravir but
did not receive
outpatient COVID19 treatment(including
molnupiravir,
monoclonal
antibodies,
remdesivir or
nirmatrelvir) fromCOVID-19 clinic
which may haveresulted inremoval of highest
risk population
Received
molnupiravir whileother outpatient
COVID-19
treatment(including
monoclonal
antibodies,
remdesivir or
nirmatrelvir) was
also allowed
Outpatient COVID19 treatment,
includingmolnupiravir, wasalso allowed
1% at 28 days

MOVe-OUT
trial [17]
COVID-19 noninstitutionalized
patients aged 18
years and older
within 5 days of
onset

0.8% at 30 days

0.04% at 28 days

1.3% at 29 days

67.7
40.6%

56.7
8%

43.0
11.7%

40.8%

12%

15.9%

Received
molnupiravir as
the only
outpatient COVID19 treatment

Received standardof care

14.1% at 29 days

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表 11 SARS-CoV-2 による感染症（COVID-19）患者における追加的有用性
重症化リスク因子を有する SARS-CoV-2 による感染症（COVID-19）患者（18 歳以上）
対象集団

但し、有効性が確立していないため、重症度*の高い COVID-19 患者を除く。
*重症度の定義は新型コロナウイルス感染症（COVID-19）診療の手引
き・第 8.1 版に準ずる。

介入

モルヌピラビル比較対照

プラセボ（標準治療）

アウトカム

追加的有用性の有無

判断の根拠となった
データ

有効性（無作為化 29 日目までの理由を問わないすべての入院又は死亡した被験者の割合）、安全性（有害事象）■ 追加的有用性あり □ 「追加的有用性なし」あるいは「ありとは判断できない」□ RCT のメタアナリシス ■ 単一の RCT（MOVe-OUT 試験）□ 前向きの比較観察研究 □ RCT の間接比較□ 単群試験の比較 □ 臨床データなし• MOVe-OUT 試験第Ⅲ相パートの主要な解析である中間解析におい追加的有用性の有無を判断した理由て、主要評価項目である無作為化 29 日目までの理由を問わないすべての入院又は死亡した被験者の割合において、優越性が検証された。
• MOVe-OUT 試験第Ⅲ相パートにおいて、安全性が比較対照と同程度
であった。

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4. 分析方法の詳細
4.1 分析方法
4.1.1 費用対効果の算出方法
本分析では、COVID-19 の発症から急性期治療終了までの分析期間（30 日）に決定木モデル
を用い、その後の分析期間（生涯：死亡又は 100 歳まで）には 1 サイクルを 1 年（但し、初年は急性期を除いた 11 か月）に設定したマルコフモデルを用いた。
決定木モデルにおいては、COVID-19 の重症化イベントとして、COVID-19 の外来（非入院）患者における入院治療への移行、及び入院治療におけるより高度なケアセッティング［ICU、又は体外式膜型人工肺（ECMO）又は人工呼吸器（MV）の使用を伴う ICU（ICU+MV/ECMO）］への移行を想定した。
なお、モルヌピラビルは主に外来治療で用いる経口薬であることから、モデルでは入院期間や入院後の症状の持続時間の短縮は考慮していない。分析モデルの構造を図 7 に示す。
図 7 分析モデルの構造*図中の点線部分が決定木分析に該当

分析モデルは、COVID-19 の外来治療から開始された成人患者を対象とし、COVID-19 の重症化に伴い、外来から入院へ移行する可能性を想定した。また、重症度として入院中に到達しう
る 3 レベルのケアセッティング（一般病棟、ICU、ICU+MV/ECMO）を想定し、入院後の患者の転帰として、完全に回復するケース、長期の後遺症を伴って回復するケース[105], [106]、入院中に死亡するケースを想定した。さらに、入院後の生存患者では、再入院を経験することも想定した[107]。

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有害事象（Adverse Events, AE）または治療上緊急を要する有害事象は、非入院 COVID-19
患者を対象とした MOVe-OUT 試験で明らかな安全性の懸念がなかったため、本分析では想定しなかった[108]。

基本分析に加えて以下の感度分析を行った。
• 一元感度分析
特定の入力パラメータの変動が及ぼす分析結果への影響を検討するために、すべてのパラメータを組み込んで実施した。
• 確率的感度分析
基本分析に対して全パラメータを同時に変化させて実施した。各パラメータの分布を、Briggs
et al (2011)[109]に従って、以下の通り選択した。
- 割合（二項）：ベータ分布- 相対リスク（有効性エンドポイントの場合）：対数正規分布- 費用：ガンマ分布- QOL 値：ベータ分布- その他のパラメータ：正規分布• シナリオ分析
新たな高病原性変異株（デルタ株相当）の流行やワクチンが無効化に向かうことを想定した悲観的条件として、MOVe-OUT 試験第Ⅲ相パートの ad hoc 解析における患者特性および疾
患特性のデータ（詳細は 4.2 分析で使用したパラメータ参照）を使用して、シナリオ分析 1-3を実施した。また、COVID-19 関連入院による短期的な労働生産性損失を踏まえ、社会の立場のシナリオ分析 4 も実施した。
1. MOVe-OUT 試験の（全集団）の患者特性および疾患特性による分析
2. MOVe-OUT 試験（軽症患者サブ集団*）の患者特性および疾患特性による分析＊息切れなし、かつ SpO2>93%など
3. MOVe-OUT 試験の（60 歳以下サブ集団）の患者特性および疾患特性による分析
4. 基本分析の設定における社会の立場での分析：入院による短期的な労働生産性損失を考慮
4.1.2 モデルで使用した仮定
本分析で使用した仮定を以下に示す。
• 分析対象集団における入院割合として、厚生労働省公表データ「新型コロナウイルス感染症
患者の療養状況等及び入院患者受入病床数等に関する調査結果」[110]における 2022 年
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各週の療養者数と入院者数から算出した入院割合（％）の平均値を仮定した。
• 入院における重症度を 3 レベルのケアセッティング（一般病棟、ICU、ICU+MV/ECMO）で定義し、到達した最も高い重症度により患者区分を設定した。
• モルヌピラビルは主に外来治療で用いられる薬剤であることから、入院後の治療効果及び症状の持続時間の短縮を考慮していない。
• 有害事象（AE）または治療上緊急を要する有害事象は含めていない。
• 再入院時の入院期間は 7 日間[111]と仮定した。
• 外来の COVID-19 による死亡率を 0％と仮定した。
• 100 歳以降の死亡確率は 100％に設定した。
• 再入院の健康状態に対する QOL 値は一般病棟の健康状態と同じと仮定した。
• 標準誤差（SE）は、入手できない場合、平均値の 5%（表 13）又は 10％（表 14）とした。
4.2 分析で使用したパラメータ
ベースラインの患者特性（年齢、女性比率、死亡時年齢など、但し入院割合を除く）および疾患特性（入院の内訳、入院日数）について、メディカル・データ・ビジョン（MDV）社が提供する診療デー
タベース EBM Provider による調査（MDV データベース調査）で得られたデータを用いた。
調査の概要を表 12 に示す。本調査では、集計対象患者の組み入れ基準及び除外基準に基づき適格な例（ユニーク識別子ベース）が同定され、その集計結果をパラメータとして用いた。

表 12 MDV データベース調査の概要
データソースEBM Provider®

対象期間

データ抽出期間を 2019 年 7 月*～2022 年 6 月とし、集計対象期間は2020 年 1 月～2022 年 6 月に設定
* 併存疾患データ取得のため集計期間前 6 か月を含む

組み入れ基準

集計対象期間に、COVID-19 の初回確定診断日がある患者
COVID-19 の定義は、ICD10 コード U071（コロナウイルス感染症
2019、ウイルスが同定されたもの）

除外基準

下記のいずれかに該当する患者は集計対象から除外• COVID-19 での受診と同月にレムデシビルの処方がある患者• 様式 1 で妊娠の情報がある患者• COVID-19 の初回確定診断日の該当月の 1 日時点で 18 歳未満の患者

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主な患者特性の定義

COVID-19 の初回診断確定日から最終受診日までを患者区分判定期間（1 コース）とし、入院に至った場合はこれを「基準入院」と定義した。なお、初回確定診断日より後に COVID-19 後遺症の診断日データがある場合
は、その前日を最終受診日とし、それまでの期間を 1 コースとした。
 年齢
COVID-19 の初回確定診断日と同月の 1 日時点の年齢
 患者区分（外来患者）
外来診療のみで治療を終えた患者
 患者区分（入院患者）
基準入院における重症度に基づき、患者区分を定義した。

一般病棟： 基準入院期間に ICU の算定なし、かつ MV 又は ECMOの算定なしの患者

ICU： 基準入院期間に ICU の算定あり、かつ MV 又は ECMO の
算定なしの患者

ICU+MV/ECMO： 基準入院期間に ICU の算定あり、かつ MV 又は ECMO 算定ありの患者
 再入院ありの患者
基準入院期間の最終日から 60 日以内の COVID-19 を主要傷病名とす
る入院がある患者
 後遺症ありの患者
COVID-19 の初回確定診断日後に COVID-19 後遺症の確定診断日がある患者。なお、COVID-19 後遺症の定義は、ICD10 コードで U09（コロナウイルス感染症 2019 後の病態）又は U099（コロナウイルス感染症
2019 後の病態、詳細不明）とした。

主な治療実態関連項目の定義 死亡例
基準入院の転帰が死亡退院である
 外来受診回数・治療期間

外来受診回数： 1 コース内の受診日数をカウント（但し、救急医療関連のデータがある場合は救急受診回数にカウント）

外来治療期間： 1 コースの日数、症状の持続期間とする。

救急受診回数： 1 コース内の救急受診日数をカウント
 入院期間基準入院の初日から退院日までの日数（但し、死亡による退院症例は集計から除外）
 再入院期間
COVID-19 主要傷病名とする再入院から退院までの日数

またシナリオ分析には、MOVe-OUT 試験の ad hoc 解析のデータを用いた（表 13）。MOVeOUT 試験から十分なデータが得られなかったその他のパラメータ（外来での症状の持続時間、外来受診回数、救急科受診回数、救急科受診患者の割合、長期の後遺症と再入院の割合、但し再入院時の入院期間を除く）についても、MDV データベース調査で得られたデータを使用した（表58Confidential14）。また、上記いずれのデータソースからも得られない項目（入院割合、再入院時の入院期間、ICU+MV/ECMO の後遺症罹患割合）については、厚生労働省から公開されている情報[110]と文献値を使用した[111],[112]（表 13 および表 14）。
表 13 ベースラインの患者特性および疾患特性
パラメータ

MDV データベース調査
または報告値（基本分析）

MOVe-OUT 試験の
ad hoc 解析（シナリオ分析）

患者特性
年齢、歳（SE）

45.3 (0.57)

死亡時年齢、歳（SE）

61 (5.86)
49 (0.02)

女性、％（SE）
入院割合、％（SE）

*

[110]

(N/A)

9.2 (0.01)

入院の内訳（患者区分別）
一般病棟、%（SE）

70 (0.06)

ICU、%（SE）

17 (0.05)

ICU+MV/ECMO、%（SE）

13 (0.04)
入院日数（患者区分別）

一般病棟、日（SE）

10 (0.82)

ICU、日（SE）

14 (1.13)

ICU+MV/ECMO、日（SE）

14 (1.33)

標準誤差（SE）は、入手できない場合、平均値の 5％とした。*厚生労働省公表データ「新型コロナウイルス感染症患者の療養状況等及び入院患者受入病床数等に関する調査結果」：2022 年における療養者数と入院者数（毎週発表）から算出した全ての週次入院割合（％）の平均値

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表 14 その他のパラメータ
MDV データベース調査
または文献値

パラメータ
外来および救急科受診関連
症状の持続期間（外来治療期間）、日（SE）
外来受診回数、回/コース（SE）
1 患者あたり救急科受診回数、回（SE）
救急科受診割合、%生存患者における長期の後遺症罹患割合（患者区分別）
外来、%
一般病棟、%ICU、%
ICU+MV/ECMO、%[112]

COVID-19 により再入院した患者の割合（患者区分別）
一般病棟、%ICU、%
ICU+MV/ECMO、%再入院時の入院期間、日
#

#
[111]

再入院例がなかったため、モデルでは ICU と同値を仮定; 標準誤差（SE）は、入手できない場合、平均値の 10％とした。

4.2.1 有効性･安全性等のパラメータの詳細
モルヌピラビルの入院に対する影響のパラメータには、MOVe-OUT 試験第Ⅲ相パート（3.2.4
検索結果）の post hoc 解析における COVID-19 関連入院の相対リスクを用い、入院後の重症化に対する影響のパラメータには、ランダム化後 29 日目までに COVID-19 に関連する理由で入院した被験者（モルヌピラビル 800mg 投与群 45 例、プラセボ投与群 64 例）についてのpost hoc 解析における相対リスクを用いた（表 15）。
表 15 MOVe-OUT 試験第Ⅲ相パートに基づくモルヌピラビルの有効性[17]治療効果

MOVe-OUT 試験 post hoc 解析[95%信頼区間]

COVID-19 関連入院への進行、RR

0.69 [0.47 – 0.98]

Score 6（ICU）への進行、RR

0.83 [0.27 – 1.97]

Score 7-9（人工呼吸器の使用）への進行、RR

0.76 [0.18 - 2.17]

COVID-19 関連死亡、RRR

0.84 [0.75 – 0.92]

注：推定値は、29 日目までの MOVe-OUT 試験第Ⅲ相パートの事後解析から得られたデータ。死亡率に対するモデルの効果
は、WHO clinical Progression Scale（11 点）の最高スコアに依存する。WHO score 4～5 は一般病棟、WHO score 6
は ICU、WHO score 7～9 は人工呼吸器の使用を想定した。RR: Risk ratio, RRR: Relative risk reduction

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また分析モデルでは、上述したモルヌピラビルによる COVID-19 関連入院および重症化の回避を介した効果として COVID-19 による死亡リスクが低減することを想定した。標準治療におけるCOVID-19 による死亡率としては MDV データベース調査で算出された死亡率（基本分析）とMOVe-OUT 試験の ad hoc 解析におけるデータ（シナリオ分析）を使用し、それぞれ患者区分別に異なる死亡率を想定した（表 16）。なお、外来患者の死亡情報は同調査で取得できなかったため、外来患者の COVID-19 による死亡率は 0 と仮定した。
表 16 COVID-19 による死亡率
MDV データベース調査（基本分析）

患者区分

MOVe-OUT 試験
ad hoc 解析（シナリオ分析）

一般病棟、% (SE)

2.2 (0.022)

ICU、% (SE)27.3 (0.134)

ICU+MV/ECMO、% (SE)62.5 (0.171)

標準誤差（SE）は、入手できない場合、平均値の 10％とした。

モデルの急性期後の生存患者には、日本人の一般集団の死亡確率を第 23 回生命表から取得し適用した[113]。なお、このモデルは 100 歳まで患者を追跡するため、100 歳以降の死亡率は100%に設定した。
• 併存疾患が死亡率に与える影響（MOVe-OUT 試験第Ⅲ相パートのパラメータを用いたシナリオ分析）について
パンデミック初期の報告では、基礎疾患を持つ COVID-19 入院患者は、COVID-19 の重症化および死亡のリスクが高いことが示されている[114], [115], [116], [117]。このモデルは、
COVID-19 の入院患者において、年齢に関係なく[118]、多くの基礎疾患が死亡のリスク上昇をもたらす可能性があることを示す文献に基づいて、入院患者と非入院患者の死亡率上昇を区別して捉えた。本モデルでは、標準化死亡比（Standardized Mortality Ratio、
SMR）として、既往の併存疾患（すなわち、重度の心臓疾患、心血管障害、糖尿病）を有する患者（患者割合％：MOVe-OUT 試験における糖尿病、高血圧、重篤な心疾患（心不全、冠動脈疾患、心筋症）を有する患者割合）にを適用し、急性期後の生存患者については入院患者と非入院患者の両方に既往の併存疾患の影響を考慮した[119]。この SMR
は、MOVe-OUT 試験のパラメータを用いたシナリオ分析に適用された。
4.2.2 QOL 値の詳細
分析対象集団におけるベースラインの QOL 値として日本人の一般集団における EQ-5D-5L 標
準値[120]を用いた。一方、日本人の COVID-19 患者の急性期治療中および治療後の健康状態
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リューセットを用いて日本人換算の QOL 値を算出し、その後本分析で定義する 6 つの健康状態における QOL 値に要約した（表 17）。なお、再入院の健康状態に対する QOL 値した。
表 17 COVID-19 患者における QOL 値
健康状態

QOL 値 (SE) *軽症・中等症
一般病棟
ICU
ICU+MV/ECMO
長期の後遺症
長期の後遺症なしの回復
再入院*英国 QOL 調査における Outpatient (mild), Outpatient (moderate)をプールしたデータに基づく日本人 QOL 換算値

4.2.3 費用のパラメータの詳細
本分析では MDV データベース調査により分析に必要な費用項目を推計し、費用パラメータとして使用した。推計方法の詳細を表 18 に示す。なお、同データベース調査では集計実施時点の最新の診療報酬（2022 年 4 月改定）及び最新薬価に換算した費用集計も行ったが、すべての入院区分（一般病棟、ICU、ICU＋MV/ECMO、COVID-19 関連再入院、すべての再入院）において 1 入院あたり医療費の集計値が実施時点薬価に基づく集計値を大きく上回ったため、本分析では保守的なアプローチとして標準治療の経済的負担を低めに想定することを選択し、治療実施
時点の最新の単価に基づく費用を使用した（但し、著しく乖離が大きかった ICU＋MV/ECMO に
ついては文献値を利用）。
モルヌピラビルの 1 コースの薬剤費については、分析実施時点の薬価（2,357.8 円）[122]に基づき、94,312 円（1 コース：4 カプセル×2 回×5 日）とした。

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表 18 治療費用の推計方法
項目
費用の推計方法

外来治療の費用

入院の費用

内容
集計対象患者に実施された診療行為及び薬剤、医療機器の使用を含むすべての医療行為のうち、下記の定義に該当する項目の合計費用を治療実施時の最新の診療報酬点数に基づいて推計した。
外来治療期間中の医療費と薬剤費の合計。なお、救急外来の費用は受診 1 回あたりの費用として別途集計した。
費用の集計範囲を以下に示す。
•
診療区分 A～L、N に該当する全ての診療報酬（但し、入院関連及び明らかに COVID-19 の治療と関係のない悪性腫瘍の治療などを除く）•
全ての薬剤費（但し、明らかに COVID-19 の治療と関係のない抗腫瘍剤などを除く）
入院期間について、期間内に退院日データがある場合は入院日から退院日まで、退院日データが無い場合は最終受診日までとした。退院以外の打ち切り症例（死亡入院、退院先が転院の入院、基準入院（かつ 1 コース内）の一部データが欠測している入院）は、全ての医療費集計から除外した。
費用の集計範囲を以下に示す。
•
診療区分 A～L、N に該当する全ての診療報酬（但し、外来診療関連及び明らかに COVID-19 の治療と関係のない悪性腫瘍や、人工関節置換術や骨折等に伴う比較的高頻度かつ高額な整形外科
関連手術などを除く）•
全ての薬剤費（但し、明らかに COVID-19 の治療と関係のない抗腫瘍剤などを除く）
基準入院における治療費用：
基準入院期間中における 1 患者 1 入院あたりの医療費の合計。但し、基準入院の転帰が死亡、退院先が転院の入院や集計対象期間中に未退院の症例、入院期間中に欠損データがある症例は集計の対象から除外した。

後遺症治療費用

再入院における治療費用：
再入院期間中における 1 患者 1 入院あたりの医療費の合計。但し、基準入院の場合と同じく、入院期間中に欠測データがある症例は集計対
象から除外した。入院後の発症病名のみの入院は含まない。
COVID-19 後遺症治療期間における 1 患者 1 か月あたりの医療費の合計基本分析では、COVID-19 の外来や入院に伴う治療費用、長期の後遺症及び COVID-19 による再入院費用に MDV データベース調査で得られたデータを使用した（表 19）。

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表 19 治療の費用
1 患者あたりの平均費用

パラメータ
外来受診費、円/コース
救急科受診費、円/回
COVID-19 入院費用（患者区分別）
一般病棟、円/コース
ICU、円/コース
ICU+MV/ECMO、円/コース[123]

再入院、円/コース*

後遺症治療費用、円/月#* COVID-19 を主傷病名とする再入院における費用、#後遺症治療は外来・入院を問わない総費用/月の平均値

労働生産性については、15 歳以上の労働力人口において 2021 年労働力調査[124]より男女別就業率、年間の平均就業日数、及び国税庁による民間給与実態統計調査[125]（令和 4 年 9 月）に基づき 5 歳階級別の年間の平均給与額を用い 1 日あたりの平均賃金を算出した（表 20）。これらを入院による生じる労働生産性損失を考慮した社会の立場でのシナリオ分析に用いた。

表 20 年齢階級別 1 日あたりの平均賃金
年齢階級

1 日あたり平均賃金（円）

<=19
20-24

8,125
12,665

25-29
30-34
35-39
40-44
45-49
50-54

15,465
17,20818,74720,01721,00921,776

55-59
60-64
65-69
>=70

22,20818,225
15,634
13,87664

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5. 分析結果
5.1 基本分析(費用対効果評価専門組織で決定された分析枠組みによる分析)の結果
下記の通り費用効果分析を実施した。

■ 費用効果分析 （増分費用効果比を算出する）□ 費用最小化分析 （効果は同等として費用を比較する）

5.1.1 基本分析の増分費用、増分効果、増分費用効果比
基本分析の結果を表 21 に、費用の内訳を表 22 に示す。評価対象集団における比較対照の標
準治療に対するモルヌピラビル+標準治療の 1 患者あたりの増分費用は 84,391 円、増分
QALY は 0.044QALY であった。従って、増分費用効果比（ICER）は 1,930,637 円/QALY であった。
表 21 基本分析の結果

モルヌピラビル+標準治療

効果(QALY)

増分効果(QALY)

費用
(円)

増分費用
(円)

ICER
(円/QALY)

25.5960.044

175,291

84,391

1,930,637

25.552

標準治療90,900

QALY: quality-adjusted life year, ICER: incremental cost-effectiveness ratio

表 22 費用の内訳
項目
1 患者あたり医療費合計

モルヌピラビル+標準治療

標準治療

（円）

（円）

175,291

90,900

内訳
薬剤
外来受診
救急科受診
入院
区分別：一般病床
区分別：ICU
区分別：ICU+MV/ECMO
再入院
後遺症治療

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5.1.2 感度分析
5.1.2.1 一次元感度分析（Deterministic sensitivity analysis、DSA）
主要パラメータについて結果への影響を検討するため一元感度分析を実施した。パラメータを変動させる範囲は、4.1.1 費用対効果の算出方法に記載の通り各パラメータの分布特性を考慮し算出した 95%信頼区間を、割引率については分析ガイドライン[9]に基づき上限を 4%、下限を0%と設定した。パラメータの設定の詳細を表 23 に示す。
表 23 パラメータの設定
Parameter

Discount rate

Base caseanalysis
Input
value

Inclusionfor DSA

Inclusionfor PSASE

Distribution

2.0%

Yes

Yes

-

0-4%

Yes

Yes

NormalYes

Yes

Normal

%

Yes

Yes

Beta

%

Yes

Yes

*

%

Yes

Yes

*

%

Yes

Yes

*

%

Yes

Yes

Yes

Yes

NormalYes

Yes

NormalYes

Yes

Normal

Yes

Yes

*

Normal

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

Patient characteristics
Age at modelstart
Age at death
FemaleDisease parameters
Hospitalization
rate
Proportion in
general ward
Proportion in
intensive care
unit
Proportion inmechanicalventilation
Length of stayin general ward,
days
Length of stay
in intensive
care unit, days
Length of stay
in mechanicalventilation
Symptom
duration
Mortality rate ingeneral ward
Mortality inintensive care
unit
Mortality rate inmechanicalventilation

DSA and PSA

Beta

Dirichlet*

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Parameter

Number ofoutpatient visit
Number of
emergency
department
visit
Proportion withemergency
department
visit
Proportion withincreasedmortality
Proportion withlong-term
sequelae,outpatient
Proportion withlong-term
sequelae,general ward
Proportion withlong-term
sequelae,intensive care
unit
Proportion withlong-term
sequelae,mechanicalventilation
Readmission,from general
ward
Readmission,from intensive
care unit
Readmission,frommechanicalventilation
Readmission,
length of stay
Costs
Cost ofoutpatient visit
Cost ofemergency visit

Base caseanalysis
Input
value

DSA and PSA
Inclusionfor DSA

Inclusionfor PSA

Yes

Yes

NormalYes

Yes

Normal

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

%

Yes

Yes

*

Beta

Yes

Yes

Yes

Yes

*

Gamma

Yes

Yes

*

Gamma

SE

Distribution*

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Parameter

Cost of generalward
Cost ofintensive care
unit
Cost ofmechanicalventilation
Cost of longterm sequelae
Cost ofreadmission
Quality of life
Mild/moderate
symptomatic
General ward
Intensive careunit
Mechanicalventilation
Long-term
sequelae
Recovered (nolong-term
sequelae)
SMR

Base caseanalysis
Input
value

DSA and PSA
Inclusionfor DSA

Inclusionfor PSA

Yes

Yes

*

Gamma

Yes

Yes

*

Gamma

Yes

Yes

*

Gamma

Yes

Yes

*

Gamma

Yes

Yes

*

Gamma

Yes

Yes

Beta

Yes

Yes

Beta

Yes

Yes

Beta

Yes

Yes

Beta

Yes

Yes

Beta

Yes

Yes

Beta

Yes

Yes

*

Yes

0.13

Log-normal

Yes

0.45

Log-normal

Yes

0.54

Log-normal

Yes

0.04

Beta

Effect estimates for molnupiravir
Relative risk
reduction,
0.69
Yes
hospitalization
Relative risk,
intensive care
0.83
Yes
unit
Relative risk,mechanical
0.76
Yes
ventilation
Relative risk
reduction,
0.8402Yes
mortality
benefitSE

Distribution

Normal

*SE was assumed to be 5% of mean for these parameters.
#Assumed same as general ward
DSA: deterministic sensitivity analysis; PSA: probabilistic sensitivity analysis; SE: standard error; SMR:
standardized mortality ratio

図 8 に示す通り、モルヌピラビル＋標準療法の標準療法に対する ICER に影響が大きい上位 5
つのパラメータは、割引率、入院割合、ベースライン QOL 値、モルヌピラビルの有効性（相対入院リスク）、及び一般病棟での死亡率であった。
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図 8 一次元感度分析

5.1.2.2 確率的感度分析（Probabilistic sensitivity analysis、PSA）
4.1.1 費用対効果の算出方法に記載の通り、基本分析の全パラメータを 1,000 回のモンテカル
ロシミュレーションにより確率的感度分析を実施した。各パラメータの変動範囲は表 23 の通りである。確率感度分析の結果として、費用効果平面上の散布図（図 9）および費用効果受容曲線（図 10）を示す。モルヌピラビルが費用対効果良好となる確率は、1QALY あたり基準値（支払意思額）を 500 万円とした場合に 100%であり、費用対効果が優れている確率が高いことが示された。
図 9 費用効果平面上の散布図

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図 10 費用効果受容曲線

5.1.2.3 シナリオ分析
4.1.1 費用対効果の算出方法および 4.2 分析で使用したパラメータにおいて述べた 4 つのシ
ナリオについて分析を実施した。
シナリオ 1： MOVe-OUT 試験（全集団）の患者特性および疾患特性による分析
患者背景およびベースラインでのリスクに MOVe-OUT 試験の全集団のデータを使用したシナリ
オ分析の結果を表 24 に示す。モルヌピラビル+標準治療の標準治療に対する ICER は円/QALY で費用対効果は良好であった。

表 24 MOVe-OUT 試験（全集団）の患者特性および疾患特性による分析
治療

効果(QALY)

増分効果(QALY)

費用
(円)

増分費用
(円)

ICER
(円/QALY)

モルヌピラビル
+標準治療
標準治療

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シナリオ 2：MOVe-OUT 試験（軽症患者サブ集団）の患者特性および疾患特性による分析
本分析では、MOVe-OUT 試験の軽症患者集団とその患者背景のデータを用いた。表 25 に示
す通り、モルヌピラビル+標準治療の標準治療に対する ICER は円/QALY で費用対効果は良好であった。

表 25 MOVe-OUT 試験（軽症患者サブ集団）の患者特性および疾患特性による分析
治療

効果(QALY)

増分効果(QALY)

費用
(円)

増分費用
(円)

ICER
(円/QALY)

モルヌピラビル+標準治療
標準治療

シナリオ 3：MOVe-OUT 試験（60 歳以下サブ集団）の患者特性および疾患特性による分析
MOVe-OUT 試験の 60 歳以下の患者集団とその患者背景のデータを用いた分析の結果を表26 に示す。モルヌピラビル+標準治療の標準治療に対する ICER は円/QALY で費用対効果は良好であった。

表 26 MOVe-OUT 試験（60 歳以下サブ集団）の患者特性および疾患特性による分析
治療

効果(QALY)

増分効果(QALY)

費用
(円)

増分費用
(円)

ICER
(円/QALY)

モルヌピラビル+標準治療
標準治療

シナリオ 4：基本分析の設定における社会の立場での分析
基本分析について、入院患者の入院日数による短期的な労働生産性損失を考慮した社会の立場での分析を実施した。表 27 に示す通り、モルヌピラビル+標準治療の標準治療に対するICER は

円/QALY で費用対効果は良好であった。

表 27 基本分析の設定における社会の立場での分析
治療

効果(QALY)

増分効果(QALY)

費用
(円)

増分費用
(円)

ICER
(円/QALY)

モルヌピラビル+標準治療
標準治療

5.1.3 分析の妥当性の検討
重症化リスク因子を有する 18 歳以上の COVID-19 患者（但し、重症度の高い COVID-19 患者を除く）を分析対象集団とし、公的医療の立場に立った基本分析において、評価対象技術（モル71Confidential

ヌピラビル＋標準治療）の比較対照技術（標準治療）に対する ICER の点推定値は基準値（500万円/QALY）を下回り、費用対効果が良好である結果が示された。また PSA にて、ICER が基準
値 500 万円/QALY を下回る確率は 100%、また 250 万円/QALY を下回る確率は 93％であり、モデルに用いた全てのパラメータの不確実性によりこの結果が覆される確率は想定したパラメータの変動範囲内においては低く、基本分析の頑健性が支持された。さらに、公的医療の立場でのシナリオ分析（MOVe-OUT の全集団、60 歳以下又は軽症患者サブ集団のベースラインデー
タを使用）の全てにおいても基本分析と同じく ICER が基準値を大きく下回ったことから、例えば
オミクロン株以降に出現する SARS-Cov2 変異株がデルタ株と同等の病原性を獲得、あるいはワクチンの有効性低下といった今後の感染状況や重症化率を左右しうる主な要因について、十分に悲観的なシナリオを仮定した場合にも基本分析と同様に費用対効果が良好と考えられた。
これまでに行われた海外の HTA 機関によるモルヌピラビルの費用対効果分析の事例として英国
NICE における Multiple Technology Assessment がある。その中では、入院患者と非入院患者に対する各種 COVID-19 治療薬の臨床的および経済的評価が行われ、主として経済的評
価の結果に基づき、NICE は重症化リスクを有する非入院の患者にモルヌピラビルを推奨しないとの暫定ガイダンスを発出するに至った[126]。しかし、この暫定ガイダンスには以下に示すいくつかの懸念がある。例えば、当該評価における重症化リスク因子の定義（McInnes report[127]に基づく）には年齢や複数の慢性疾患を含む COVID-19 重症化に関連する重要なリスク因子が含まれないこと、臨床的有効性のエビデンスとして重視された PANORAMIC 試験[101]では著者ら自身が認める通り全体として重症化リスクを有する患者の割合が少なかったこと、システマティ
ックレビューとメタアナリシスに採用された個別試験の間には広範な臨床的異質性が認められたこと、それにも関わらずそういった異質性や分析の限界を評価するために通常取られるべき手法に従っていなかったことなどが指摘できる。また、経済的評価の手法は NICE のマニュアルからは逸脱した簡易化されたものであったため、少なくとも評価手順の観点からはその妥当性に懸念がある。さらに PSA が行われない代わりとして、臨床的有効性の推定値として平均値と上下両信頼限界を設定したシナリオ分析が行われたのみであり、主要パラメータの分布の不確実性を考慮に入れた評価が行われていないことから、決定エラーの起こりやすさが十分に評価されていな
い。なお、上記暫定ガイダンス以後、3 社の COVID-19 治療薬開発企業による NICE に対する
不服申し立ての手続きが継続されており 2023 年 5 月 2 日の時点では最終的な結論に至っていない。

本分析結果については以下の強みが挙げられる。まず、本分析で用いた費用対効果分析の基本（グローバル）モデルに関して、MOVe-OUT 試験結果と予測モデルとの比較による内的妥当性の検証が行われた結果、良好な再現性が確認されている。また、海外のリアルワールドデータを用いた急性期アウトカムに関する外的妥当性の検証も実施され、良好な予測性が示されている
72

Confidential（データの不足のため長期アウトカムは含まず）。今回我々が評価に用いた基本モデルは NICEの経済的評価モデルとは異なり、感度分析や種々のシナリオ分析によりパラメータの不確実性に起因する決定エラーの懸念が小さいことが示されていることから、現時点で利用可能なエビデンスを用いたモデルの妥当性と不確実性への対応に関して言えば、NICE で行われた手法と比べて方法論上の妥当性がより高いと考えられる。

上記の基本モデルをベースに、以下のアプローチにより日本の治療実態を反映するパラメータを組み入れた分析モデルを構築した。モデルの構築に先立ち、国内 COVID-19 治療に関する
MDV データベース調査（データ期間：2020 年 1 月～2022 年 6 月、N=）を行い、重症度別 COVID-19 患者割合、医療資源利用、直接医療費、急性期治療のアウトカム等に関するデータを収集し、それらに由来する数値をモデルパラメータとして使用した。また、COVID-19
関連の QOL 値としては英国で実施された vignette を用いた EQ-5D-5L の被験者レベル調査
データを日本人バリューセットによりマッピングした値を用い、分析ガイドライン 9 で推奨される効果指標の要件に対応させた。臨床的有効性のパラメータには、2022 年に最高峰の医学誌である The New England Journal of Medicine 誌に掲載された MOVe-OUT 試験第Ⅲ相パートの有効性アウトカムを使用した 17。本試験に組み入れられた患者は重症化リスクを有する非入院の COVID-19 患者であり、分析前協議において合意された分析対象患者集団の定義と一致する。また、3.8 追加的有用性の有無に関する評価で述べたとおり最新の大規模観察研究で類似のアウトカムが示されている。以上のように、本分析では分析ガイドライン並びに事前に分析前協議で了承された分析枠組みに沿って、パラメータとして日本人のリアルワールドデータ並びにQOL 値を組み入れた分析モデルを構築するとともに、エビデンスレベルの高い臨床的有効性のデータが用いられたことから、全体として妥当な分析結果を示しているといえる。

一方、本分析については以下の限界があると考えられる。まず、COVID-19 発症者の入院割合に関しては、感染者数、主たる変異株の病原性、病床逼迫度、ワクチン接種率、入院基準/集計
方法等の影響を受けやすく、不確実性が高い。そこで、本分析では 2022 年の状況（オミクロン株と同等の病原性とワクチン接種率維持）が継続することを想定し、入院割合として 2022 年通年の平均値[110]である％を用いた（表 13）。但し、この値は国内療養者全体（重症化リスク因

子を持たない患者を含む）に対する入院割合としては妥当なものと考えられるが、本分析の対象集団である重症化リスク保有患者に限定した場合の入院割合はこれより高いものである可能性が否定できない（参考：MDV データベース調査における 2022 年 1-6 月に基準日に持つ患者の入院割合は％）。一方、入院以降の重症度別患者割合（表 13）、後遺症罹患割合及びCOVID-19 による再入院割合（表 14）、死亡率（表 16）等に関しては MDV データベース調査で得られた全データ期間の平均値を用いており、ワクチン接種の進展や変異株の出現等に伴う変化を精密には反映していないため不確実性が高い。これらの指標に関してはデータ期間別（673Confidential

か月ごと集計値）の変動が入院割合ほどには顕著でなかったことに加え、一元感度分析の結果からも分析結果への影響は限定的と考えられた（図 8）。また、新たな変異株の出現により
COVID-19 の疾患特性自体が変化する可能性も重要な不確実性として挙げられる。この点を考慮して、入院あるいは重症化割合の上昇につながる可能性のある新たな高病原性変異株の流行やワクチンが無効化に向かうことを想定した悲観的条件（MOVe-OUT 試験実施時相当）に設定したシナリオ分析を実施し、いずれのシナリオにおいても基本分析の結果が覆らないことを確認した（表 24～表 26）。
さらに、利用可能なデータの不足に起因する限界も挙げられる。具体的には、本モデルで想定するモルヌピラビルの有効性は MOVe-OUT 試験第Ⅲ相パートの主要アウトカムに基づき入院又は院内死亡率の減少によるものに限定しており、COVID-19 罹患に伴うその他の疾病負荷（非入院患者の死亡率、入院期間、症状の持続期間、後遺症（罹患後症状）の重症度や持続期間等）とこれらに対する治療の影響を考慮していない。また、社会の立場でのシナリオ分析（表 27）では入院期間の労働生産性損失のみを考慮しているため、自宅待機中や療養後の休業期間の労働
生産性損失、罹患後症状による労働生産性損失、介護における COVID-19 関連費用、その他
一般的な社会経済活動への影響等、リアルワールドでは少なからず発生したと考えられる社会的損失とこれらに対する治療の影響を考慮しておらず、主に外来患者で使用されるモルヌピラビル
がこれらの損失の回避に少なくとも部分的には寄与する可能性が考えられることから、社会の立場の分析としては極めて保守的なアプローチであるといえる。
5.1.4 分析結果の解釈
表 28 分析結果の解釈
重症化リスク因子を有する SARS-CoV-2 による感染症（COVID-19）患者（18 歳以上）
対象集団

但し、有効性が確立していないため、重症度*の高い COVID-19 患者を除く。
*重症度の定義は新型コロナウイルス感染症（COVID-19）診療の手引
き・第 8.1 版に準ずる。

比較対照

標準治療

ICER の基準値■ 通常の品目 □ 配慮が必要な品目

74Confidential□ 費用削減あるいはドミナント■ 500 万円以下 (750 万円以下)
ICER の所属する確□ 500 万円超 (750 万円超)かつ 750 万円以下 (1125 万円以下)率が最も高いと考え□ 750 万円超 (1125 万円超)かつ 1000 万円以下 (1500 万円以る区間

下)□ 1000 万円超 (1500 万円超)
□ 効果が同等（あるいは劣り）、かつ費用が高い
重症化リスク因子を有する SARS-CoV-2 による感染症（COVID-19）患者におけるモルヌピラビル＋標準治療の標準治療に対する Incremental

そのように判断した理
由

Cost-Effectiveness Ratio (ICER) は 1,930,637 円/QALY であり、500 万円以下の区分に該当すると考えられたため。また、実施した PSA
では ICER が基準値の 500 万円を下回る確率は 100%であり、さらに公的医療の立場でのシナリオ分析全てにおいて ICER が 500 万円以下となり、基本分析と同様の結果が示されたため。

5.1.5 価格調整率の重み [該当する場合のみ]
該当なし
5.1.6 価格の引き上げ [該当する場合のみ]該当なし
5.2 公的介護費用や生産性損失を含めた分析 [該当する場合のみ]
該当なし
5.3 その他の分析 [該当する場合のみ]
該当なし

75

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6. 再分析用のデータ使用したソフトウェア

バージョン

Microsoft Excel for

2208

Microsoft 365 MSO

ファイル名

提出メディア
電子メール
添付ファイル76

Confidential

7. 実施体制
記載事項なし77Confidential

8. 参考文献[1] Imai M, Ito M, Kiso M, et al. Efficacy of Antiviral Agents against Omicron
Subvariants BQ.1.1 and XBB. N Engl J Med. 2023;388(1):89-91.
[2] Uraki R, Ito M, Kiso M, et al. Antiviral and bivalent vaccine efficacy against an
omicron XBB.1.5 isolate. Lancet Infect Dis. 2023;23(4):402-403.
[3] ラゲブリオカプセル 200mg 添付文書（2023 年 4 月改訂、第 5 版）
https://www.info.pmda.go.jp/go/pack/6250051M1028 1 03/?view=frame&style=X
ML&lang=ja （アクセス日：2023 年 4 月 25 日）[4] 厚生労働省. 新型コロナウイルス感染症診療の手引き 第 9.0 版. 2023.
https://www.mhlw.go.jp/content/000936655.pdf（アクセス日：2023 年 4 月 25 日）[5] 厚生労働省.第 121 回新型コロナウイルス感染症対策アドバイザリーボード（令和 5 年 4 月 19日）資料. 2023.
https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000121431 00395.html（アクセス日：2023 年 4 月 28 日）[6] ラゲブリオカプセル 200mg インタビューフォーム（2023 年 4 月改訂、第 3 版）
https://www.info.pmda.go.jp/go/interview/1/170050 6250051M1028 1 004 1F.p
df （アクセス日：2023 年 4 月 25 日）[7] ラゲブリオカプセル 200mg 特定使用成績調査 中間報告
[8] 厚生労働省. 新型コロナウイルス感染症診療の手引き 第 8.1 版. 2022.
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用対効果評価の分析ガイドライン 第 3 版. 2022.
https://c2h.niph.go.jp/tools/guideline/guideline ja.pdf（アクセス日：2023 年 4 月 25 日）[10] Mahmud R, Rahman MM, Alam I, et al., et al. Ivermectin in combination withdoxycycline for treating COVID-19 symptoms: a randomized trial. Journal ofInternational Medical Research. 2021;49(5): 3000605211013550.
[11] World Health Organization. Therapeutics and COVID-19: living guideline.
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Published on July 14, 2022. （アクセス日：2023 年 4 月 25 日）

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Confidential[12] European Medicines Agency. EMA advises against use of ivermectin for theprevention or treatment of COVID-19 outside randomised clinical trials.
https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectinprevention-treatment-covid-19-outside-randomised-clinical-trials. Published 2021.
（アクセス日：2023 年 4 月 25 日）[13] National Institutes of Health. COVID-19 Treatment Guidelines: Ivermectin.
https://www.covid19treatmentguidelines.nih.gov/therapies/antiviraltherapy/ivermectin/. Published 2021. （アクセス日：2023 年 4 月 25 日）[14] Food and Drug Administration. Why You Should Not Use Ivermectin to Treat orPrevent COVID-19.
https://www.fda.gov/consumers/consumer-updates/why-you-should-not-useivermectin-treat-or-prevent-covid-19. Published 2021.
（アクセス日：2023 年 4 月 25 日）[15] Reardon S. Flawed ivermectin preprint highlights challenges of COVID drug
studies. Nature. 2021;596(7871):173-174.
[16] Adhikari P, Koirala J, Shrestha A, et al. Efficacy of Favipiravir in treatment ofmild & moderate COVID-19 infection in Nepal: a multi-center, randomized, openlabelled, phase III clinical trial. International Journal of Infectious Diseases.
2022;116:S45-S46.
[17] Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral
treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509520.
[18] Strizki J, Grobler JA, Johnson MG, et al. Virologic outcomes from MOVe-OUT, arandomised, controlled phase III trial evaluating molnupiravir for treatment of
COVID-19 in non-hospitalised adults. ECCMID 2022.
[19] Guan Y, Puenpatom A, Johnson MG, et al. Impact of molnupiravir treatment onpatient-reported COVID-19 symptoms in the MOVe-OUT study. ECCMID 2022.
[20] Johnson MG, Strizki J, Brown ML, et al. Molnupiravir for treatment of COVID19 in immunocompromised patients: efficacy, safety, and virology results from thephase III MOVe-OUT trial. Infection. 2023 Jan 17:1-12.

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Biomarkers, Respiratory Interventions, and Medical Services in COVID-19: A
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[22] Bosaeed M, Alharbi A, Mahmoud E, et al. Efficacy of favipiravir in adults withmild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical
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[24] Pfizer Inc. Pfizer Announces Additional Phase 2/3 Study Results Confirming
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90Confidential

AppendixConfidential

別添 1： SLR1 に用いた検索式
SLR 1: May 2021 (original search)
MEDLINE (Ovid MEDLINE Daily Update and OVID MEDLINE In-Process, In-Data-Review & Other Non-Indexed
Citations) search strategy*, optimized with MeSH terms applicable to EMBASE, used in May 2021 (original
search)SearchSearch syntax

line
Population1

exp Coronavirinae/

2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Interventions/comparators
4(Remdesivir or Veklury or GS-5734).mp.

5(Prednisone or Deltasone or Prednicot or Rayos or Sterapred or Orasone or A07EA03).mp.

6(Hydrocortisone or Cortef or Plenadren or NSC*10483 or ).mp

7

(Methylprednisolone or Medrol).mp.

8(Favipiravir or Favivir or Favir or Avigan or T-705).mp.

9(Budesonide or Pulmicort).mp.

10(AT-527 or RO7496998).mp.
92

Confidential

SearchSearch syntax

line
11

(REGEN-COV or REGN-COV or Regeneron).mp.

12(casirivimab and imdevimab) or (REGN10933 and REGN10987).mp.

13(VIR-7831 or sotrovimab or GSK4182136).mp.

14

Camostat mes*late.mp.

15(Nitazoxanide or Alinia).mp.

16(Colchicine or Colcrys or Mitigare).mp.

17(Molnupiravir or MK-4482 or EIDD-2801).mp.

18

Bamlanivimab.mp.

19(bamlanivimab and etesevimab).mp.

20

LY-CoV555.mp.

21(LY-CoV555 and LYCoV016).mp.

22((AZD7442 or AZD8895) and AZD1061).mp.

23(Regdanvimab or Regkirona or CT-P59).mp.

24

Peginterferon Lambda-1.mp.

25(Baricitinib or Olumiant).mp.

26(doxycycline and ivermectin) or (Doxteric or Stromectol).mp.

27(Famotidine or Pepcid).mp.

28(Fluvoxamine or Floxyfral or Luvox).mp.

29

PF-07321332.mp.

93

Confidential

SearchSearch syntax

line
30

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
or 24 or 25 or 26 or 27 or 28 or 29

Included study design
32

Randomized Controlled Trials as Topic/

33

randomized controlled trial/

34

Random Allocation/

35

Double Blind Method/

36

Single Blind Method/37

clinical trial/

38

clinical trial, phase i.pt

39

clinical trial, phase ii.pt

40

clinical trial, phase iii.pt

41

clinical trial, phase iv.pt

42controlled clinical trial.pt

43

randomized controlled trial.pt

44

multicenter study.pt

45

clinical trial.pt

46

exp Clinical Trials as topic/

47

32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46

48(clinical adj trial$).tw
94Confidential

SearchSearch syntax

line
49

((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw

50

PLACEBOS/

51

placebo$.tw

52

randomly allocated.tw53(allocated adj2 random$).tw

54

48 or 49 or 50 or 51 or 52 or 53

55

47 or 54

Excluded study designs
56

case report.tw

57

letter/58

historical article/

59

56 or 57 or 58

60

55 not 59

61

3 and 30 and 60

Total hits
62

limit 61 to yr="2020 -Current"*For further details of the search terms and fields used in MEDLINE please see the OVID Database guide:
https://ospguides.ovid.com/OSPguides/medline.htm#advanced. Search strategy designed to be compatible with EMBASE indexing system - however, all searchstrategies were searched in the same 5 key databases (EMBASE, MEDLINE Daily Update, MEDLINE In-Process, In-Data-Review & Other Non-Indexed Citations,
APA PsychInfo, Econlit), for completeness..
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); pt: publication type; tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or
abstract only).

95Confidential

EMBASE (1974 to 2021) search strategy*, optimized with MeSH terms applicable to EMBASE, used in May 2021
(original search)
SearchSearch syntax

line
Population1

exp Coronavirinae/

2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Interventions/comparators
4(Remdesivir or Veklury or GS-5734).mp.

5(Prednisone or Deltasone or Prednicot or Rayos or Sterapred or Orasone or A07EA03).mp.

6(Hydrocortisone or Cortef or Plenadren or NSC*10483 or ).mp

7

(Methylprednisolone or Medrol).mp.

8(Favipiravir or Favivir or Favir or Avigan or T-705).mp.

9(Budesonide or Pulmicort).mp.

10(AT-527 or RO7496998).mp.

11(REGEN-COV or REGN-COV or Regeneron).mp.

12(casirivimab and imdevimab) or (REGN10933 and REGN10987).mp.

13(VIR-7831 or sotrovimab or GSK4182136).mp.

14

Camostat mes*late.mp.
96Confidential

SearchSearch syntax

line
15

(Nitazoxanide or Alinia).mp.

16(Colchicine or Colcrys or Mitigare).mp.

17(Molnupiravir or MK-4482 or EIDD-2801).mp.

18

Bamlanivimab.mp.

19(bamlanivimab and etesevimab).mp.

20

LY-CoV555.mp.

21(LY-CoV555 and LYCoV016).mp.

22((AZD7442 or AZD8895) and AZD1061).mp.

23(Regdanvimab or Regkirona or CT-P59).mp.

24

Peginterferon Lambda-1.mp.

25(Baricitinib or Olumiant).mp.

26(doxycycline and ivermectin) or (Doxteric or Stromectol).mp.

27(Famotidine or Pepcid).mp.

28(Fluvoxamine or Floxyfral or Luvox).mp.

29

PF-07321332.mp.

30

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or
23 or 24 or 25 or 26 or 27 or 28 or 29

Included study designs
31

Clinical Trial/

32

Randomized Controlled Trial/97Confidential

SearchSearch syntax

line
33

controlled clinical trial/

34

multicenter study/

35

Phase 3 clinical trial/

36

Phase 4 clinical trial/

37

RANDOMIZATION/

38

Single Blind Procedure/

39

Double Blind Procedure/

40

Crossover Procedure/

41

PLACEBO/

42

randomi?ed controlled trial$.tw.

43

rct.tw.

44(random$ adj2 allocat$).tw.

45

single blind$.tw.

46

double blind$.tw.

47((treble or triple) adj blind$).tw.

48

Placebo$.tw.

49

Prospective Study/

50

31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or
49

Excluded study designs
98Confidential

SearchSearch syntax

line
51

Case Study/

52case report.tw.

53

abstract report/ or letter/54

editorial/

55

letter/

56

note/

57

51 or 52 or 53 or 54 or 55 or 56

58

50 not 58

59

3 and 30 and 58

Total hits
60

limit 59 to yr="2020 -Current"*For further details of the search terms and fields used in EMBASE please see the OVID Database guide: https://ospguides.ovid.com/OSPguides/embase.htm.
Search strategy designed to be compatible with EMBASE indexing system - however, all search strategies were searched in the same 5 key databases (EMBASE,
MEDLINE Daily Update, MEDLINE In-Process, In-Data-Review & Other Non-Indexed Citations, APA PsychInfo, Econlit), for completeness.
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or abstract only).

99Confidential

別添 2： SLR2 に用いた検索式
SLR2: September 2021 (first update search)
Medline (Ovid MEDLINE Daily Update and OVID MEDLINE In-Process, In-Data-Review & Other Non-Indexed
Citations) search strategy*, optimized with MeSH terms applicable to EMBASE, used in September 2021 (first
update search)
SearchSearch syntax

line
Population1

exp Coronavirinae/

2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Intervention/comparators
4

Baricitinib.mp.

5(doxycycline and ivermectin).mp.

6

Famotidine.mp.

7

Fluvoxamine.mp.

8

PF-07321332.mp.

9

sotrovimab.mp.

10

S-217622.mp.
100Confidential

SearchSearch syntax

line
11

MP-0420.mp.

12

ensovibep.mp.

13

ADG20.mp.

14MP-0423.mp.

15

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

Included study designs
16

Randomized Controlled Trials as Topic/

17

randomized controlled trial/

18

Random Allocation/

19

Double Blind Method/

20

Single Blind Method/21

clinical trial/

22

clinical trial, phase i.pt.

23

clinical trial, phase ii.pt.

24

clinical trial, phase iii.pt.

25

clinical trial, phase iv.pt.

26

controlled clinical trial.pt.

27

randomized controlled trial.pt.

28

multicenter study.pt.

101Confidential

SearchSearch syntax

line
29

clinical trial.pt.

30

exp Clinical Trials as topic/

31

16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30

32(clinical adj trial$).tw.

33((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw.

34

PLACEBOS/

35

placebo$.tw.

36

randomly allocated.tw.

37(allocated adj2 random$).tw.

38

32 or 33 or 34 or 35 or 36 or 37

39

31 or 38

Excluded study designs
40case report.tw.

41

letter/42

historical article/

43

40 or 41 or 42

44

39 not 43

45

3 and 15 and 44

46

limit 45 to yr="2020 -Current"

102Confidential

SearchSearch syntax

line
47

limit 46 to yr="2021 -Current"

Total hits
48

remove duplicates from 47*For further details of the search terms and fields used in MEDLINE please see the OVID Database guide:
https://ospguides.ovid.com/OSPguides/medline.htm#advanced. Search strategy designed to be compatible with EMBASE indexing system - however, all searchstrategies were searched in the same 5 key databases (EMBASE, MEDLINE Daily Update, MEDLINE In-Process, In-Data-Review & Other Non-Indexed Citations,
APA PsychInfo, Econlit), for completeness.
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); pt: publication type; tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or
abstract only).

EMBASE (1974 to 2021) search strategy*, optimized with MeSH terms applicable to EMBASE, used in
September 2021 (first update search)
SearchSearch syntax

line
Population
1
2
3

exp Coronavirinae/(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.
1 or 2

Intervention/comparators
4

Baricitinib.mp.

5(doxycycline and ivermectin).mp.

103

Confidential

SearchSearch syntax

line
6

Famotidine.mp.

7

Fluvoxamine.mp.

8

PF-07321332.mp.

9

sotrovimab.mp.

10

S-217622.mp.

11MP-0420.mp.

12

ensovibep.mp.

13MP-0423.mp.

14

ADG20.mp.

15

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

Included study designs
16

Clinical Trial/

17

Randomized Controlled Trial/

18

controlled clinical trial/

19

multicenter study/

20

Phase 3 clinical trial/

21

Phase 4 clinical trial/

22

RANDOMIZATION/

23

Single Blind Procedure/104Confidential

SearchSearch syntax

line
24

Double Blind Procedure/

25

Crossover Procedure/

26

PLACEBO/

27

randomi?ed controlled trial$.tw.

28

rct.tw.

29(random$ adj2 allocat$).tw.

30

single blind$.tw.

31

double blind$.tw.

32((treble or triple) adj blind$).tw.

33

Placebo$.tw.

34

Prospective Study/

35

16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 32 or
34

Excluded study designs
36

Case Study/

37

case report.tw.

38

abstract report/ or letter/39

editorial/

40

letter/105

Confidential

SearchSearch syntax

line
41

note/

42

36 or 37 or 38 or 39 or 40 or 41

43

35 not 42

44

3 and 15 and 43

Total hits
45

limit 44 to yr="2020 -Current"*For further details of the search terms and fields used in EMBASE please see the OVID Database guide: https://ospguides.ovid.com/OSPguides/embase.htm.
Search strategy designed to be compatible with EMBASE indexing system - however, all search strategies were searched in the same 5 key databases (EMBASE,
MEDLINE Daily Update, MEDLINE In-Process, In-Data-Review & Other Non-Indexed Citations, APA PsychInfo, Econlit), for completeness.
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or abstract only).

106Confidential

別添 3： SLR3 に用いた検索式
SLR3：May 2022 (updated search)
Medline (Ovid MEDLINE Daily Update and OVID MEDLINE In-Process, In-Data-Review & Other Non-Indexed
Citations) search strategy*, optimized with MeSH terms applicable to EMBASE, used in May 2022 (updated
search)Search line

Search syntax

Population1

exp Coronavirinae/

2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Intervention/comparators
4(Remdesivir or Veklury or GS-5734).mp.

5(Prednisone or Deltasone or Prednicot or Rayos or Sterapred or Orasone or A07EA03).mp.

6(Hydrocortisone or Cortef or Plenadren or NSC*10483).mp

7(Methylprednisolone or Medrol).mp.

8(Favipiravir or Favivir or Favir or Avigan or T-705).mp.

9(Budesonide or Pulmicort).mp.

10(AT-527 or RO7496998).mp.

11(REGEN-COV or REGN-COV or Regeneron).mp.
107

Confidential

Search line

Search syntax

12(casirivimab and imdevimab) or (REGN10933 and REGN10987).mp.

13(VIR-7831 or sotrovimab or GSK4182136 or Xevudy).mp.

14

Camostat mes*late.mp.

15(Nitazoxanide or Alinia).mp.

16(Colchicine or Colcrys or Mitigare).mp.

17(Molnupiravir or MK-4482 or EIDD-2801).mp.

18

Bamlanivimab.mp.

19(bamlanivimab and etesevimab).mp.

20

LY-CoV555.mp.

21(LY-CoV555 and LYCoV016).mp.

22((AZD7442 or AZD8895) and AZD1061).mp.

23(Regdanvimab or Regkirona or CT-P59).mp.

24

Peginterferon Lambda-1.mp.

25(Baricitinib or Olumiant).mp.

26(doxycycline and ivermectin) or (Doxteric or Stromectol).mp.

27(Famotidine or Pepcid).mp.

28(Fluvoxamine or Floxyfral or Luvox).mp.

29(Paxlovid or (nirmatrelvir and ritonavir) or PF-07321332).mp.

30(Ensitrelvir or Xocova or S-217622).mp.

31

MP-0420.mp.

32

Ensovibep.mp.
108

Confidential

Search line

Search syntax

33

ADG20.mp.

34

MP-0423.mp.

35(Kineret or anakinra).mp.

36

Lenzilumab.mp.

37(Bebtelovimab or LY-CoV1404 or LY3853113)

38(Umifenovir or Arbidol)

39(Clevudine or Levovir or Revovir)

40

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or
23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39

Included study designs
41

Randomized Controlled Trials as Topic/

42

randomized controlled trial/

43

Random Allocation/

44

Double Blind Method/

45

Single Blind Method/46

clinical trial/

47

clinical trial, phase i.pt

48

clinical trial, phase ii.pt

49

clinical trial, phase iii.pt

50

clinical trial, phase iv.pt

51controlled clinical trial.pt
109

Confidential

Search line

Search syntax

52

randomized controlled trial.pt

53

multicenter study.pt

54

clinical trial.pt

55

exp Clinical Trials as topic/

56

41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55

57(clinical adj trial$).tw

58((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw59

PLACEBOS/

60

placebo$.tw

61

randomly allocated.tw62(allocated adj2 random$).tw

63

57 or 58 or 59 or 60 or 61 or 62

64

56 or 63

Excluded study designs
65

case report.tw

66

letter/67

historical article/

68

65 or 66 or 67

69

64 not 68

70

3 and 40 and 69

Total hits110Confidential

Search line

Search syntax

71

limit 70 to yr="2021-Current" and deduplicate

For further details of the search terms and fields used in MEDLINE please see the OVID Database guide:
https://ospguides.ovid.com/OSPguides/medline.htm#advanced
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); pt: publication type; tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or
abstract only).
*

EMBASE (1974 to 2021) search strategy*, optimized with MeSH terms applicable to EMBASE, used in
September 2021 (first update search)
Search line

Search syntax

Population1

exp Coronavirinae/d2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Intervention/comparators
4(Remdesivir or Veklury or GS-5734).mp.

5(Prednisone or Deltasone or Prednicot or Rayos or Sterapred or Orasone or A07EA03).mp.

6(Hydrocortisone or Cortef or Plenadren or NSC*10483).mp

7(Methylprednisolone or Medrol).mp.

8(Favipiravir or Favivir or Favir or Avigan or T-705).mp.

9(Budesonide or Pulmicort).mp.

10(AT-527 or RO7496998).mp.
111

Confidential

Search line

Search syntax

11(REGEN-COV or REGN-COV or Regeneron).mp.

12(casirivimab and imdevimab) or (REGN10933 and REGN10987).mp.

13(VIR-7831 or sotrovimab or GSK4182136 or Xevudy).mp.

14

Camostat mes*late.mp.

15(Nitazoxanide or Alinia).mp.

16(Colchicine or Colcrys or Mitigare).mp.

17(Molnupiravir or MK-4482 or EIDD-2801).mp.

18

Bamlanivimab.mp.

19(bamlanivimab and etesevimab).mp.

20

LY-CoV555.mp.

21(LY-CoV555 and LYCoV016).mp.

22((AZD7442 or AZD8895) and AZD1061).mp.

23(Regdanvimab or Regkirona or CT-P59).mp.

24

Peginterferon Lambda-1.mp.

25(Baricitinib or Olumiant).mp.

26(doxycycline and ivermectin) or (Doxteric or Stromectol).mp.

27(Famotidine or Pepcid).mp.

28(Fluvoxamine or Floxyfral or Luvox).mp.

29(Paxlovid or (nirmatrelvir and ritonavir) or PF-07321332).mp.

30(Ensitrelvir or Xocova or S-217622).mp.

31

MP-0420.mp.
112

Confidential

Search line

Search syntax

32

Ensovibep.mp.

33

ADG20.mp.

34

MP-0423.mp.

35(Kineret or anakinra).mp.

36

Lenzilumab.mp.

37(Bebtelovimab or LY-CoV1404 or LY3853113)

38(Umifenovir or Arbidol)

39(Clevudine or Levovir or Revovir)

40

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or
23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39

Included study designs
41

Clinical Trial/

42

Randomized Controlled Trial/

43

controlled clinical trial/

44

multicenter study/

45

Phase 3 clinical trial/

46

Phase 4 clinical trial/

47

RANDOMIZATION/

48

Single Blind Procedure/

49

Double Blind Procedure/

50

Crossover Procedure/113

Confidential

Search line

Search syntax

51

PLACEBO/

52

randomi?ed controlled trial$.tw.

53

rct.tw.

54(random$ adj2 allocat$).tw.

55

single blind$.tw.

56

double blind$.tw.

57((treble or triple) adj blind$).tw.

58

Placebo$.tw.

59

Prospective Study/

60

41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58
or 59

Excluded study designs
61

Case Study/

62

case report.tw.

63

abstract report/ or letter/

64

editorial/

65

letter/

66

note/

67

61 or 62 or 63 or 64 or 65 or 66

68

60 not 67

69

3 and 40 and 68
114

Confidential

Search line

Search syntax

Total hits
70limit 69 to yr="2021-Current"

For further details of the search terms and fields used in EMBASE please see the OVID Database guide: https://ospguides.ovid.com/OSPguides/embase.htm
mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or abstract only).

*115

Confidential

別添 4： SLR4 に用いた検索式
SLR 4: December 2022 (updated search)
Embase and MEDLINE (MEDLINE and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed
Citations, Daily and Versions) search strategy*, optimized with MeSH terms applicable to EMBASE, used in
December 2022 (updated search)

Search line

Search syntax

Population1

exp Coronavirinae/

2(coronavirus or covid or covid19 or sars-cov-2 or sarscov2 or Sars-coronavirus-2 or Severe AcuteRespiratory Syndrome Coronavirus 20 or 2019-nCoV).mp.

3

1 or 2

Intervention/comparators
4(Remdesivir or Veklury or GS-5734).mp.

5(Prednisone or Deltasone or Prednicot or Rayos or Sterapred or Orasone or A07EA03).mp.

6(Hydrocortisone or Cortef or Plenadren or NSC*10483).mp

7(Methylprednisolone or Medrol).mp.

8(Favipiravir or Favivir or Favir or Avigan or T-705).mp.

9(Budesonide or Pulmicort).mp.

10(AT-527 or RO7496998).mp.

11(REGEN-COV or REGN-COV or Regeneron).mp.
116

Confidential

Search line

Search syntax

12(casirivimab and imdevimab) or (REGN10933 and REGN10987).mp.

13(VIR-7831 or sotrovimab or GSK4182136 or Xevudy).mp.

14

Camostat mes*late.mp.

15(Nitazoxanide or Alinia).mp.

16(Colchicine or Colcrys or Mitigare).mp.

17(Molnupiravir or MK-4482 or EIDD-2801).mp.

18

Bamlanivimab.mp.

19(bamlanivimab and etesevimab).mp.

20

LY-CoV555.mp.

21(LY-CoV555 and LYCoV016).mp.

22((AZD7442 or AZD8895) and AZD1061).mp.

23(Regdanvimab or Regkirona or CT-P59).mp.

24

Peginterferon Lambda-1.mp.

25(Baricitinib or Olumiant).mp.

26(doxycycline and ivermectin) or (Doxteric or Stromectol).mp.

27(Famotidine or Pepcid).mp.

28(Fluvoxamine or Floxyfral or Luvox).mp.

29(Paxlovid or (nirmatrelvir and ritonavir) or PF-07321332).mp.

30(Ensitrelvir or Xocova or S-217622).mp.

31

MP-0420.mp.

32

Ensovibep.mp.
117

Confidential

Search line

Search syntax

33

ADG20.mp.

34

MP-0423.mp.

35(Kineret or anakinra).mp.

36

Lenzilumab.mp.

37(Bebtelovimab or LY-CoV1404 or LY3853113)

38(Umifenovir or Arbidol)

39(Clevudine or Levovir or Revovir)

40

or/4-39

Included study design
41

Randomized Controlled Trials as Topic/

42

randomized controlled trial/

43

Random Allocation/

44

Double Blind Method/

45

Single Blind Method/46

clinical trial/

47

clinical trial, phase i.pt

48

clinical trial, phase ii.pt

49

clinical trial, phase iii.pt

50

clinical trial, phase iv.pt

51controlled clinical trial.pt

52

randomized controlled trial.pt
118

Confidential

Search line

Search syntax

53

multicenter study.pt

54

clinical trial.pt

55

exp Clinical Trials as topic/

56

or/41-557(clinical adj trial$).tw

58((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw59

PLACEBOS/

60

placebo$.tw

61

randomly allocated.tw62(allocated adj2 random$).tw

63

or/57-62

64

56 or 63

Excluded study design
65

case report.tw

66

letter/67

historical article/

68

65 or 66 or 67

69

64 not 68

Total hits
71*

3 and 40 and 69

For further details of the search terms and fields used in EMBASE please see the OVID Database guide: https://ospguides.ovid.com/OSPguides/embase.htm

119Confidential

mp: multi-purpose (i.e. mp after a search term will search for references where this term appears across several fields including the title, abstract, subject
heading and author keywords); tw: text word (i.e. tw after a search term will search for reference where the word appears in the title or abstract only).

ICHUSHI search strategy used in December 2022

Search line

Search syntax

Population
1(コロナウイルス科/TH or コロナウイルス科/AL)2(コロナウイルス/TH or コロナウイルス/AL or Coronavirus/AL or コビッド/AL or Covid/AL or COVID-19/TH or
COVID-19/AL or コビッド-19/AL or コビッド・ナインティーン/AL or SARS コロナウイルス-2/TH or SARS-COV2/AL or SARSCOV2/AL or SARS-Coronavirus-2/AL or 重症急性呼吸器症候群コロナウイルス 2/AL or 2019nCoV/AL or Novel/AL and (コロナウイルス/TH or Coronavirus/AL) or 新型コロナウイルス/AL)

3#1 or #2

Intervention/comparators
4(Remdesivir/TH or レムデシビル/AL or Veklury/AL or ベクルリー/AL or GS-5734/AL)

5(Prednisone/TH or Prednisone/AL or プレドニゾン/AL or Deltasone/AL or デルタゾン/AL or Prednicort/AL or プ
レドニコート/AL or Rayos/AL or レイオス/AL or Sterapred/AL or ステラプレド/AL or Orasone/AL or オラソン/AL or
A07EA03/AL)

6(Hydrocortisone/TH or Hydrocortisone/AL or ヒドロコルチゾン/AL or Cortef/AL or コルテフ/AL or Plenadren/AL
or プレナドレン/AL or "NSC 10483"/AL)

7(Methylprednisolone/TH or Methylprednisolone/AL or メチルプレドニゾロン/AL or Medrol/AL or メドロール/AL)

8(Favipiravir/TH or Favipiravir/AL or ファビピラビル/AL or Favivir/AL or ファビビル/AL or Avifavir/AL or アビファビ
ル/AL or Avigan/AL or アビガン/AL or T-705/AL)

9(Budesonide/TH or Budesonide/AL or ブデソニド/AL or Pulmicort/AL or パルミコート/AL)120

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10AT-527/AL or RO7496998/AL

11(REGEN-COV/AL or REGN-COV/AL or Regeneron/AL or 抗体カクテル療法/AL)12(Casirivimab/TH or Casirivimab/AL or カシリビマブ/AL) and (Imdevimab/TH or imdevimab/AL or イムデビマブ/AL) or ((Casirivimab/TH or REGN10933/AL) and (Imdevimab/TH or REGN10987/AL)) or (CasirivimabImdevimab/TH or カシリビマブ・イムデビマブ/AL)

13(Sotrovimab/TH or ソトロビマブ/AL or VIR-7831/AL or GSK4182136/AL)

14(Camostat/TH or "Camostat mesylate"/AL and カモスタットメシル酸塩/AL)

15(Nitazoxanide/TH or Nitazoxanide/AL or ニタゾキサニド/AL or Alinia/AL or アリニア/AL)

16(Colchicine/TH or Colchicine/AL or コルヒチン/AL or Colcrys/AL or Mitigare/AL)

17(Molnupiravir/TH or Molnupiravir/AL or モルヌピラビル/AL or MK-4482/AL or EIDD-2801/AL)

18(Bamlanivimab/TH or Bamlanivimab/AL or バムラニビマブ/AL)

19(Bamlanivimab/TH or Bamlanivimab/AL or バムラニビマブ/AL) and (エテセビマブ/AL or etesevimab/AL)

20

LY-CoV555/AL

21

LY-CoV555/AL and LYCoV016/AL

22(AZD7442/AL or AZD8895/AL) and AZD1061/AL

23(Regdanvimab/AL or レグダンビマブ/AL) or (Regkirona/AL or レッキロナ/AL) or CT-P59/AL

24

Peginterferon Lambda-1/AL or ペグインターフェロンラムダ-1/AL

25(Baricitinib/TH or Baricitinib/AL or バリシチニブ/AL or Olumiant/AL or オルミエント/AL)

26((Doxycycline/TH or Doxycycline/AL or ドキシサイクリン/AL) and (Ivermectin/TH or Ivermectin/AL or イベルメ
クチン/AL)) or ((Doxycycline/TH or Doxteric/AL or ドクステリック/AL) or (Ivermectin/TH or Stromectol/AL or
ストロメクトール/AL))
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27(Famotidine/TH or Famotidine/AL or ファモチジン/AL or Pepcid/AL or ペプシッド/AL or ペプシド/AL)

28(Fluvoxamine/TH or Fluvoxamine/AL or フルボキサミン/AL or Floxyfral/AL or フロキシフラル/AL or Luvox/AL or
ルボックス/AL)

29(Nirmatrelvir/TH or ニルマトレルビル/AL or PF-07321332/AL)

30(Ensitrelvir/TH or ゾコーバ/AL) or (Ensitrelvir/TH or エンシトレルビル/AL) or (Ensitrelvir/TH or S-217622/AL)

31

MP0420/AL

32

Ensovibep/AL

33

ADG20/AL

34

MP-0423/AL

35(Anakinra/TH or Kineret/AL) or (Anakinra/TH or anakinra/AL)

36

Lenzilumab/AL or レンジルマブ/AL37(Bebtelovimab/TH or Bebtelovimab/AL) or (Bebtelovimab/TH or ベブテロビマブ/AL) or (Bebtelovimab/TH or
LY-CoV1404/AL) or (Bebtelovimab/TH or LY3853113/AL)

38(Umifenovir/TH or Arbidol/AL) or (Umifenovir/TH or umifenovir/AL) or (Umifenovir/TH or ウミフェノビル/AL)

39

Levovir/AL or Revovir/AL or (Clevudine/TH or clevudine/AL) or (Clevudine/TH or クレブジン/AL)

40#4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or#31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39

Included study designs
41(ランダム化比較試験/TH or RCT/AL) or ((((ランダム化比較試験/TH or ランダム化/AL) or (ランダム割付け/TH or
ランダム化/AL)) or ((ランダム化比較試験/TH or 無作為化/AL) or (ランダム割付け/TH or 無作為化/AL))) and122

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Search syntax(比較試験/AL or 対照試験/AL))42

ランダマイズ/AL and コントロール/AL and トライアル/AL

43(ランダム/AL or 無作為/AL) and 割り付け/AL

44(二重盲検法/TH or 二重盲検/AL)

45

盲検/AL

46

(臨床試験/TH or 臨床試験/AL)

47(臨床試験/TH or 臨床試験/AL) and (第 I 相/AL or 第 1 相/AL or フェーズ 1/AL or フェーズ I/AL)

48(臨床試験/TH or 臨床試験/AL) and (第 II 相/AL or 第 2 相/AL or フェーズ 2/AL or フェーズ II/AL)

49(臨床試験/TH or 臨床試験/AL) and (第 III 相/AL or 第 3 相/AL or フェーズ 3/AL or フェーズ III/AL)

50(臨床試験/TH or 臨床試験/AL) and (第 IV 相/AL or 第 4 相/AL or フェーズ 4/AL or フェーズ IV/AL or 市販後/AL)

51

比較臨床試験/AL

52("ランダム化比較試験"/TH or "randomized controlled trial"/AL)

53

多施設/AL and 試験/AL

54("臨床試験"/TH or "clinical trial"/AL)55

クリニカルトライアル/AL

56#41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or#55

57

クリニカル/AL and トライアル/AL

58(single/AL or double/AL or trebe/AL or triple/AL) and ((視覚障害者/TH or blind/AL) or (マスク/TH or
mask/AL))59(プラセボ/TH or プラセボ/AL)
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60(プラセボ/TH or placebo/AL)

61

randomly allocated/AL

62

ランダム/AL and アロケート/AL

63#57 or #58 or #59 or #60 or #61 or #62

64#56 or #63

Excluded study designs
65(ケース/AL or 症例/AL) and (レポート/AL or (研究/TH or 研究/AL))

66(書簡/TH or letter/AL) or レター/AL or 速報/AL

67

ヒストリカル/AL and (記事/AL or (学術論文/TH or 論文/AL) or (研究/TH or 研究/AL))68#65 or #66 or #67

69#64 not #68

70#3 and #40 and #69

Total hits
71

#70 and DT=2020/01/01:2022/12/06

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別添 5： 同定した臨床研究(論文)の詳細
Table 1. Study characteristics of RCTs for antiviral therapies
Author and year, trial
Intervention(s) andidentifier(s), enrollment,
comparator
location
Adhikari et al. 2021[16]>Favipiravir>
Placebo (mild infection)
Adhikari et al. 2021 favipiravir>
Remdesivir (moderate
infection)
Nepal
Bernal et al. 2022[17]>MOVe-OUT
NCT04575597
Multinational>

Molnupiravir: Oraladministration, 800 mg
total delivered as four
200 mg capsules, BID
for 5 days
Placebo: Oraladministration, 800 mg
delivered as four 200
mg capsules, BID for 5
days

Patient characteristics

>

>

>

Patients (aged18-80 years)
with COVID-19
confirmed with
RT-PCR
Non-hospitalized
adults with mild
or moderate
COVID-19 withlab confirmed
SARS-CoV-2
infection no
more than 5days prior to
study
randomization
At least one
developed signor symptom of
COVID-19 and at≥1 risk factor
related to severe
progression of
COVID-19

Primary (efficacy)
endpoint(s)>Clinical
improvement or
treatment failure[Note: Not stated as
primary endpoint]>
Incidence of
hospitalization
for any cause(defined as ≥24hours of acutecare in a
hospital or any
similar facility)
or death at Day
29

Secondary endpoint(s)
NR

>

>

WHO 11-point clinicalprogression scale andpatient reported signs
and symptoms
through Day 29
The time to sustained
resolution orabatement of signs or
symptoms[Note: The incidence ofadverse events was theprimary safety end point]125Confidential

Author and year, trial
identifier(s), enrollment,
location
Johnson et al. 2022b[21]Intervention(s) andcomparator>

MOVe-OUT
NCT04575597>

06/06/2021-02/10/2022(Bernal et al 2022) []Patient characteristics

Primary (efficacy)
endpoint(s)Molnupiravir: Oraladministration, 800 mg
every 12 hours for 5
days
Placebo: Oraladministration, every 12hours for 5 days>

Non-hospitalized
patients (aged≥18 years) withlaboratory
confirmed mildto-moderate
COVID-19>

Favipiravir: Oraladministration, 1800 mg(nine tablets) BID as aloading dose on Day 1,
followed by 800 mg(four tablets) BID as amaintenance dose for a
total duration of 5-7
days of therapy
Placebo: Oraladministration, 1800 mg(nine tablets) BID as aloading dose on Day 1
followed by 800 mg(four tablets) BID as amaintenance dose for a
total duration of 5-7
days of therapy>

Patients from
community
settings who had
been diagnosed
with mild
COVID-19>

Africa, Asia-Pacific region,
Europe, Latin America, North
AmericaBosaeed et al. 2022[22]>Bosaeed et al. 2022 favipiravir
Saudi Arabia>

The use of
respiratoryinterventions,(including
conventional
oxygen therapy,
a high flow
heated andhumidified
device, noninvasive
mechanicalventilation, andinvasivemechanicalventilation),
acute care visits,
and COVID-19related acutecare visits (mITT
population)
Time from startof treatment toviral clearance,
defined asconversion of
SARS-CoV-2 RTPCR results frompositive tonegative within
15 daysSecondary endpoint(s)
NR

>
>
>
>
>

Time to symptom
resolution,
hospitalization
Need to use antibiotics
within 15 days after
starting the medicine
ICU admission
Adverse events
28-day mortality

126Confidential

Author and year, trial
identifier(s), enrollment,
location
Hammond et al. 2022[23]Intervention(s) andcomparator>

EPIC-HR
NCT04960202
Multinational>

Nirmatrelvir/ritonavir:
300 mg of nirmatrelvirplus
100 mg of ritonavir
every 12 hours for 5days (10 doses total)
Placebo: Administered
every 12 hours for 5
days

Patient characteristics

>

>

>

EPIC-SR 202214>>

Nirmatrelvir/ritonavir:
Oral administration,
every 12 hours for 5days (10 doses total)
Placebo>

Confirmed
SARS-CoV-2
infection andsymptom onset
no more than 5days prior to
randomization
At least one signor symptom of
COVID-19 on the
day ofrandomization
At least one
characteristic or
coexisting
condition
associated with ahigh risk ofprogression tosevere COVID19
Patients (aged≥18 years) withconfirmed SARSCoV-2 infection 5days prior to
randomization;
initial onset of
COVID-19
signs/symptoms
within 5 days of
randomization

Primary (efficacy)
endpoint(s)>Percentage ofpatients with
COVID-19related
hospitalization
or death fromany causethrough Day 28
in the twogroups>Self-reported
sustained
alleviation of all
symptoms for 4
consecutive days

Secondary endpoint(s)>Primary comparison
analyzed similarly
among patients whose
treatment began
within 5 days after the
onset of COVID-19
signs and symptom[Note: Key endpoint]>
Detection andquantification of
SARS-CoV-2 viral loadin NP swabs by RTPCR assay>>>

Hospitalizations ordeaths
Viral load
Adverse events

127Confidential

Author and year, trial
identifier(s), enrollment,
location
Holubar et al. 2022[25]Holubar et al. 2022 favipiravir
NCT04346628

Intervention(s) andcomparator

>
>

US

Gottlieb et al. 2022[26]>

PINETREE
NCT04501952
Denmark, Spain, UK, and US>

Patient characteristics

Favipiravir: 1800 mg
BID on Day 1, then 800
mg BID on Days 2-10
Placebo: 1800 mg BID
on Day 1, then 800mg
BID on Days 2-10>

Remdesivir: IV
administration, 3-daycourse, 200 mg Day 1
and 100 mg Days 2-3
Placebo: Same asintervention

>

>

OR

>

Asymptomatic or
symptomatic
adults without
respiratory
distress who had
a positive SARSCoV-2 reverse
transcription
polymerase
chain reaction
assay (RT-PCR)
collected within
72 hours ofenrollment
Patients testing
positive for
COVID-19 within
4 days of thestart of study
with symptoms
for 7 days or lessAged 12 years orolder with atleast one risk
factor related tosevereprogression
Aged 60 years orolder with orwithout a risk
factor linked tosevereprogression

Primary (efficacy)
endpoint(s)>>Secondary endpoint(s)SARS-CoV-2
shedding
cessation,
defined as timefrom enrollment
to the first of
two consecutive
negative nasal
RT-PCRs>

COVID-19
relatedhospitalization
or death fromany cause by
Day 28

>

>

>
>

>

Incidence of
hospitalization or
emergency
department visits
Adverse events gradedfor severity

The composite of
COVID-19-related
medically attended
visits or death fromany cause by Days 14
and 28COVID-19-related
hospitalization by Days
14 and 28
The time-weighted
average change in NP
SARS-CoV-2 viral loadfrom baseline to Day 7
The time to alleviationof baseline COVID-19
symptoms ascompared with thosereported on thebaseline FLUpro Plus
questionnairecompleted before thefirst infusion

128

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Author and year, trial
identifier(s), enrollment,
location
Kumarasamy et al. 2022[29]Kumarasamy et al. 2022
molnupiravir
India

Intervention(s) andcomparator>>

Molnupiravir plus SOC:
800 mg BID ofmolnupiravir plus SOC
for 5 days
SOC

Patient characteristics>

Adults with mild
SARS-CoV-2
infection

Primary (efficacy)
endpoint(s)>Secondary endpoint(s)>Rate ofhospitalization
up to Day 14>>
Painter et al. 2021[30]>

Painter et al. 2021
molnupiravir>

Molnupiravir: 200 mg
BID of molnupiravir for
5 daysPlacebo: BID for 5 days>

Molnupiravir 200 mg:
Oral administration, 200
mg BID for 5 days
Molnupiravir 400 mg:
Oral administration, 400
mg BID for 5 days
Molnupiravir 800 mg:
Oral administration, 800
mg BID for 5 days
Matching placebo>

US

Fischer et al. 2021[31]>Fischer et al. 2021
molnupiravir [later portion of
trial]>

Fischer et al. 2022[32]>Fischer et al. 2022
molnupiravir>

NCT04405570
19/06/2020-25/01/2021

Patients withsigns andsymptoms of
COVID-19 within
7 days ofenrollment, anda positive PCR
test within 4days ofenrollment
Outpatients(unvaccinatedadults) withsigns andsymptoms of
COVID-19 within
7 days ofenrollment, anda positive PCR
test within 4days ofenrollment>

Viral loadchange (rate of
positive viralculture at Days
3 and 5)>Time to viral
RNA clearance,
as measured by
qRT-PCR,
defined as viral
RNA <1,018
copies/mL (limitof quantification)

NR

>
>
>
>

Proportion with a 2point improvement in
WHO 11-Point Clinical
Progression Scale
Rate of SARS-CoV-2
RT-PCR negativity innaso/oropharyngeal
swab at Days 5, 10
and 14
Incidence of adverse
eventsTime to infectious
virus elimination by
study end
Viral RNA change frombaseline on Days 3, 5,
7, 14, and 28
Severity and durationof self-reported
COVID-19 symptoms
Adverse events thatwere grade 3 or higher
and those that led toearly treatment
discontinuation

US

129

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Author and year, trial
identifier(s), enrollment,
location
Lowe et al. 2022a[33]Intervention(s) andcomparator

>

FLARE
NCT04499677
UK

>
>
>

Favipiravir plus
lopinavir-ritonavir: 1800
mg BID on day 1
followed by 400 mg fourtimes daily on Days 2-7
plus lopinavir-ritonavir(400 mg/100 mg BID on
Day 1, followed by 200
mg/50 mg four times
daily on Days 2-7)
Favipiravir plus placebo
Lopinavir-ritonavir plus
placebo
Placebo

Patient characteristics>

Outpatients withearly COVID-19

Primary (efficacy)
endpoint(s)>SARS-CoV-2
viral load at Day
5, accounting forbaseline viralload

Secondary endpoint(s)

>

>
>

>

The proportion ofparticipants with
undetectable viralloads at Day 5
Rate of decrease inviral load during the 7day treatment course
Duration of fever,proportion ofparticipants withmedicationrelated toxicity at
Days 7 and 14
The proportion ofparticipants admitted
to hospital or intensive
care, or dead due to a
COVID-19 related
illness130Confidential

Author and year, trial
identifier(s), enrollment,
location
Lowe et al. 2022b[34]Intervention(s) andcomparator

>

>

>

Favipiravir plus
lopinavir-ritonavir:
Favipiravir administered
at a dose of 1800 mg
BID on Day 1, followed
by 400 mg 4 times daily
from Day 2-7;Lopinavir-ritonavir given
at a dose of 400 mg/100
mg BID on Day 1,
followed by 200 mg/50
mg 4 times daily fromDay 2-7
Favipiravir plus
lopinavir-ritonavir
placebo
Favipiravir placebo plus
lopinavir-ritonavir
Placebos only>>

AT-527: 550 mg BID
AT-527: 1100 mg BID

>

FLARE
NCT04499677
06/10/20-04/11/21
UK>>

MOONSONG 2021
MOONSONG[35]

Patient characteristics>

Patients (aged18-70 years)
who had recently(within the last 5days) developed
symptoms of
COVID-19, or
who had tested
positive for
SARS-CoV-2 by
PCR and were
within 7 days ofsymptom onset,
or who wereasymptomatic
but had tested
positive by PCR
within theprevious 48
hours
Adult mild or
moderate
COVID-19
patients
High-risk
patients with
underlying
health conditions

Primary (efficacy)
endpoint(s)>Secondary endpoint(s)>Viral load
measured by
qPCR performedon saliva
samples at Day
5, accounting forthepretreatment
Day 1 viral load

>
>
>

>

>

Reduction frombaseline in theamount of
SARS-CoV-2
virus

Proportion ofparticipants with
undetectable viralloads at Day 5
Rate of decrease inviral load during the 7day treatment course
Duration of fever
Proportion ofparticipants withmedication-related
toxicity at Days 7 and
14
Proportion ofparticipants admitted
to hospital, intensive
care of dead due to
COVID-19-related
illnessNR

131

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Author and year, trial
identifier(s), enrollment,
location
Ramachandran et al.
2022[36]
Ramachandran et al. 2022
umifenovir
CTRI/2020/09/027535
India

Intervention(s) andcomparator>>

Umifenovir: Oraladministration, 800mg
BID (2 x 400 mg) for 14
days
Placebo

Patient characteristics>

Asymptomatic,
mild, ormoderatepatients (aged18-75 years) at
the time ofsigning an
informed
consent form
with a positive
NP swab test

Primary (efficacy)
endpoint(s)>>For mildasymptomaticpatients, theprimary
endpoint wastime fromrandomization tonasopharyngeal
swab negativity
by two RT-PCR
tests, for SARSCoV-2 antigens,taken 24 hours
apart
For moderatepatients, theendpoint wastime toimprovement by
one category
fromrandomizationon the WHO 8category ordinal
scale

Secondary endpoint(s)>>Time fromrandomization toclinical recovery or
deterioration,assessed at Days 0, 7,
14, 21, and 28 on the
WHO 8-category
ordinal scale
The proportion ofpatients to clinicalrecovery or
deterioration, at Days
0, 7, 14, 21, and 28
on the WHO defined 8category ordinal scale132

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Author and year, trial
identifier(s), enrollment,
location
Ruzhentsova et al.
2020[37]* **Intervention(s) andcomparator>

Ruzhentsova et al. 2021
favipiravir
NCT04501783
23/05/2020-30/06/2020
Russia>Favipiravir: Oraladministration at aloading dose of 1800 mg
BID (with a 12-hourinterval) on Day 1,
followed by amaintenance dose 800
mg BID on Days 2-10
SOC:o
Umifenovir plus
intranasal interferonalpha 2b: 200 mg
umifenovir and10000 IU/mL ofinterferon alpha 2b(3 drops in eachnasal channel fivetimes a day)ORo
Umifenovir plus
hydroxychloroquine:
200 mg umifenovir
and 400 mg BID on
Day 1 followed by
200 mg BID or 200
mg BID on Day 1
followed by 100 mg
BID ofhydroxychloroquine[Note: Both SOC groups weretreated for 10 days, and the SOC
treatment depended on theseverity of the condition of thepatient]

Patient characteristics>

Patients (aged18-60 years)
with confirmed
mild-tomoderate
COVID-19 withsigns andsymptoms of
COVID-19 within
6 days ofenrollment

Primary (efficacy)
endpoint(s)>>Time to clinicalimprovement
Time to viralclearance[Note: Both fromrandomization to Day 28]

Secondary endpoint(s)

>
>
>
>
>
>
>
>
>
>
>

Rate of clinicalimprovement at Days
7 and 14
Rate of viral clearance
at Days 3, 5, 7, 10,
14, 21, and 28
Time to bodytemperaturenormalization
Rate of resolution oflung changes on CT at
Day 14
WHO 8-Category
Ordinal Scale at Days
7 and 14
The time to resolutionof the main disease
symptoms
The rate of
hospitalization for
outpatients
The rate of artificiallung ventilation use
The rate of transfer to
ICU
The death rate
through Day 28
Safety endpoints[Note: Key secondary
endpoints were the rate ofclinical improvement at Day 7
and the rate of viral clearance
at Day 5]133

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Author and year, trial
identifier(s), enrollment,
locationYotsuyanagi et al. 2022[38]Yotsuyanagi et al. 2022 S217662/ensitrelvir
Zhao et al. 2021[39]Intervention(s) andcomparator

>
>
>
>

Zhao et al. 2021 favipiravir
NCT04333589
China

>

S-217622 (ensitrelvir):
375/125 mg
S-217622 (ensitrelvir):
750/250 mg
Placebo
Favipirivir: Orally
administered, 1600 mg(BID) on the first day,and 600 mg (BID) fromDay 2-7. After that, theresearchers decided
whether to continue
favipiravir according to
the patient’s condition,
but no more than 14days of treatment
Other drugs: Patientsassigned to the control
group received drugs
other than favipiravir
and treatment according
to the needs of thediseasePatient characteristics
NR>

Patients positive
for COVID-19 via
sputum, NP
swabs, blood,
feces, or othersamplesPrimary (efficacy)
endpoint(s)Secondary endpoint(s)>Virologicalresponse by viral
infectious titer>>

Pharmacokinetics
Safety outcomes>

The primary
outcome wastime to achievea consecutive
twice (atintervals of morethan 24 h)negative RT-PCR
result for SARSCoV-2 RNA in NP
swab andsputum sample
from the start ofthe study
treatment>

Changes of bloodroutine and C-reactive
proteinCount and proportionofT lymphocyte subsets
in peripheral blood
Changes in cytokines

>

>

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Author and year, trial
identifier(s), enrollment,
location
Khoo et al. 2022[40]Intervention(s) andcomparator>

AGILE CST-2
NCT04746183
18/11/2020-16/03/2022
UK>

Molnupiravir: Oraladministration, 800 mg
BID (every 12 h, in themorning and evening
with water) for 5 days
on Days 1-5 (or Days 16 if the first dose wasgiven in the evening),
totaling ten 800 mg
doses
Placebo: Oraladministration, BID(every 12 h; in themorning and evening
with water) for 5 days
on Days 1-5 (or Days 16 if the first dose wasgiven in the evening),
totaling ten doses

Patient characteristics>

Adult outpatients(aged ≥18
years) with PCRconfirmed, mildto-moderate
SARS-CoV-2
infection, whowere within 5days of symptom
onset

Primary (efficacy)
endpoint(s)>The time fromrandomization toa negative
SARS-CoV-2
PCR test

Secondary endpoint(s)

>

>

>

>
>

>

11-point WHO Clinical
Progression Scale for
COVID-19 at Days 15
and 2932-item NEWS2 score(UK Royal College ofPhysicians, 2017),
measuring acuteillness, at Days 15 and29
FLU-PRO (version 1.2)
questionnaire of thepresence and severityof influenza-like
symptoms across six
domains at Days 15
and 29Overall survival andmortality
Time to hospital
admission,
hospitalization rates,
duration of mechanicalventilation, duration ofoxygen use, oxygenfree days, and theincidence of peripheral
capillary oxygen
saturation of <92%
Safety135

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Author and year, trial
identifier(s), enrollment,
location
Golan et al. 2022[41]Intervention(s) andcomparator>

PRESECO
NCT04600895
01/11/2020-01/10/2021>

US, Mexico, Brazil

Favipiravir: Oraladministration, 1800 mg
BID on Day 1, followed
by 800 mg BID on Days
2-10
Placebo: Oraladministration, 9 pills
BID on Day 1, followedby 2 pills BID on Days
2-10

Patient characteristics>>>
Zhao et al. 2022[42]Zhao et al. 2022 arbidolhydrochloride
NCT04260594
Patients enrolled by
19/02/2020
China

>

>

SOC plus arbidol: Oraladministration, 200 mg
per time, 3 times a day
for 14 days
SOC: Oraladministration, 3 times
a day for 14 days>

Adult patients(aged ≥18
years) with atleast 2 moderateor severe
COVID-19
symptoms
First positive RTPCR or Rapid
Antigen assay
within 3 days ofenrollment
First symptoms
within 5 days ofenrollment
Patients (aged18-65 years)
with confirmed
severe acuterespiratory
syndrome SARSCoV-2 infection

Primary (efficacy)
endpoint(s)>>Secondary endpoint(s)Time tosustained clinicalrecovery,calculated as thenumber of days
from start ofstudy medication
to sustained
symptom
alleviation>

Negative
conversion of
SARS-CoV-2
within the first
week, defined as
the percentageof viral negativechanges
detected inpathogen nucleic
acid on Day 7
afteradministration

>

>

>
>
>

Proportion of patientswith COVID-19
progression, defined
as requiring
emergency
department visit or
hospitalization
Time to undetectable
SARS-CoV-2 load insaliva assays

Viral clearance rate in
the second week
Overall viral negative
conversion rate
Clinical recovery rate
Alleviation of clinicalsymptoms

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Author and year, trial
identifier(s), enrollment,
location
McMahon et al. 2022[43]Intervention(s) andcomparator

>

VIRCO
NCT04445467>

31/07/2020-19/09/2021

Patient characteristics

Favipiravir: Oraladministration, 1800 mg
BID on Day 1 followed
by 800 mg BID
Placebo: Oraladministration, BID>

Favipiravir: Oraladministration, 1800 mg
BID for 1 day (9 tablets
per dose) and 800 mg
BID (4 tablets per dose)
thereafter until clinicalimprovement or saliva
RT–PCR became
negative (min-max of 514 days)
Symptomatic therapy(placebo): IV fluid
administration, oxygentherapy, and medication(e.g., antipyretics,
antihistamines,
antitussives, etc.) as
required by each patient>

Australia

Sirijatuphat et al. 2022[44]>Sirijatuphat et al. 2022
favipiravir
TCTR20200514001
12/2020-06/2021
Thailand>

Adults (aged≥18 years) with
PCR confirmed
COVID-19 on NP
or combined
nose and throatswab and onset
of COVID-19
relatedsymptoms (oneor more of:fever, cough,sore throat,shortness ofbreath, fatigue,
myalgia) in theprior 5 days
Patients (aged≥18 years) with
PCR-confirmed
SARS-CoV-2
infection with
mild-tomoderate
symptoms,
without
pneumonia

Primary (efficacy)
endpoint(s)>>Secondary endpoint(s)Time tovirological cure,defined as 2
successive
swabs negative
for SARS-CoV-2
by PCR>

Time to clinicalimprovement,
defined by aNEWS of ≤1

>

>
>

>

Progression of disease
severity
Symptom resolution
SafetyViral load and time todetectable load of
SARS-CoV-2
Safety137

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Author and year, trial
identifier(s), enrollment,
location
Zou et al. 2022[45]Intervention(s) andcomparator>

Patient characteristics

Primary (efficacy)
endpoint(s)Secondary endpoint(s)Patients (aged>The time of viral>
Percentage of patients≥18 years andRNA clearance
negative for SARSZou et al. 2022 molnupiravir≤80 years) who
measured using
CoV-2 on Days 5, 7
tested positive
RT-PCR analysis
and 10ChiCTR2200056817
for SARS-CoV-2
of pharyngeal>
SafetyOmicron variant
swab
03/03/2021-21/03/2022
and had initialonset ofChina
symptoms for>≤5 days prior to
the day oftreatment
BID: twice daily; CT: computerized tomography; CTRI: Clinical Trial Registry of India; FLU-PRO: InFLUenza Patient-Reported Outcome; ICU: intensive care unit;
IU: incidence units; IV: intravenous; mg: milligram; mITT: modified intention-to-treat; NEWS: National Early Warning Score; NP: nasopharyngeal; NR: notreported; PCR: polymerase chain reaction; RT-PCR: reverse transcription polymerase chain reaction; qPCR: quantitative polymerase chain reaction; RNA:ribonucleic acid; RT-PCR: reverse transcription polymerase chain reaction; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; SCT: standard
care treatment; SOC: standard of care; UK: United Kingdom: US: United States; WHO: World Health Organization.
Molnupiravir plus basic
treatment: Oraladministration, 800 mg
BID for 5 days in thehospital plus basic
treatment (vitamin C,
lianhuaqingwen granule,and nasal irrigation)
Basic treatment>

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Table 2. Patients baseline characteristics for RCTs for antiviral therapies
Author and year, trial
Number randomized
Age (years)
identifier(s)Adhikari et al. 2021[16]Mild cases
NR>
Overall: 70
Adhikari et al. 2021>
Favipiravir: 38
favipiravir>
Placebo: 32
Moderate cases>
Overall: 20>
Favipiravir: 11>
Placebo: 9
Bernal et al. 2022[17]Median (range)>
Overall: 1433>
Overall: 43.0 (18-90)>
Molnupiravir: 716
MOVe-OUT>
Molnupiravir: 42.0>
Placebo: 717(18-90)
NCT04575597>
Placebo: 44.0 (18-88)

Sex
NR

Female, n (%)>
Overall: 735 (51.3)>
Molnupiravir arm:
384 (53.6)>
Placebo arm: 351(49.0)>>

Molnupiravir: 716
Placebo: 717

Median (range)>
Molnupiravir: 43 (1890)>
Placebo: 44 (1888)

Female, n (%)>
Molnupiravir: 380(53.5)>
Placebo: 345 (49.2)>>

Favipiravir: 112
Placebo: 119

Median (IQR)>
Favipiravir: 37 (31.545)>
Placebo: 36 (32-44)

Hammond et al.
2022[23]>>

EPIC-HR>

Overall: 2246
Nirmatrelvir-ritonavir:
1120
Placebo: 1126

Median (range)>
Overall: 46.00(18.00-88.00)>
Nirmatrelvir-ritonavir:
45.00 (18.00-86.00)>
Placebo: 46.00(18.00-88.00)

Male, female, n (%)>
Favipiravir: 72(64.2), 40 (35.7%)>
Placebo: 83 (69.7),
36 (30.2)
Male, n (%), female, n (%)>
Overall: 1148 (51.1),
1098 (48.9)>
Nirmatrelvir-ritonavir:
566 (50.5%), 554(49.5)>
Placebo: 582 (51.7),
544 (48.3)

Johnson et al.
2022b[21]MOVe-OUT
NCT04575597
Bosaeed, 2022[22]Bosaeed et al. 2022
favipiravir

NCT04960202

Time to symptom
onset (days)NR≤3 days, n (%)>
Overall: 684(47.7)>
Molnupiravir:
342 (47.8)>
Placebo: 342(47.7)Median (range)>
Molnupiravir: 4(1-5)>
Placebo: 4 (15)Median (IQR)>
Overall: 3
(2-4)

>

3 days (mITT
population
only)

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Author and year, trial
identifier(s)EPIC-SR 2022[24]Holubar et al. 2022[25]Holubar et al. 2022
favipiravir
NCT04346628

Gottlieb et al. 2022[26]
PINETREE
NCT04501952
Kumarasamy et al.
2022[29]
Kumarasamy et al. 2022
molnupiravir
Painter et al. 2021[30]
Painter et al. 2021
molnupiravir

Number randomized

Age (years)

Sex

Time to symptom
onset (days)>
Within 5 days

Interim analysis>
Nirmatrelvir-ritonavir: 333>
Placebo: 329
Follow-on analysis>
Nirmatrelvir-ritonavir: 428>
Placebo: 426

NR

NR

mITT population>
Favipiravir: 59>
Placebo: 57
smITT population>
Favipiravir: 65>
Placebo: 70

Mean (SD), mITT population>
Favipiravir: 43.4
(12.8)>
Placebo: 43.4 (12.8)
Mean (SD), smITT population>
Favipiravir: 42.9
(12.3)>
Placebo: 42.8 (12.6)

Female, mITT population, n(%)>
Favipiravir: 28(47.5%)>
Placebo: 29 (50.9%)
Female, smITT population, n(%)>
Favipiravir: 32(49.2%)>
Placebo: 37 (52.9%)>>>

Overall: 562
Remdesivir: 279
Placebo: 283

Mean (SD)>Overall: 50 (15)>Remdesivir: 50 (15)>Placebo: 51 (15)Female, n (%)>
Overall: 269 (47.9)>
Remdesivir: 131 (47)>
Placebo: 138 (48.8)>>>

Overall: 1218
Molnupiravir plus SOC: 608
SOC: 610

NR

Male, %>Overall: 173

NR

>
>

[Note: both arms werebalanced for age]
NR>

Overall: 65
Molnupiravir plus
SOC: NR
SOC: NRMedian (IQR), mITT
population>
Favipiravir: 5(3-7)>
Placebo: 5 (46)Median (IQR), smITT
population,>
Favipiravir: 5(3-7)>
Placebo: 5 (47)>Within 7 days

NR

Median (range)>
Overall: 4.62
(1.40-7.54)

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Author and year, trial
identifier(s)Fischer et al. 2021[31]Fischer et al. 2021
molnupiravir [later
portion of trial]

Number randomized
Molnupiravir 200 mg: 23
Molnupiravir 400 mg: 62
Molnupiravir 800 mg: 55
Placebo: 62

Median (range)>
Molnupiravir 200 mg:
32.0 (19-65)>
Molnupiravir 400 mg:
42.5 (19-82)>
Molnupiravir 800 mg:
42.0 (18-68)>
Placebo: 39.0 (19-71)

Female, n (%)>
Molnupiravir 200 mg:
11 (47.8)>
Molnupiravir 400 mg:
32 (51.6)>
Molnupiravir 800 mg:
27 (49.1)>
Placebo: 34 (54.8)>>

Overall: 240
Favipiravir plus
lopinavir-ritonavir: 61
Favipiravir plus placebo: 59
Lopinavir-ritonavir plus
placebo: 60
Placebo: 60

Mean (SD)>Overall: 40.6 (12.2)>
Favipiravir plus
lopinavir-ritonavir:
40.3 (13.1)>
Favipiravir plus
placebo: 40.3 (12.1)>
Lopinavir-ritonavirplus placebo: 38.6
(11.5)>
Placebo: 40.6 (12.2)

Male, female, n (%)>
Overall: 123 (51.2),
117 (48.8)>
Favipiravir plus
lopinavir-ritonavir: 31(50.8), 30 (49.2)>
Favipiravir plus
placebo: 32 (54.2),
27 (45.8)>
Lopinavir-ritonavirplus placebo: 29(48.3), 31 (51.7)>
Placebo: 31 (51.7),
29 (48.3)

NCT04405570

FLARE
NCT04499677

Sex

>
>
>
>

Fischer et al. 2022[32]Lowe et al. 2022a[33]Age (years)>>>

Time to symptom
onset (days)
Median (range)>
Molnupiravir
200 mg: 4.00
(1.8 to 7.0)>
Molnupiravir
400 mg: 4.85
(2.5 to 7.1)>
Molnupiravir
800 mg: 4.60
(1.4 to 7.1)>
Placebo: 4.55
(1.8 to 7.5)
≤5 days, >5 days, n(%)>
Overall: 157(65.7), 82(34.3)>
Favipiravir plus
lopinavirritonavir: 43(70.5), 19(29.5)>
Favipiravir plus
placebo: 39(66.1), 20(33.9)>
Lopinavirritonavir plus
placebo: 38(63.3), 22(36.7)>
Placebo: 37(62.7), 22(37.3)

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Author and year, trial
identifier(s)Lowe et al. 2022b[34]FLARE
NCT04499677

Number randomized

>
>
>
>
>

MOONSONG 2021[35]
MOONSONG

Overall: 240
Favipiravir plus lopinavirritonavir: 61
Favipiravir plus placebo: 59
Lopinavir-ritonavir plus
placebo: 60
Placebo: 60

Prespecified subgroup analysis>
AT-527 550 mg: 7>
Placebo: 11
Exploratory subgroup analysis>
AT-527 1100 mg: 7>
Placebo: 11

Age (years)

Sex

Mean (SD)>Overall: 40 (12.2)>
Favipiravir plus
lopinavir-ritonavir:
40.3 (13.1)>
Favipiravir plus
placebo: 40.3 (12.1)>
Lopinavir-ritonavirplus placebo: 38.6
(11.5)>
Placebo: 40.6 (12.2)

Male, female, n (%)>
Overall: 123 (51.2),
117 (48.8)>
Favipiravir plus
lopinavir-ritonavir: 31(50.8), 30 (49.2)>
Favipiravir plus
placebo: 32 (54.2),
27 (45.8)>
Lopinavir-ritonavirplus placebo: 29(48.3), 31 (51.7)>
Placebo: 31 (51.7),
29 (48.3)

Mean

NR

>

Overall: 37

Time to symptom
onset (days)≤5 days, >5 days, n(%)>
Overall: 157(65.7), 82(34.3)>
Favipiravir plus
lopinavirritonavir: 43(70.5), 18(29.5)>
Favipiravir plus
placebo: 39(66.1), 20(33.9)>
Lopinavirritonavir plus
placebo: 38(63.3), 22(36.7)>
Placebo: 37(62.7), 22(37.3)NR

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Author and year, trial
identifier(s)Ramachandran et al.
2022[36]
Ramachandran et al.
2022 umifenovir

Number randomized

Age (years)

Sex

Umifenovir: 60
oMild/asymptomatic: 40oModerate: 20
Placebo: 63
oMild/asymptomatic: 42oModerate: 21

Mean (SE)>Umifenovir: 46.08(1.93)
oMildasymptomatic:
42.35 (2.38)
oModerate: 53.55(2.61)>
Placebo: 47.35 (1.96)
oMildasymptomatic:
45.50 (2.45)oModerate: 51.05(3.71)>

Favipiravir: 112 (83outpatients)
SOC: 56 (44 outpatients)

Mean (SD)>
Favipiravir: 41.7
(10.6)>
SOC: 42.0 (10.4)

Male, female, n (%)>
Umifenovir: 48 (80),
12 (20)o
Mildasymptomatic:
31 (78), 9 (23)oModerate: 17(85), 3 (15)>Placebo: 44 (70), 19(30)
oMildasymptomatic:
28 (67), 14 (33)Moderate: 16o(78), 5 (24)Male, n (%)>
Favipiravir: 63 (56.2)>
SOC: 26 (46.6)>>>

Overall: 46
Ensitrelvir 375/125 mg: 23
Ensitrelvir 750/250 mg: 23

NR

NR

Mean (SD)>Overall: 55.7 (13.6)>
Favipiravir: 55.8
(14.2)>
Control: 55.5 (12.6)

Female, male, n (%)>
Overall: 30 (54.5), 25(45.5)>
Favipiravir: 20(55.6), 16 (44.4)>
Control: 10 (52.6), 9(47.4)>>

CTRI/2020/09/027535

Ruzhentsova et al.
2020[37]* **Ruzhentsova et al. 2021
favipiravir>

NCT04501783
Yotsuyanagi et al.
2022[38]
Yotsuyanagi et al. 2022
S-217622/ensitrelvir

Zhao et al. 2021[39]Zhao et al. 2021
favipiravir
NCT04333589[Note: Numbers reported assume
no participants discontinued thestudy]>Overall: 55>
Favipiravir: 36>
Control: 19

Time to symptom
onset (days)
No more than 7 days
(for mild cases)

Mean (SD), ≤3 days, 4
to 6 days, n (%)>
Favipiravir: 3.5(1.4), 53(47.3), 59(52.7)>
SOC: 3.6 (1.4),
24 (42.9), 32(57.1)NR

NR

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Author and year, trial
identifier(s)Khoo et al. 2022[40]AGILE CST-2

Number randomized>>>

Overall: 180
Molnupiravir: 90
Placebo: 90

Median (IQR)>
Overall: 43 (28-55)>
Molnupiravir: 45 (3155)>
Placebo: 43 (28-54)

Male, female, n (%)>
Overall: 77 (43), 103(57)>
Molnupiravir: 38(42), 52 (58)>Placebo: 39 (43), 51(57)

Time to symptom
onset (days)
Median (IQR)>
Overall: 3.0(3.0-4.0)>
Molnupiravir:
3.5 (3.0-4.0)>
Placebo: 3.0(3.0-4.0)>>

Favipiravir: 599
Placebo: 588

Aged <60 years, n (%)>
Favipiravir: 506(84.5)>
Placebo: 506 (86.1)
Aged ≥60 years, n (%)>
Favipiravir: 93 (15.5)>
Placebo: 82 (13.9)

Male, n (%), female, n (%)>
Favipiravir: 282(47.1), 317 (52.9)>
Placebo: 261 (44.4),
327 (55.6)

Median (min-max)>
Favipiravir: 3(0-6)>
Placebo: 3 (07)>>>Overall: 97
SOC plus arbidol: 64
SOC: 33

Mean (SD)>Overall: 46.51(11.23)>
SOC plus arbidol:46.16 (11.21)>
SOC: 47.18 (11.42)

Male, n (%)>
Overall: 44 (45.4)>
SOC plus arbidol: 27(42.2)>
SOC: 17 (51.5)

NR

>
>

Favipiravir: 99
Placebo: 100

Median (IQR)>
Favipiravir: 36.0
(28.0-49.0)>
Placebo: 35.0 (27.552.5)

Male, n (%)>
Favipiravir: 55 (55.6)>
Placebo: 54 (54.0)

NR

>
>

Favipiravir: 64
Placebo: 32

Median (IQR)>
Favipiravir: 32 (2739)>
Placebo: 28 (25-35)

Male, n (%)>
Favipiravir: 21 (33.9)>
Placebo: 12 (38.7)

Median (IQR)>
Favipiravir: 0(0-7)>
Placebo: 0 (06)

NCT04746183

Golan et al. 2022[41]PRESECO
NCT04600895

Zhao et al. 2022[42]Zhao et al. 2022 arbidolhydrochloride
NCT04260594
McMahon et al.
2022[43]
VIRCO
NCT04445467
Sirijatuphat et al.
2022[44]
Sirijatuphat et al. 2022
favipiravir

Age (years)

Sex

TCTR20200514001

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Author and year, trial
identifier(s)Zou et al. 2022[45]Number randomized>

Age (years)

Sex

Time to symptom
onset (days)≤5 days prior to the dayof treatment

Median (range)
Male, n (%)>
Molnupiravir plus>
Molnupiravir plus
Zou et al. 2022
basic treatment: 39
basic treatment: 43>
molnupiravir(20-63)(55.8)>
Basic treatment: 42>
Basic treatment: 17
ChiCTR2200056817(22-61)(54.8)
CTRI: Clinical Trial Registry of India; IQR: interquartile range; mg: milligram; ITT: intention-to-Treat; mITT: modified intention-to-treat population; NR: notreported; RCT: randomized controlled trial; SD: standard deviation; SE: standard error; smITT: symptomatic modified intention-to-treat population; SOC:
standard of care; US: United States.
Molnupiravir plus basic
treatment: 80
Basic treatment: 36145

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Table 3. Results from RCTs assessing antiviral therapies; primary outcome(s)Author and year, trial
Primary efficacy outcome(s)identifier(s)Adhikari et al. 2021[16]Mild cases>
Clinical improvement, n (%):
Adhikari et al. 2021 favipiraviroFavipiravir: 30 (78.9)oPlacebo: 27 (84.4)>
Treatment failure, n (%):
oFavipiravir: 8 (21.1)
oPlacebo: 5 (15.6)

Bernal et al. 2022[17]MOVe-OUT
NCT04575597

Johnson et al. 2022b[20]MOVe-OUT
NCT04575597

Moderate cases>
Clinical improvement, n (%):
oFavipiravir: 9 (81)oPlacebo: 8 (88.9)>
Treatment failure, n (%):
oFavipiravir: 2 (18.2)
oPlacebo: 1 (11.1)
Number of hospitalizations or deaths through Day 29 in
all-randomized sample, n (%)>
Molnupiravir: 48/709 (6.8)>
Placebo: 68/699 (9.7)>
Difference: -3.0% (95% CI: -5.9 to -0.1)

Proportion of patients requiring all respiratoryinterventions (mITT population), n (%)>
Molnupiravir: 42 (5.9)>
Placebo: 63 (9.0)>
RRR (95% CI): 34.3% (4.3-54.9)

Safety outcome(s)Patients who experienced an AE, n (%)>
Favipiravir: 3 (6.12)>
Remdesivir: 0 (0.0)>
Placebo: 0 (0.0)

Participants who experienced ≥1 AE, n (%)>
Molnupiravir: 216/710 (30.4)>
Placebo: 231/701 (33)>
Estimated Difference: -2.5
Participants who experienced ≥1 SAE, n (%)>
Molnupiravir: 49/710 (6.9)>
Placebo: 67/701 (9.6)>
Estimated Difference: -2.7
NR

Proportion of patients requiring all respiratoryinterventions (hospitalized mITT population), n (%)>
Molnupiravir: 31 (64.6)>
Placebo: 55 (82.1)>
RRR (95% CI): 21.3% (0.2-38.0)

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Author and year, trial
identifier(s)Bosaeed et al. 2022[22]Bosaeed et al. 2022 favipiravir

Hammond et al. 2022[23]EPIC-HR
NCT04960202

Primary efficacy outcome(s)Safety outcome(s)Time (days) to viral clearance within 15 days, median(IQR)>
Favipiravir: 10 (6-12)>
Placebo: 8 (6-12)>
HR: 0.87 for the favipiravir group (95% CI:
0.571-1.326; p=0.51)

NR[Note: Endpoints for hospitalization or death are alsoavailable in the DEF]
COVID-19-related hospitalization or all-cause mortality by
Day 28 (interim analysis), n (%)>
Nirmatrelvir plus ritonavir: 3/389 (0.77)>
Placebo: 27/385 (7.01)>
Difference: -6.32% (95% CI: -9.04 to -3.59;
P<0.001)>
RRR: 89.1%

Patients who experienced an AE, n (%)>
Nirmatrelvir plus ritonavir: 251/1109 (22.6)>
Placebo: 266/1115 (23.9)
Patients who experienced a SAE, n (%)>
Nirmatrelvir plus ritonavir: 18/1109 (1.6)>
Placebo: 74/1115 (6.6)

COVID-19-related hospitalization or all-cause mortality by
Day 28 (final analysis), n (%)>
Nirmatrelvir plus ritonavir: 5/697 (0.72)>
Placebo: 44/682 (6.53)>
Difference ([95% CI], p-value): -5.81
percentage points ([-7.78 to -3.84], P<0.001)>
RRR: 88.9%

EPIC-SR 2022[24][Note: Further endpoints for hospitalization or death areavailable in the DEF]
Incidence of hospitalization or death (interim analysis), n>Nirmatrelvir plus ritonavir: 2/333>
Placebo: 8/329
Incidence of hospitalization or death (follow on analysis),n>Nirmatrelvir plus ritonavir: 3/428>
Placebo: 10/426>
Reduction: 70%, p=0.051

Patients who experienced a TEAE, %>Nirmatrelvir plus ritonavir: 22>
Placebo: 21
Patients who experienced a SAE, %:>Nirmatrelvir plus ritonavir: 1.4>
Placebo: 1.9147

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Author and year, trial
identifier(s)Holubar et al. 2022[25]Holubar et al. 2022 favipiravir
NCT04346628

Gottlieb et al. 2022[26]
PINETREE
NCT04501952

Kumarasamy et al. 2022[29]Kumarasamy et al. 2022
molnupiravir

Painter et al. 2021[30]
Painter et al. 2021 molnupiravir

Primary efficacy outcome(s)Safety outcome(s)Time (days) until shedding cessation, median (IQR)>
Favipiravir: 14 (9-21)>
Placebo: 13 (9-14)>
Adjusted HR: 0.76 (CI: 0.481.20; p=0.24)

Occurrence of AEs through Day 28, n>
Favipiravir: 27>
Placebo: 15[Note: Endpoints for hospitalization are also available in
the DEF]COVID-19-related hospitalization or all-cause mortality by
Day 28, n (%)>
Remdesivir: 2/279 (0.7)>
Placebo: 15/283 (5.3)>
Risk reduction: 87%>
HR ([95% CI], p-value): 0.13 ([0.03-0.59],
p=0.008)
Proportion of patients requiring hospitalization by Day 14,n (%)>
Molnupiravir plus SOC: 9 (1.5)>
SOC: 26 (4.3)

Patients receiving molnupiravir were more likely to have anegative viral culture versus placebo at Day 3 (p=0.56)
and Day 5 (p=0.001)

Occurrence of AEs, n (%)>
Remdesivir: 118/279 (42.3)>
Placebo: 131/283 (46.3)
Occurrence of SAEs, n (%)>
Remdesivir: 5/279 (1.8)>
Placebo: 19/283 (6.7)
Patients who experienced a mild and self-limiting AE, %>Molnupiravir plus SOC: 4.8>
SOC: 2.6
Patients who experienced a SAE, %>Molnupiravir plus SOC: 0>
SOC: 0NR[Note: Total patients analyzed n=78]

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Author and year, trial
identifier(s)Fischer et al. 2021[31]Fischer et al. 2021 molnupiravir[later portion of trial]
Fischer et al. 2022[32]
NCT04405570

Lowe et al. 2022a[33]FLARE
NCT04499677

Primary efficacy outcome(s)Safety outcome(s)Time (days) to viral clearance, median (95% CI)>
Molnupiravir 200 mg: 22 (15.0-28.0)>
Molnupiravir 400 mg: 27 (15.0-28.0)>
Molnupiravir 800 mg: 14 (13.0-14.0)>
Placebo: 15 (15.0-27.0)

Patients who experienced an AE, n (%)>
Molnupiravir 200 mg: 11 (48)>
Molnupiravir 400 mg: 20 (32)>
Molnupiravir 800 mg: 11 (20)>Placebo: 18 (29)

Molnupiravir 800 mg was significantly superior to placebo(p=0.013), and the placebo was non-significantly
superior to molnupirvir 200 mg and 400 mg (p>0.5)

Patients who experienced any AE leading to death, n>
Molnupiravir 200 mg: 0>
Molnupiravir 400 mg: 0>
Molnupiravir 800 mg: 0>
Placebo: 1

Undetectable viral load (log10) at Day 5 (ITT population)accounting for baseline viral load, coefficient ([95%CI], p-value)>
Favipiravir plus lopinavir-ritonavir: 0.59 ([-0.32
to 1.50], p=0.20)>
Favipiravir plus placebo: -0.57 ([-1.21 to 0.07],
p=0.08)>Lopinavir-ritonavir plus placebo: -0.18 ([-0.82 to0.46], p=0.58)
Undetectable viral load (log10) at Day 5 (ITT population)accounting for baseline viral load, coefficient ([95%CI], p-value)>
Favipiravir plus lopinavir-ritonavir: 0.65 ([-0.33
to 1.63], p=0.19)>
Favipiravir plus placebo: -0.59 ([-1.29 to 0.11],
p=0.10)>
Lopinavir-ritonavir plus placebo: -0.18 ([-0.87 to0.51], p=0.61)

Patients who experienced a SAE, n (%)>
Molnupiravir 200 mg: 0 (0)>Molnupiravir 400 mg: 2 (3)>Molnupiravir 800 mg: 1 (2)>Placebo: 1 (2)Patients who experienced ≥1 related AE, n (%)>
Favipiravir plus lopinavir-ritonavir: 53 (87.9)>
Favipiravir plus placebo: 27 (45.8)>
Lopinavir-ritonavir plus placebo: 56 (93.3)>
Placebo: 21 (35.0)
Number of related AEs, n (%)>
Favipiravir plus lopinavir-ritonavir: 108 (67.9)>
Favipiravir plus placebo: 44 (47.3)>
Lopinavir-ritonavir plus placebo:116 (65.9)>
Placebo: 27 (29.3)

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Author and year, trial
identifier(s)Lowe et al. 2022b[34]FLARE
NCT04499677

MOONSONG 2021[35]
MOONSONG

Ramachandran et al. 2022[36]Ramachandran et al. 2022
umifenovir
CTRI/2020/09/027535

Primary efficacy outcome(s)Safety outcome(s)Change in viral load at Day 5 (ITT population) accounting
for baseline viral load, coefficient ([95% CI], p-value)>
Favipiravir plus lopinavir-ritonavir: 0.59 ([-0.32
to 1.50], p=0.20)>
Favipiravir plus placebo: -0.57 ([-1.21 to 0.07],
p=0.08)>Lopinavir-ritonavir plus placebo: -0.18 ([-0.82 to0.46], p=0.58)

Patients who experienced ≥1 AE, n (%)>
Favipiravir plus lopinavir-ritonavir: 55 (90.1)>
Favipiravir plus placebo: 38 (64.4)>
Lopinavir-ritonavir plus placebo: 59 (98.3)>
Placebo: 39 (65.0)

Change in viral load at Day 5 (mITT population)accounting for baseline viral load, coefficient ([95%CI], p-value)>
Favipiravir plus lopinavir-ritonavir: 0.65 ([-0.33
to 1.63], p=0.19)>
Favipiravir plus placebo: -0.59 ([-1.29 to 0.11],
p=0.10)>
Lopinavir-ritonavir plus placebo: -0.18 ([-0.87 to0.51], p=0.61)
Reduction in SARS-CoV-2 viral load from baseline to Day
7 (log10)>
AT-527 550 mg: 0.5>
AT-527 1100 mg: 0.5
Proportion of patients with NP swab negativity on Day 5, n(%)>
Umifenovir: 29/40 (73)>Placebo: 17/42 (40)>Difference: 32%, p=0.002

Patients who experienced ≥1 related AE, n (%)>
Favipiravir plus lopinavir-ritonavir: 53 (87.9)>
Favipiravir plus placebo: 27 (45.8)>
Lopinavir-ritonavir plus placebo: 56 (93.3)>
Placebo: 21 (35.0)
Occurrence of SAE, n>Favipiravir plus lopinavir-ritonavir: 1>
Favipiravir plus placebo: 1>
Lopinavir-ritonavir plus placebo: 1>
Placebo: 0
Patients who experienced an AE, %>AT-527 550 mg: 20>
AT-527 1100 mg: 27>
Placebo: 20
3 non-drug related SAEs in each of the treatment groups
Patients who experienced an AE, n>
Umifenovir: 7>
Placebo: 7[Note: the primary efficacy endpoint was “time fromrandomization to nasopharyngeal swab negativity by two
RT-PCR tests, for SARS-CoV-2 antigens, taken 24 hours
apart.” However, this was presented in a figure in the
publication and not reported clearly]

150Confidential

Author and year, trial
identifier(s)Ruzhentsova et al.
2020[37]* **Ruzhentsova et al. 2021
favipiravir
NCT04501783

Primary efficacy outcome(s)Safety outcome(s)Time (days) to clinical improvement for outpatientparticipants, median (IQR)>
Favipiravir: 6 (4-12)>
SOC: 14 (5-28)>
HR: 1.65 (95% CI: 1.08-2.52; p=0.019;
significant improvement)

Patients who experienced an AE, n (%) 1>
Favipiravir: 6/83 (7)>SOC: 14/44 (38)Time (days) to viral clearance for outpatient participants,
median (IQR)>
Favipiravir: 3 (3-3.5)>
SOC: 3 (3-7)>
HR: 1.11 (95% CI: 0.76-1.61; p=0.46; nonsignificant)Yotsuyanagi et al. 2021[38]Yotsuyanagi et al. 2021
ensitrelvir
Zhao et al. 2021[39]Zhao et al. 2021 favipiravir
NCT04333589[Note: Endpoints for hospitalization are also available in
the DEF]
Viral titer reduction compared with placebo on Day 4:>
Ensitrelvir 375/125mg: -3 log10 (TCID50/mL) (2.42 log10 (TCID50/mL) compared to baseline)>
Ensitrelvir 750/250mg: -1.54 log10 (TCID50/mL)
Time (days) to achieve negative NP and sputum swab,
median>Favipiravir: 17>
Control: 26>
HR: 2.1 (95% CI: 1.1–4.0; p=0.038; significant)Patients who experienced a SAE, n (%) 2>
Favipiravir: 2/83 (2)>SOC: 0/44 (0)NR

Occurrence of AEs, n>
Favipiravir: 12>
Control: 7*
During the third update a discrepancy between report and reference was found. Results reported in reference1. Ruzhentsova, T., et al., Phase 3 trial of coronavir(favipiravir) in patients with mild to moderate COVID-19. Social Science Research Network Preprint Repository, 2020, 2.
Ruzhentsova, T.A., et al., Phase 3 trialof coronavir (favipiravir) in patients with mild to moderate COVID-19. Am J Transl Res, 2021. 13(11): p. 12575-12587. for patients who experienced an AE:
80/108 and 33/55 for favipravir and SOC, respectively. Results reported for total population.
**
During the third update a discrepancy between report and reference was found. Results reported in reference1. Ruzhentsova, T., et al., Phase 3 trial of coronavir(favipiravir) in patients with mild to moderate COVID-19. Social Science Research Network Preprint Repository, 2020, 2.
Ruzhentsova, T.A., et al., Phase 3 trialof coronavir (favipiravir) in patients with mild to moderate COVID-19. Am J Transl Res, 2021. 13(11): p. 12575-12587. for patients who experienced a SAE:
2/108 and 1/55 favipravir and SOC, respectively. Results reported for total population.

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Author and year, trial
identifier(s)Khoo et al. 2022[40]AGILE CST-2
NCT04746183

Golan et al. 2022[41]PRESECO
NCT04600895

Primary efficacy outcome(s)Safety outcome(s)Time (days) from randomization to a negative SARS-CoV2 PCR test, median (95 CI%)> Molnupiravir: 8 (8-9)> Placebo: 11 (10-11)> Molnupiravir group versus placebo group log-rank pvalue: 0.074> Molnupiravir group versus placebo group BreslowGehan-Wilcoxon p-value: 0.032

Patients who experienced an AE, n (%)>
Molnupiravir: 73 (81)>Placebo: 68 (76)Time (days) to sustained clinical recovery (mITT
population), median (95% CI)>
Favipiravir: 7 (7-8)>
Placebo: 7 (6-8)>
Favipiravir group versus placebo group p-value:
0.8

Patients who experienced a SAE, n (%)>
Molnupiravir: 0 (0)>Placebo: 4 (4)Occurrence of treatment discontinuation, n>
Molnupiravir: 1>
Placebo: 0
Patients who experienced an AE, n (%)>
Favipiravir: 84 (13.8)>
Placebo: 89 (14.8)
Patients who experienced a SAE, n (%)>
Favipiravir: 12 (2.0)>
Placebo: 14 (2.3)
Patients who experienced a CTCAE Grade 3 or 4 TEAE, n (%)>
Favipiravir: 2 (0.3)>
Placebo: 1 (0.2)

Zhao et al. 2022[42]Zhao et al. 2022 arbidolhydrochloride
NCT04260594

Negative conversion rate of SARS-CoV-2 within the first
week, n (%)>
SOC plus arbidol: 45 (70.3)>
SOC: 14 (42.4)>
Difference ([95% CI], p-value): 27.9% ([7.748.1], p=0.008)

Occurrence of treatment discontinuation due to AE, n (%)>
Favipiravir: 7 (1.2)>
Placebo: 9 (1.5)
Patients who experienced an AE, n>
SOC plus arbidol: 18>
SOC: 5
Patients who experienced a SAE, n>
SOC plus arbidol: 0>
SOC: 0Occurrence of treatment discontinuation due to AE, n>
SOC plus arbidol: 0>
SOC: 0152

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Author and year, trial
identifier(s)McMahon et al. 2022[43]VIRCO

Primary efficacy outcome(s)Safety outcome(s)Difference in time to virological cure for favipiravir groupversus placebo group>
Log-rank p-value: 0.6

Patients who experienced ≥1 AE, n>Favipiravir: 63>
Placebo: 65

NCT04445467

Sirijatuphat et al. 2022[44]Sirijatuphat et al. 2022
favipiravir
TCTR20200514001

Zou et al. 2022[45]Zou et al. 2022 molnupiravir
ChiCTR2200056817

Patients who experienced a related AE, n>Favipiravir: 24>
Placebo: 27

Time (days) to sustained clinical improvement by NEWS,median (range)>
Favipiravir: 2 (1-28)>
Placebo: 14 (1-28)>
Favipiravir group versus placebo group p-value<0.001
Proportion of patients with clinical improvement by NEWSby Day 14, n (%)>
Favipiravir: 49 (79.0)>
Placebo: 10 (32.3)>
Favipiravir group versus placebo group p-value<0.001Time (days) for viral clearance, median (95% CI):>
Molnupiravir plus basic treatment: 9 (7-9)>
Basic treatment: 10 (9-11)>
Molnupiravir group versus basic treatment groupp-value=0.0092

Occurrence of a SAE, n>Favipiravir: 14>
Placebo: 9
Occurrence of AEs, n>
Favipiravir: 36>
Placebo: 10
Occurrence of discontinuation due to AE, n>Overall: 1

Patients who experienced a grade ≥3 AE, n (%)>
Molnupiravir plus basic treatment: 0 (0.0)>
Basic treatment: 0 (0.0)

Occurrence of treatment discontinuation due to AE, n (%)>
Molnupiravir plus basic treatment: 0 (0.0)>
Basic treatment: 0 (0.0)
AE: adverse event; ALT: alanine transaminase; AST: aspartate transaminase; COVID-19: Coronavirus disease 2019; CI: confidence interval; CTCAE: common
terminology criteria for adverse events; CTRI: Clinical Trial Registry of India; DEF: data extraction form; HR: hazard ratio; mITT: modified intention-to-treat; mg:
milligram; mL: milliliter; NEWS: National Early Warning Score; NP: nasopharyngeal; NR: not reported; IQR: interquartile range; ITT: intention-to-treat; RRR:
relative risk reduction; SAE: Serious Adverse Event; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOC: standard of care; TEAE: treatment
emergent adverse event; UK: United Kingdom; US: United States; WHO: World Health Organization.

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Table 4. RCTs assessing neutralizing antibodies
Author andSourceTitle
year
Weinreich et
The BMJREGN-COV2, a Neutralizing Antibody Cocktail, inal. 2020[46]MAGIC-WHO
Outpatients with COVID-19
Weinreich etal. 2021a[47]Reporttype
JournalarticleIdentified byresearchers,
outside of thesearches
specified in
section 2
OVID

REGEN-COV Antibody Cocktail Clinical Outcomes Study in
COVID-19 Outpatients

Journalarticle(pre-print)

REGEN-COV Antibody Cocktail Combination and Outcomesin Outpatients with COVID-19

Gupta et al.
2021[49]

NIH guidelines

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing
Antibody Sotrovimab

Gupta et al.
2022a[50]OVID

Effect of Sotrovimab on Hospitalization or Death Among
High-risk Patients with Mild to Moderate COVID-19

Shapiro et al.
2022[52]
Gupta et al.
2022c[53]CROI 2022

Chen et al.
2020[54]
Gottlieb et al.
2021[55]

OVID

Dougan et al.
2021a[56]OVID

Intramuscular sotrovimab is noninferior to intravenous
sotrovimab for COVID-19
Safety, Tolerability, and Viral Pharmacodynamics of the IgG
Monoclonal Antibody Sotrovimab Administered via
Intramuscular Injection for the Treatment of Early Mild-toModerate COVID-19
SARS-CoV-2 Neutralizing Antibody LY-CoV555 in
outpatients with COVID-19
Effect of Bamlanivimab as Monotherapy or in Combination
with Etesevimab on Viral Load in Patients with Mild toModerate COVID-19: a Randomized Clinical Trial
Bamlanivimab + etesevimab for treatment of COVID-19 inhigh-risk ambulatory patients

Journalarticle(published)
Journalarticle(pre-print)
Journalarticle(published)
Conference
abstract
Conference
abstract

Dougan et al.
2021b[57]OVID

Bamlanivimab plus Etesevimab in Mild or Moderate COVID19

JournalarticleDougan et al.
2022[59]

OVID

A Randomized, Placebo-Controlled Clinical Trial of
Bamlanivimab and Etesevimab Together in High-Risk
Ambulatory Patients With COVID-19 and Validation of the
Prognostic Value of Persistently High Viral Load

JournalarticleWeinreich etal. 2021b[48]

December ID
Week 2022

OVID

JournalarticleJournalarticleConference
abstract

Trial identifier(s)Phase

REGEN-COV
NCT04425629

2
3

COMET-ICE
NCT04545060

3

COMET-TAIL
NCT04913675
COMET-PEAK (Parts B
and C)
NCT04779879

3

BLAZE-1
NCT04427501

2

2

3

154

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Author andyear
Chen et al.
2022[60]

Source

Title

Clinicaltrials.gov

Williams et al.
2022[61]

ATS 2021-2022

Davis et al.
2022[62]

OVID

Huang et al.
2021[63]

OVID

Bamlanivimab and Etesevimab Improve Symptoms andAssociated Outcomes in Ambulatory Patients at Increased
Risk for Severe Coronavirus Disease 2019: Results from thePlacebo-Controlled Double-Blind Phase 3 BLAZE-1 Trial
Bebtelovimab, Alone and Together with Bamlanivimab andEtesevimab,
as a Broadly Neutralizing Monoclonal Antibody Treatment
and a Slow
Intravenous Push Option for Ambulatory COVID-19
Pharmacokinetics and pharmacodynamics of casirivimab
and imdevimab in a dose-ranging study in outpatients with
COVID-19
Effectiveness of casirivimab and imdevimab, andsotrovimab during Delta variant surge: a prospective cohort
study and comparative effectiveness randomized trial

Chew et al.
2021[64]

OVID

Chew et al.
2022[65]
Boucau et al.
2022[66]
Kumarasamy etal. 2022[67]OVID

Streinu-Cercel
et al. 2022[68]

OVID

OVID
CROI 2022

Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA
levels but not symptom duration in non-hospitalized adults
with COVID-19
Antiviral and clinical activity of bamlanivimab in arandomized trial of non-hospitalized adults with COVID-19
Monoclonal antibody treatment drives rapid culture
conversion in SARS-CoV-2 infection
Interim results from the randomized, controlled EMPATHY
phase II/III study evaluating ensovibep, a DARPintherapeutic, in patients with mild to moderate COVID-19
Efficacy and Safety of Regdanvimab (CT-P59): A Phase 2/3
Randomized, Double-Blind, Placebo-Controlled Trial in
Outpatients with Mild to Moderate Coronavirus Disease
2019

Reporttype
JournalarticleTrial identifier(s)Conference
abstract

BLAZE-4
NCT4634409

2

Conference
abstract

Davis et al. 2022
casirivimab/imdevimab
NCT04666441
UPMC Quality
Improvement Review
Committee Project ID
3282.
University ofPittsburgh Institutional
Review Board
STUDY210220179
NCT04790786

2

Journalarticle(pre-print)

Phase
2/3 (Results fromphase 3)

4
(Please note that
this is described
as a phase 4(post-marketing)trial; however,patients wererandomized totreatment, rather
than assigned
according tophysician's
discretion.)
2

Journalarticle(pre-print)
JournalarticleJournalarticleConference
abstract

ACTIV-2/A5401
NCT04518410

EMPATHY
NCT04828161

2/3

JournalarticleCT-P59
NCT04602000

2/3 (Results fromphase 2)

2/3

155

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Author andyear
Montgomery et
al. 2022a[69]SourceTitle

ECCMID 2022

Montgomery et
al. 2022b[70]Clinicaltrials.gov

Hobbs et al.
2022[71]

December ID
Week 2022

STAMP 2022[72]AdagioTherapeutics
2022

O’Brien et al.
2022[73]

OVID

Mazzaferri etal. 2022[74]

OVID

Efficacy and safety of intramuscular administration of
AZD7442 (tixagevimab/cilgavimab) for early outpatient
treatment of COVID-19: the TACKLE phase III trial
Efficacy and safety of intramuscular administration of
tixagevimab-cilgavimab for early outpatient treatment of
COVID-19 (TACKLE): a phase 3, randomized, double-blind,placebo-controlled trial
Outpatient Treatment With the SARS-CoV-2-Neutralizing
Antibody Combination AZD7442 (Tixagevimab/Cilgavimab)
for Preventing COVID-19 Hospitalizations in the Phase 3
TACKLE Trial
Adagio Therapeutics Announces ADG20 (adintrevimab) is
the First Monoclonal Antibody to Meet Primary Endpoints
with Statistical Significance Across Pre- and Post-exposure
Prophylaxis andTreatment for COVID-19 and Plans to Seek US Emergency
Use Authorization
Effect of Subcutaneous Casirivimab and Imdevimab
Antibody Combination vs Placebo on Development ofSymptomatic COVID-19 in Early Asymptomatic SARS-CoV-2
Infection: A Randomized Clinical Trial
Exploratory data on the clinical efficacy of monoclonal
antibodies against SARS-CoV-2 Omicron variant of concern

Portal-Celhay
et al. 2022[75]OVID

Kim et al.
2022[76]
Schilling et al.
2022[77]

Reporttype
Conference
abstract

Trial identifier(s)Phase

TACKLE
NCT04723394

3

Press
release

STAMP

2/3

JournalarticleO’Brien et al. 2022
casirivimab/imdevimab
NCT04452318

3

JournalarticleMANTICO
NCT05205759

3

Virologic Efficacy of Casirivimab and Imdevimab COVID-19
Antibody Combination in Outpatients With SARS-CoV-2
Infection A Phase 2 Dose-Ranging Randomized Clinical Trial

Journalarticle2

OVID

A Randomized Clinical Trial of Regdanvimab in High-Risk
Patients with Mild-to-Moderate Coronavirus Disease 2019

JournalarticleOVID

Pharmacometric assessment of the in vivo antiviral activityof ivermectin in early symptomatic COVID-19

Portal-Celhay et al.
2022
casirivimab/imdevimab
NCT04666441
Kim et al. 2022
regdanvimab
NCT04602000
PLATCOV
NCT05041907

JournalarticleConference
abstract

3

Journal2
article(pre-print)
BMJ: British Medical Journal; COVID-19: COVID-19: Coronavirus disease 2019; MAGIC: Making GRADE the Irresistible Choice; NIH: National Institutes of Health;
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; US: United States; WHO: World Health Organization.

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Table 5. Study characteristics of RCTs for neutralizing antibodies
Author and year,
Intervention(s) andPatient characteristics
trial identifier(s)comparators
enrollment,
location
Weinreich et al.
2020[46]>

REGEN-COV (phase 2
portion)
NCT04425629
16/06/2020-13/08/2020

>

US

>

2.4 g
casirivimab/imdevimab:
IV administration, 250
mL of 2.4 g ReGN-COV2(casirivimab/imdevimab
in equal doses) over
one hour on Day 1(single dose)
8g
casirivimab/imdevimab:
IV adminstration, 250
mL of 8 g ReGN-COV2(casirivimab/imdevimab
in equal doses) over
one hour on Day 1(single dose)
Placebo: IVadministration, 250 mLof saline placebo over
one hour on Day 1(single dose)>

Patients (aged ≥18
years) withconfirmed SARSCoV-2 infection(positive test ≤72
hours before
randomization andsymptom onset ≤7days before
randomization),
non-hospitalized,
and oxygen
saturation ≥93% ofroom airPrimary (efficacy)
endpoint(s)>>Viral load change
through Day 7
Physician visit rate
through Day 29

Secondary endpoint(s)

NR

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Author and year,
trial identifier(s)enrollment,
location
Weinreich et al.
2021[47],[48]Intervention(s) andcomparators>

REGEN-COV (phase 3
portion)
NCT04425629
24/09/2020-17/01/2021
US, Chile, Mexico,
Romania

>

>

1.2 g
casirivimab/imdevimab(low dose): IV
administration, 250 mL
of 1.2 g ReGN-COV2(casirivimab/imdevimab
in equal doses) over
one hour on Day 1(single dose)
2.4 gcasirivimab/imdevimab(high dose): IV
administration, 250 mL
of 2.4 g ReGN-COV2(casirivimab/imdevimab
in equal doses) over
one hour on Day 1(single dose)
Placebo: IVadministration, 250 mLof saline placebo over
one hour on Day 1(single dose)

Patient characteristics>

Patients (aged ≥18
years) withconfirmed SARSCoV-2 infection(positive test ≤72
hours before
randomization andsymptom onset ≤7days before
randomization),
non-hospitalized,
and oxygen
saturation ≥93% ofroom airPrimary (efficacy)
endpoint(s)>Proportion ofpatients with ≥1
COVID-19-related
hospitalization or
all-cause deaththrough Day 29

Secondary endpoint(s)> Proportion of patients with

≥1 COVID-19-related
hospitalization or all-cause
death from Day 4 throughDay 29> Time to COVID-19
symptoms resolution (19of the 23 recorded
symptoms)> Safety158

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Author and year,
trial identifier(s)enrollment,
location
Gupta et al. 2021[49]Intervention(s) andcomparators>

COMET-ICE
NCT04545060>

27/08/2020-04/03/2021
US, Canada, Brazil, andSpain

Sotrovimab: IVadministration, single
500 mg, over 1 hour at
day 1
Placebo: IVadministration, single
dose over 1 hour at day
1

Patient characteristics>>

Gupta et al. 2022a[50]
COMET-ICE
NCT04545060
27/08/2020-08/04/2021

Primary (efficacy)
endpoint(s)Patients (aged ≥18
years) withconfirmed SARSCoV-2 infection,
symptom onset ≤5days before
randomization, andhigh risk for COVID19 progression
Exclusion criteria
included being
currently
hospitalized, likely
to require
hospitalization, andsymptoms
consistent withsevere COVID-19>

Patients (aged ≥12years) with a highrisk of diseaseprogression>

Secondary endpoint(s)>Proportion ofpatients withhospitalization for
more than 24 hours
or death, due to any
cause, through Day
29

>
>
>

Brazil, Canada, Peru,
Spain, and US
Shapiro et al. 2022[52]
COMET-TAIL
NCT04913675
06/2021-08/2021
US

>
>
>

Sotrovimab IV: IV
administration, single
500mg dose
500 mg sotrovimab IM:
IM administration,
single 500mg dose
250 mg sotrovimab IM:
IM administration,
single 250mg dose
[discontinued early due
to a greater number ofhospitalizations seen]>

The efficacy of 500
mg IM versus 500
mg IV sotrovimab inpreventing
hospitalization for>24 hours for acutemanagement of
illness due to any
cause or death

NR

Proportion ofpatients with
progression tosevere or criticalrespiratory COVID19 requiring
supplemental
oxygen (severe
disease) or
mechanicalventilation (criticaldisease) throughDay 29All-cause mortality
at Day 29
Mean change in
FLUpro score
Changes in viral loadfrom baseline to Day
8 using aquantitative RT-PCR
test

159

Confidential

Author and year,
trial identifier(s)enrollment,
location
Gupta et al. 2022c[53]
COMET-PEAK (Parts B andC)
NCT04779879

Intervention(s) andcomparators>>

02/2021-07/2021

Patient characteristics

Primary (efficacy)
endpoint(s)Sotrovimab IV: IV
administration, single
dose of 500 mg
sotrovimab
Sotrovimab IM: IVadministration, single
dose of 500 or 250 mg
sotrovimab>

Adult patients (aged≥ 18 years) withearly mild-tomoderate COVID-19>

Bamlanivimab: IVadministration, single
dose of either 700,
2800 or 7000 mg of LYCoV555 (bamlanivimab)
over approximately 1
hour
Placebo: IVadministration ofplacebo over 1 hour>

Patients withconfirmed SARSCoV-2 infection and≥1 mild-ormoderate symptoms
Exclusion criteria
included oxygen
saturation ≤93%,
respiratory rate ≥30
per minute, heart
rate ≥125/ minute,or requires (oranticipatedimpending need for)mechanicalventilation>

Multinational

Chen et al. 2020[54]>BLAZE-1
NCT04427501
17/06/2020-21/09/2020
US

>

>

Compare thevirologic response to
sotrovimab IM to IV,
with an endpoint ofmean AUC of SARSCoV-2 viral load, as
measured by RTqPCR from day 1 today 8 (AUC(D1-8)) inNP swabs andpredefined 90% CI
limits of 0.5-2.0
indicating
equivalence
Change in viral load

Secondary endpoint(s)>Safety>>Safety assessments
Patient reported
symptom burden
COVID-19-related
inpatienthospitalization, avisit to theemergency
department, or
death

>

160

Confidential

Author and year,
trial identifier(s)enrollment,
location
Gottlieb et al. 2021[55]Intervention(s) andcomparators>

BLAZE-1
NCT04427501
17/06/2020-03/09/2020
US

>

>

Bamlanivimab: IVadministration, single
dose of either 700,
2800 or 7000 mg ofbamlanivimab
Bamlanivimab/etesevim
ab: IV administration,
single dose of 2800 mg
bamlanivimab and 2800
mg etesevimab
Placebo: IVadministration ofplacebo over 1 hour

Patient characteristics>>

Patients (aged ≥18
years) withconfirmed SARSCoV-2 infection, ≥1
mild-to-moderate
symptoms, and apositive test <3days before
treatment
Exclusion criteria
included oxygen
saturation ≤93%,
respiratory rate ≥30
per minute, heart
rate ≥125/ minute,or requires (oranticipatedimpending need for)mechanicalventilation

Primary (efficacy)
endpoint(s)>Effect on viral loadfrom baseline to Day
11 (± 4 days)

Secondary endpoint(s)

>
>

>
>
>
>
>

Time to viralclearance
Proportion ofpatients with viralclearance at Days 7,
11, 15, and 22
Viral lead area under
the curve at Day 29
Change in symptomscore at Days 7, 11,15, and 22
Time to symptom
improvement
Time to symptom
resolution
Proportion ofpatients with a
COVID-19-related
hospitalization,
emergency
department visit, or
death at Day 29

161

Confidential

Author and year,
trial identifier(s)enrollment,
location
Dougan et al. 2021a[56]Intervention(s) andcomparators>

BLAZE-1
NCT04427501
04/09/2020-08/12/2020
US>

Bamlanivimab/etesevim
ab: IV administration,
single dose of 2800 mg
bamlanivimab and 2800
mg etesevimab
Placebo: IVadministration ofplacebo over 1 hour

Patient characteristics>>

Outpatients withconfirmed SARSCoV-2 infection, ≥1
mild-to-moderate
symptoms, and apositive test <3days before
treatment
Exclusion criteria
included oxygen
saturation ≤93%,
respiratory rate ≥30
per minute, heart
rate ≥125/ minute,or requires (oranticipatedimpending need for)mechanicalventilation

Primary (efficacy)
endpoint(s)>Proportion ofpatients with
COVID-19 related
hospitalization or
any cause death by
Day 28

Secondary endpoint(s)

NR

162

Confidential

Author and year,
trial identifier(s)enrollment,
location
Dougan et al. 2021b[57]Intervention(s) andcomparators>

BLAZE-1
NCT04427501
04/09/2020-08/12/2020
US>

Bamlanivimab/etesevim
ab: IV administration,
single dose of 2800 mg
bamlanivimab and 2800
mg etesevimab
Placebo: IVadministration ofplacebo over 1 hour

Patient characteristics>>

Outpatients withconfirmed SARSCoV-2 infection, ≥1
mild-to-moderate
symptoms, at least
one for severe
COVID-19 risk
factor, and apositive test <3days before
treatment
Exclusion criteria
included oxygen
saturation ≤93%,
respiratory rate ≥30
per minute, heart
rate ≥125/ minute,or requires (oranticipatedimpending need for)mechanicalventilation

Primary (efficacy)
endpoint(s)>Overall clinicalstatus of thepatients, defined as
COVID-19-related
hospitalization(acute care for ≥24
hours) or death fromany cause by Day 29

Secondary endpoint(s)

>

>

>

>
>

>

>

Composite of
COVID-19 related
hospitalization, avisit to an
emergency
department, or
death from any
cause at Day 29
Time to sustained
patient reported
resolution ofsymptoms
A reduction in the
SARS-CoV-2 viralload from baseline
to Days 3 and 5
Time to viralclearance
The area under the
response-time curvefor the viral load
through Day 7
The time to a
reduction andresolution ofsymptoms
Safety163

Confidential

Author and year,
trial identifier(s)enrollment,
location
Dougan et al. 2022[59]Intervention(s) andcomparators>

BLAZE-1
NCT04427501
09/12/20-07/01/21>

US

Chen et al.

2022[60]>

BLAZE-1
NCT04427501
09/12/2020-07/01/2021
US>

Bamlanivimab andetesevimab: IVadministration, single
dose of 700 mg
bamlanivimab and 1400
mg etesevimab
Placebo: IVadministration, single
dose

Bamlanivimab andetesevimab: IVadministration, single
dose of 700 mg
bamlanivimab and 1400
mg etesevimab
Placebo: IVadministration, single
dose

Patient characteristics>>

Primary (efficacy)
endpoint(s)Non-hospitalized
patients (aged ≥12years) with mild-tomoderate COVID-19
symptoms and ≥1
risk factor for
progressing tosevere COVID-19
and/orhospitalization>

Adolescent (aged12-17 years) andadult (aged ≥18
years) patients with
≥1 risk factor for
progression tosevere COVID-19>

Proportion ofpatients
experiencing COVID19-related
hospitalization (≥24
hours of acute care)or any-cause deathby Day 29

Secondary endpoint(s)

>

>
>
>

Time to sustained
symptom resolution,
symptom resolution,
sustained complete
symptom resolution,and symptom
improvement>>>

Change in SARSCoV-2 viral loadfrom baseline toDays 3, 5, and 7(±2 days)Time to viralclearance
Percentage ofpatients with PHVL
at Day 7 (±2 days)
Time to sustained
symptom
improvement andresolution
SafetyTime to firstsustained resolution
for each symptom
presented(excluding loss ofappetite, loss oftaste, and loss of
smell)
COVID-19-related
hospitalizations
through Day 29

164

Confidential

Author and year,
trial identifier(s)enrollment,
locationIntervention(s) andcomparators

Williams et al.
202246[61]Open-label population:>
BEB 175 mg>
BEB 175 mg + BAM
700mg + ETE 1400 mg

BLAZE-4
NCT4634409>

05/2021-07/2021

Davis et al. 2022[62]>Patients with alaboratory diagnosis
within 3 days of
randomization

Primary (efficacy)
endpoint(s)Secondary endpoint(s)>NR[note: the reported primary
outcome was safety]

IV administration over
30 seconds>>>

Davis et al. 2022
casirivimab/imdevimab
NCT04666441

Patient characteristics>

Casirivimab/imdevimab
IV: IV administration,
single dose of 300 mg,
500 mg, 1200 mg, or2400 mg ofcasirivimab/imdevimab
Casirivimab/imdevimab
SC: SC administration,
single dose of 600 mg
or 1200 mg casirivimab/
imdevimab>

Outpatients (aged≥18 years and ≤50
years) with mild tomoderate COVID19, SARS‐CoV‐2
PCR‐positive andseronegative>

Efficacy, safety, andtolerability

NR

The proportion ofpatients withpersistently highviral load (log viralload >5.27) on Day
7Time to sustained
symptom resolution
COVID-19
hospitalization andall-cause mortality
through Day 29

165

Confidential

Author and year,
trial identifier(s)enrollment,
locationIntervention(s) andcomparators

Huang et al. 2021[63]>

UPMC Quality
Improvement Review
Committee Project ID
3282.
University of Pittsburgh
Institutional Review Board
STUDY210220179>

Casirivimab/imdevimab(dosage NR)
Sotrovimab (dosage
NR)

Patient characteristics>

Patients (aged 12120 years) who
received mAb
treatment at UPMC
infusion centers andemergency
departments

Primary (efficacy)
endpoint(s)>Hospital-free days ≤28 daysSecondary endpoint(s)>Mortality at Day 28

NCT04790786
14/07/2021-29/09/2021
US

166

Confidential

Author and year,
trial identifier(s)enrollment,
location
Chew et al. 2021[64]Intervention(s) andcomparators>

ACTIV-2/A5401
NCT04518410
19/08/2020-15/11/2020>

Bamlanivimab: IVadministration, single
dose of 7000 or 700 mg
bamlanivimab
Placebo: IVadministration, single
dose

Patient characteristics

>

US

>

>

>

Patients with
documented SARSCoV-2 infection by
an FDA-authorized
antigen or nucleic
acid test from asample collected
within 7 days prior
to anticipated study
entry
No more than 10days of COVID-19
symptoms at time of
anticipated study
entry
Ongoing symptoms(not including loss oftaste or smell)
within 48 hours prior
to study entry
Resting peripheral
oxygen saturationlevels 92%, andwithout the need for
hospitalization

Primary (efficacy)
endpoint(s)

>

>

>

Detection of NP
SARS-CoV-2 RNA at
Days 3, 7, 14, 21,
and 28Time toimprovement of allof 13 targeted
COVID-19
symptoms by daily
self-assessment
through Day 28
Grade 3 or higher
TEAEs through Day
28[Note: Additional primary
outcomes reported onclinicaltrials.gov]

Secondary endpoint(s)

>
>
>

>
>
>

Quantitative NP
SARS-COV-2 RNA
Composite all-cause
hospitalizations anddeath
Area under the
curve of symptomscores from Day 0
through Day 28
Plasmabamlanivimab
concentrations
Plasma and serum
inflammatory
biomarkers
Safety through week
24

[Note: Additional secondary
outcomes reported onclinicaltrials.gov]

167

Confidential

Author and year,
trial identifier(s)enrollment,
location
Chew et al. 2022[65]Intervention(s) andcomparators>

ACTIV-2/A5401
NCT04518410
12/10/20-17/11/20>

US

Boucau et al. 2022[66]>ACTIV-2/A5401
NCT04518410
19/08/20-17/11/20
US>

Patient characteristics

Bamlanivimab: IVadministration, single
dose over a 1-hour
period, 7000 or 700 mg
of bamlanivimab
Placebo: IVadministration, single
dose over a 1-hour
period>Bamlanivimab: IVadministration, single
dose of 7000 mg(n=20) or 700 mg(n=10) of bamlanivimab
Placebo: IVadministration, single
dose>

Primary (efficacy)
endpoint(s)Non-hospitalized
patients (aged ≥18
years) with
documented SARSCoV-2 infection by
an FDA-authorized
antigen or nucleic
acid test from asample collected
within 7 days prior
to anticipated study
entry

>

Non-hospitalized
participants withpositive SARS-CoV-2
antigen or nucleic
acid test within 7days and less than
10 days of COVID19 symptoms>>

Secondary endpoint(s)>Detection of SARSCoV-2 RNA from NP
swabs at Days 3, 7,
14, 21, and 28
Duration of targeted
COVID-19associatedsymptoms from Day
0

Viral culture
dynamics (viral load
by qPCR and viralculture)

>
>
>

NR

>

All-cause
hospitalization anddeath
Quantitative NP
SARS-CoV-2 RNA
levels
AUC of symptomscores from Days 028
Progression of 1 ormore COVID-19associatedsymptoms to worse
status than recorded
at study entry
Safety168

Confidential

Author and year,
trial identifier(s)enrollment,
location
Kumarasamy et al.
2022[67]Intervention(s) andcomparators>

EMPATHY
NCT04828161
US, Hungary, India,
Netherlands, Poland,South Africa>

Ensovibep: IV
administration, single
dose of 75, 225, or 600
mg, given over 60
minutes
Placebo: IVadministration, single
dose given over 60
minutesPatient characteristics>

Patients (aged ≥ 18
years) positive for
COVID-19 and thepresence of ≥2
COVID-19
symptoms and onset
within 7 days prior
to dosingPrimary (efficacy)
endpoint(s)>Time-weighted
change frombaseline in log10
SARS-CoV-2 viralload in NP swabs to
Day 8Secondary endpoint(s)

>

>

>

Proportion ofpatients withhospitalizations
and/or ER visits
related to COVID19, or death fromany cause to Day 29
Time to sustained
clinical recovery
based on resolution
or improvement inclinical symptoms(patient reported
outcome) with noworsening up to Day
29
Safety169

Confidential

Author and year,
trial identifier(s)enrollment,
location
Streinu-Cercel et al.
2022[68]

Intervention(s) andcomparators>

CT-P59
NCT04602000
07/10/2020-18/12/2020
South Korea, Romania,
Spain, and US>

Regdanvimab: IVadministration, single
dose of 40 or 80 mg/kg
regdanvimab reconstituted in 250mL of
0.9% sodium chloride,
given over 90±15minutes (Day 1)
Placebo: IVadministration, single
dose of re-constituted in
250mL of 0.9% sodium
chloride, given over
90±15 minutes (Day 1)

Patient characteristics>

Patients with mildto-moderate disease
as defined by the
WHO criteria withoxygen saturation>94% on room air,
not requiring oxygen
support, onset ofsymptoms within 7days before study
drug administration,and presenting withsymptoms 2 days
prior torandomization

Primary (efficacy)
endpoint(s)>>Time to conversion
to negative NP swab
specimen based on
RT-qPCR (negative
titer threshold of
2.33 log10
copies/mL) up to
Day 28Time to clinicalrecovery up to Day
14

Secondary endpoint(s)

>

>

>
>

>

>
>
>

The proportion ofpatients with clinicalsymptoms requiring
oxygen therapy or
hospitalization due
to COVID-19 up to
Day 28The proportion ofpatients achieving
conversion tonegative RT-qPCR
result
The proportion ofpatients withhospital admission
The proportion ofpatients requiring
supplementary
oxygenThe proportion ofpatients withmechanicalventilation use
The proportion ofpatients requiring
rescue therapy
The proportion ofpatients with ICU
admission
The proportion ofpatients with allcause mortality

170

Confidential

Author and year,
trial identifier(s)enrollment,
locationMontgomery et al.
2022a[69]Intervention(s) andcomparators>

TACKLE
NCT04723394>
Montgomery et al.
2022b[70]>TACKLE
NCT04723394
28/01/21-22/07/21
US, Latin America,
Europe, and Japan>

Tixagevimab/cilgavimab: IM administration,
single dose 600 mg of
two injections of
AZD7442(tixagevimab/cilgavimab; 300 mg of each))
Placebo: IM
administration, single
dose
Tixagevimabcilgavimab: IM
administration, single
dose of two consecutive
3 mL injections of 300
mg tixagevimab and300 mg cilgavimab
Placebo: IM
administration, single
dose given as twoconsecutive 3 mL
injections

Patient characteristics

Primary (efficacy)
endpoint(s)Secondary endpoint(s)>Non-hospitalized
adult patients (aged≥18 years) with
mild-to-moderate
COVID-19 anddosed ≤ 7 days fromsymptom onset>

Severe COVID-19 ordeath from any
cause throughDay 29>Safety>Non-hospitalized
patients (aged ≥18
years) withlaboratoryconfirmed SARSCoV-2 infection,
determined by RTPCR or an antigen
test, from a sample
collected 3 or lessdays before
enrollment
WHO Clinical
Progression Scalescore of >1 to <4
Mild-to-moderate
COVID-19, receiving
the study drug ≤7days from selfreported symptom
onset

>

Proportion ofpatients with severe
COVID-19 or deathfrom any cause to
day 29, with severe
COVID-19 being
defined as aminimum of either
pneumonia (fever,cough, tachypnoea
or dyspnea, andlung infiltrates) or
hypoxaemia (oxygen
saturation <90% inroom air, severe
respiratory distress,
or both), plus a
WHO Clinical
Progression Scalescore of 5 or more>

Incidence of
respiratory failure,levels of SARS-CoV2 RNA in nasal
swab, and
progression ofparticipant-reported
COVID-19associatedsymptoms throughDay 29Death from any
cause orhospitalization for
COVID-19
complications or
sequalae to Day 169
Safety

>
>

>

>

171

Confidential

Author and year,
trial identifier(s)enrollment,
location
Hobbs et al. 2022[71]Intervention(s) andcomparators>

TACKLE
NCT04723394
28/01/2021-21/08/2021
Multinational

STAMP 2022[72]

>

>

STAMP

>

Tixagevimab/cilgavimab(AZD7442): IM
adminstration, single
dose of 600 mg (twoconsecutive injections,
300 mg of eachtixagevimab andcilgavimab)
Placebo: IM
administration, single
dose of two consecutive
injections

Adintrevimab: IM
administration, single
dose of 300mg ofadintrevimab
Placebo: IM
administration, single
dose

Patient characteristics>>

Non-hospitalized
adults with mild tomoderate COVID19, dosed ≤7 days
from symptom onset

Patients with mildto-moderate COVID19

Primary (efficacy)
endpoint(s)>Secondary endpoint(s)>Severe COVID-19 ordeath from any
cause through Day
169, defined as aminimum of either
pneumonia (fever,cough, tachypnea,
or dyspnea, andlung infiltrates) or
hypoxemia (SpO2<90% in room air
and/or severe
respiratory distress)
and a WHO Clinical
Progression Scalescore of 5 or higher[Note: Severe COVID-19
definition fromclinicaltrials.gov]>
COVID-related
hospitalization or
all-cause mortality
at Day 29

SafetyNR[note: primary endpoint not
specified]172

Confidential

Author and year,
trial identifier(s)enrollment,
location
O’Brien et al. 2022[73]Intervention(s) andcomparators>

O’Brien et al. 2022
casirivimab/imdevimab
NCT04452318
13/07/2020-28/01/2021
US, Romania, Moldova>

Casirivimab/imdevimab:
SC administration,
single dose of 1200 mg(1200 mg/mL) of
casirivimab andimdevimab (fourinjections of 2.5mL
solution) (Day 1)
Placebo: SC
administration, single
dose (four injections of
2.5mL solution) (Day 1)

Patient characteristics

>

OR

>

OR

>

OR

>

Adult participants(aged ≥18 years)(irrespective of
weight) at thesigning of informed
consent
Adolescentparticipants (aged≥12 to <18 years)
Pediatric participants(aged <12 years at
the signing of theassent(parent/guardiansigns the informed
consent))

Primary (efficacy)
endpoint(s)>Proportion ofparticipants who had
a positive RT-qPCR
result at baseline or
during the 28-day
efficacy assessment
period and who
developed signs andsymptoms of
COVID-19 within 14
days of the positive
RT-qPCR result

Secondary endpoint(s)>>The number ofweeks ofsymptomatic SARSCoV-2 infection
The number ofweeks of high viralload (>4 log10
copies/mL)[Note: The full list of
secondary endpoints isavailable in the
supplementary materials]

Asymptomatic
household contact ofsomeone who has
tested positive for
COVID-19 and has
been judged by theinvestigator to be ingood health173

Confidential

Author and year,
trial identifier(s)enrollment,
location
Mazzaferri et al.
2022[74]

Intervention(s) andcomparators>

MANTICO
NCT05205759
Patients enrolled from
09/12/2021
Italy

Portal-Celhay et al.
2022[75]
Portal-Celhay et al. 2022
casirivimab/imdevimab

>

>

>

>

NCT04666441
15/12/2020-04/03/2021
US>

Bamlanivimab andetesevimab: IVadministration, single
dose over a 1-hour
period, 700 mg ofbamlanivimab and 1400
mg of etesevimab
Sotrovimab: IVadministration, single
dose over a 1-hour
period, 500 mg dose
Casirivimab andimdevimab: IVadministration, single
dose over a 1-hour
period, 600 mg ofcasirivimab and 600 mg
of imdevimab
Casirivimab/imdevimab
IV: IV administration,
single dose of 300, 600,
1200 or 2400 mg
Casirivimab/imdevimab
SC: SC administration,
single dose of 600 or
1200 mg
Placebo: IV or SC
administration, single
dose

Patient characteristics>

Outpatients (aged≥50 years) with apositive test (direct
antigen or nucleic
acid SARS-CoV-2)
and mild-tomoderate COVID-19
symptoms within 4days of the onset

Primary (efficacy)
endpoint(s)>COVID-19
progression, defined
as hospitalization,need ofsupplemental
oxygen therapy, or
death from any
cause through Day
14

Secondary endpoint(s)

>

>

>

Patients (aged ≥18
years) with apositive SARS-CoV-2
diagnostic test froma sample collected
within 72 hours prior
to randomization>

Time-weighted
average dailychange from Day
1/baseline to Day 7
in viral load in NP
swab samples(measured by RTqPCR)>>

Emergency
department visits
through Day 28, allcause mortality
through Day 28,
duration of
supplemental
oxygen therapy, andrate and duration of
non-invasive
ventilation andmechanicalventilation
Time to sustained
patient-reported
symptom resolution
Evaluation of
additional virologic
efficacy andtolerability
Safety174

Confidential

Author and year,
trial identifier(s)enrollment,
locationIntervention(s) andcomparators

Primary (efficacy)
endpoint(s)Secondary endpoint(s)Patients (aged ≥18>
Proportion of>
Disease progression
years) with COVIDpatients withup to Day 28
Kim et al. 2022
19 confirmed bydisease progression>
Time to clinicalregdanvimab
rapid antigen kit or
up to day 28 inrecovery up to Day
RT-PCR, with ≥1
high-risk patients,
14
NCT04602000
COVID-19defined as meeting>
Safetyassociated symptom
at least 1 of the>
18/01/2021-24/04/2021
with onset ≤7 days
following COVID-19
and ≥1 pre-specified
events:
US, European Union, andsymptom ≤48 hours
hospitalization,
Asia
before drug
oxygen therapy, or
administrationmortality due to
SARS-CoV-2>
Oxygen saturation of
infection>94% on room air
and did not require
supplemental
oxygenSchilling et al. 2022[77]>Casirivimab/imdevimab:>
Patients (aged 18>
The rate of viral>All-causeIV administration, single
50 years) presenting
clearance
hospitalization for
PLATCOV
dose of 600 mg ofto the Acute(expressed as aclinical deterioration
casirivimab and 600 mg
Respiratory
slope coefficient anduntil Day 28
NCT05041907
of imdevimab
Infections outpatientpresented as a half>
Safetyclinic for COVID-19,
life)>
No study drug
Patients enrolled fromwith early
30/09/2021
symptomatic[Note: Ivermectin group was not
COVID-19
assessed in this report]
Thailand(symptoms for no
more than 4 days),oxygen saturation≥96%, and
unimpeded in
activities of dailyliving
AE: adverse event; AESI: adverse event of special interest; AUC: area under the curve; BAM: Bamlanivimab; BEB: Bebtelovimab; Ct: cycle threshold; ED:emergency department; ETE: Etesevimab; FDA: Food and Drug Administration; ICU: intensive care unit; IM: intramuscular; IV: intravenous; mAB: monoclonal
antibody; mg: milligram; mL: milliliter; NP: nasopharyngeal; PCR: polymerase chain reaction; PHVL: persistently high viral load; qPCR: quantitative polymerase
chain reaction; RT-PCR: reverse transcription-polymerase chain reaction; RNA: ribonucleic acid; RT-qPCR reverse transcription-quantitative polymerase chain
reaction; SAE: serious adverse event; SC: subcutaneous; TEAE: Treatment Emergent Adverse Events; US: United States; WHO: World Health Organization.
Kim et al. 2022[76]>Patient characteristics

Regdanvimab: IVadministration, single
dose over 60 ± 15
minutes, 40 mg/kg
reconstituted in 250 mL
of 0.9% sodium chloride
Placebo: IVadministration, single
dose over 60 ± 15
minutes, reconstituted
in 250 mL of 0.9%
sodium chloride>

175

Confidential

Table 6. Patients baseline characteristics for RCTs for neutralizing antibodies
Author and year, trial
Number randomized
Age (years)
identifier(s)Weinreich et al.
Median (IQR)>
Overall: 269
2020[46]>
Overall: NR>
2.4 g casirivimab/>
2.4 g casirivimab/
imdevimab: 92
REGEN-COV (phase 2
imdevimab: 43.0>
8 g casirivimab/
portion)(33.5-51.0)
imdevimab: 90>
8 g casirivimab/>
Placebo: 93
NCT04425629
imdevimab: 44(36.0-53.0)>
Placebo: 45.0
(34.0-54.0)
Weinreich et al.
Median (IQR)>
Overall: 3088
2021[47],[48]>2.4 g casirivimab/>
2.4 g casirivimab/
imdevimab: 50.0
imdevimab: 1355
REGEN-COV (phase 3(39.0-60.0)>
Placebo (2.4 g portion):
portion)>Placebo (2.4 g1341
portion): 50.0>
1.2 g casirivimab/
NCT04425629(37.0-58.0)
imdevimab: 736>
1.2 g casirivimab/>
Placebo (1.2 g portion):
imdevimab: 48.5
748
(37.0-57.5)>
Placebo (1.2 g
portion): 48.0
(35.0-57.0)

SexMale, n (%)>
Overall: 134 (49)>
2.4 g casirivimab/
imdevimab: 46 (50)>
8 g casirivimab/
imdevimab: 38 (42)>Placebo: 50 (54)Male, n (%)>
Overall: 1977 (48.7)>
2.4 g casirivimab/
imdevimab: 656(48.4)>
Placebo (2.4 g
portion): 633 (47.2)>
1.2 g casirivimab/
imdevimab: 364(49.5)>
Placebo (1.2 g
portion): 352 (47.1)

Time to symptom onset(days)Median (range)>
Overall: NR>
2.4 g casirivimab/
imdevimab: 3.5 (0-7)>
8 g casirivimab/
imdevimab: 3.0 (0-8)>
Placebo: 3.0 (0-8)

Median (range)>
2.4 g casirivimab/
imdevimab: 3.0 (2-5)>
Placebo (2.4 g
portion): 3.0 (2-5)>
1.2 g casirivimab/
imdevimab: 3.0 (2-5)>
Placebo (1.2 g
portion): 3.0 (2-4)

176

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Author and year, trial
identifier(s)Gupta et al. 2021[49]
COMET-ICE
NCT04545060

Gupta et al. 2022a[50]
COMET-ICE
NCT04545060

Number randomized

Age (years)

Sex

Interim analysis>
Overall: ITT, 583;
Safety, 868>
Sotrovimab: ITT, 291;
safety, 430>
Placebo: ITT, 292;
safety, 438

Interim analysis
Median (range) (ITT
population)>
Overall: 53.0 (1896)>
Sotrovimab: 53.0
(18-96)>
Placebo: 52.5 (1888)

Interim analysis
Male, n (%) (ITT population)>
Overall: 266 (46)>
Sotrovimab: 135(46)>
Placebo: 131 (45)

Final analysis>
Overall: 1057>
Sotrovimab: 528>
Placebo: 529

Final analysis
Median (IQR), ≥65 years,>70 years, n (%)>
Sotrovimab: 53(41.5-62), 105(20), 56 (11)>Placebo: 53 (4363), 108 (20), 56(11)

Final analysis
Female, male, n (%)>
Overall: 572 (54),485 (46)>
Sotrovimab: 299(57), 229 (43)>Placebo: 273 (52),256 (48)

Time to symptom onset(days)
Interim analysis
NR

Final analysis
Within the prior 5 days

177

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Author and year, trial
identifier(s)Shapiro et al. 2022[52]
COMET-TAIL
NCT04913675
Gupta et al. 2022c[53]
COMET-PEAK (Parts B andC)
NCT04779879

Number randomized>>>
Part B:>>>

Part C:>>>

Chen et al. 2020[54]BLAZE-1
NCT04427501>>>

Overall: 754
500mg IV sotrovimab:
378
500mg IM sotrovimab:
376
Overall: 166
Sotrovimab 500 mg IV:
84
Sotrovimab 500 mg IM:
82
Overall: 157
Sotrovimab 500 mg IV:
79
Sotrovimab 250 mg IM:
78
Overall: 452
700, 2800 or 7000 mg
bamlanivimab: 317
Placebo: 150

Age (years)

Sex≥65, %

NR>>

Overall: ~25%500mg IV
sotrovimab: NR>
500mg IM
sotrovimab: NR
Part B, median:>
Overall: 47>
Sotrovimab 500
mg IV: NR>
Sotrovimab 500
mg IM: NR
Part C, median:>
Overall: 52>
Sotrovimab 500
mg IV: NR>
Sotrovimab 250
mg IM: NR
Median (range)>
Overall: NR>
700, 2800 or 7000
mg bamlanivimab:
45 (18-86)>
Placebo: 46 (1877)

Time to symptom onset(days)≤7 days (according toclinicaltrials.gov)

NR

NR

Female, n (%)>
Overall: NR>
700, 2800 or 7000
mg bamlanivimab:
171 (55.3)>
Placebo: 78 (54.5)

Median>>>Overall: NR
700, 2800 or 7000
mg bamlanivimab: 4
Placebo: 4178

Confidential

Author and year, trial
identifier(s)Gottlieb et al. 2021[55]BLAZE-1
NCT04427501

Number randomized

>
>
>
>
>
>

Dougan et al. 2021a[56]BLAZE-1>>

NCT04427501>

Dougan et al. 2021b[57]>>

BLAZE-1
NCT04427501>

Overall: 592
700 mg bamlanivimab:
1042800 mg bamlanivimab:
109
7000 mg bamlanivimab:
1042800 mg bamlanivimab
and 2800 mg
etesevimab: 114
Placebo: 161

Overall: 1035
2800 mg bamlanivimab
and 2800 mg
etesevimab: 518
Placebo: 517

Overall: 1035
2800 mg bamlanivimab
and 2800 mg
etesevimab: 518
Placebo: 517

Age (years)

Sex

Median (IQR)>
Overall Mean
(SD): 44.7 (15.7)>
700 mgbamlanivimab: 39(31-58)>2800 mgbamlanivimab: 45(31-56)>7000 mgbamlanivimab: 46(34-55)>2800 mgbamlanivimab and2800 mgetesevimab: 44(30-60)>
Placebo: 46 (3557)
Mean (SD)>Overall: 53.8
(16.8)>
2800 mgbamlanivimab and2800 mgetesevimab: NR>
Placebo: NR
Mean (SD)>Overall: 53.8
(16.8)>
2,800 mgbamlanivimab and2,800 mgetesevimab: 54.3
(17.1)>
Placebo: 53.3
(16.4)

Female, n (%)> Overall: 315 (54.6)> 700 mgbamlanivimab: 63(62.4)> 2800 mg
bamlanivimab: 51(47.7)> 7000 mg
bamlanivimab: 58(57.4)> 2800 mg
bamlanivimab and2800 mgetesevimab: 58(51.8)> Placebo: 85 (54.5)

Time to symptom onset(days)
Within 4 days (median)Female, n (%)>
Overall: 538 (52)>2800 mgbamlanivimab and2800 mgetesevimab: NR>
Placebo: NR

Within 3 days of laboratory
diagnosis

NR

Median (range)>
Overall: 4 (0-29)>
2800 mgbamlanivimab and2800 mg etesevimab:
4 (0-29)>
Placebo: 4 (0-13)[Note: Conference abstractstates- female: 538 (52%)]179

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Author and year, trial
identifier(s)Dougan et al. 2022[59]BLAZE-1

Number randomized>>

Balmanivimab/etesevima
b: 511
Placebo: 258

NCT04427501
Chen et al.

2022[60]

BLAZE-1
NCT04427501

Williams et al. 2022[61]>>>Overall: 769
Balmanivimab/etesevima
b: 511
Placebo: 258

NCT4634409

Open-label population>
Bebtelovimab: 100>
Bebtelovimab (BEB)+
Bamlanivimab (BAM) andetesevimab (ETE): 176

Davis et al. 2022[62][Note: the BEB + BAB + ETE
population presented here wereusing the expanded CDC criteria
for high-risk]
NR

BLAZE-4

Davis et al. 2022
casirivimab/imdevimab

Age (years)

Sex

Median (range)>
Balmanivimab/
etesevimab: 57(12-93)>
Placebo: 55 (1389)
Median (min-max)>
Overall: 56 (1293)>
Balmanivimab/
etesevimab: 57(12-93)>
Placebo: 55 (1389)
NR

Male, n (%)>
Balmanivimab/
etesevimab: 247(48.3)>
Placebo: 114 (44.2)

NRTime to symptom onset(days)Median (range)>
Balmanivimab/
etesevimab: 4 (0-19)>
Placebo: 3 (1-15)

Male, n (%)>
Overall: 361 (46.9)>
Balmanivimab/
etesevimab: 247(48.3)>
Placebo: 114 (44.2)

Median (min-max)>
Overall: NR>
Balmanivimab/etesevi
mab: 3 (1-15)>
Placebo: 4 (0-19)

NR

Randomization ≤3 days fromsymptom onsetNR≤7 days (according toclinicaltrials.gov)

NCT04666441

180

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Author and year, trial
identifier(s)Huang et al. 2021[63]
UPMC Quality
Improvement Review
Committee Project ID
3282.
University of Pittsburgh
Institutional Review Board
STUDY210220179

Number randomized>>

Casirivimab/imdevimab:
2454
Sotrovimab: 1104

Age (years)

Sex

Mean (SD)>
Casirivimab/imdev
imab: 54 (18)>
Sotrovimab: 53(18)

Female, n (%)>
Casirivimab/imdevi
mab: 1320 (54)>
Sotrovimab: 599(54)Time to symptom onset(days)
Mean>
Casirivimab/imdevima
b: 4.5>
Sotrovimab: 4.6

NCT04790786

181

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Author and year, trial
identifier(s)Chew et al. 2021[64]Number randomized

ACTIV-2/A5401>>>

NCT04518410>>>

Chew et al. 2022[65]>ACTIV-2/A5401>>

NCT04518410

Boucau et al. 2022[66]ACTIV-2/A5401
NCT04518410

Overall (7000 mg): 94
Overall (700 mg): 223
Bamlanivimab (7000mg): 48
Bamlanivimab (700 mg):111
Placebo (7000 mg): 46
Placebo (700 mg): 112>

Bamlanivimab (7000mg): 48
Placebo (7000 mg): 46
Bamlanivimab (700 mg):111
Placebo (700 mg): 112>>

Bamlanivimab: 30
Placebo: 39

Age (years)

Sex

Median (IQR)>
Overall (7000mg): 44.5 (30.056.0)>
Overall (700 mg):
47.0 (35.0-55.0)>
Bamlanivimab(7000 mg): 45.5
(33.5-57.5)>
Bamlanivimab(700 mg): 46.0
(35.0-54.0)>
Placebo (7000mg): 42.0 (28.054.0)>
Placebo (700 mg):48.5 (36.0-55.0)
Median (IQR)>
Bamlanivimab(7000 mg): 45.5
(33.5-57.5)>
Placebo (7000mg): 42.0 (28.054.0)>
Bamlanivimab(700 mg): 46.0
(35.0-54.0)>
Placebo (700 mg):48.5 (36.0-55.0)
Median (range)>
Bamlanivimab:
50.5 (25-73)>
Placebo: 50 (2071)

Female, male, n (%)>
Overall (7000 mg):49 (52.1), 45 (47.9)>
Overall (700 mg):
113 (50.7), 110(49.3)>
Bamlanivimab(7000 mg): 26(54.2), 22 (45.8)>
Bamlanivimab (700mg): 57 (51.4), 54(48.6)>
Placebo (7000 mg):
23 (50.0), 23 (50.0)>
Placebo (700 mg):56 (50.0), 56 (50.0)

Time to symptom onset(days)Median (IQR)>
Overall (7000 mg): 6(4.0-7.0)>
Overall (700 mg): 6(4.0-8.0)>
Bamlanivimab (7000mg): 6 (4.0-8.0)>
Bamlanivimab (700mg): 6 (4.0-8.0)>
Placebo (7000 mg):
5.5 (4.0-7.0)>
Placebo (700 mg): 6(4.0-7.0)

Male, female, n (%)>
Bamlanivimab(7000 mg): 22(45.8), 26 (54.2)>
Placebo (7000 mg):
23 (50.0), 23 (50.0)>
Bamlanivimab (700mg): 54 (48.6), 57(51.4)>
Placebo (700 mg):56 (50.0), 56 (50.0)≤5 days, >5 days, n (%)>
Bamlanivimab (7000mg): 17 (35.4), 31(64.6)>
Placebo (7000 mg):
17 (37.0), 29 (63.0)>
Bamlanivimab (700mg): 41 (36.0), 70(63.1)>
Placebo (700 mg): 41(36.6), 71 (63.4)

Female, n (%)>
Bamlanivimab: 15(50)>
Placebo: 24 (62)Median (range)>
Bamlanivimab: 5 (38)>Placebo: 4 (1-10)

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Author and year, trial
identifier(s)Kumarasamy et al.
2022[67]

Number randomized

Age (years)

Sex

Ensovibep (75 mg): 101
Ensovibep (225 mg):100
Ensovibep (600 mg):
100
Placebo: 99NR

NR

Male, n (%)>
Regdanvimab 40
mg/kg: 59 (56.2)>
Regdanvimab 80
mg/kg: 59 (53.2)>
Either dosage ofintervention: 118(54.6)>
Placebo: 48 (43.2)>>>

Overall: 903
AZD7442: 452
Placebo: 451

Median (IQR), ≥60 years,<60 years>
Regdanvimab 40
mg/kg: 51.0 (4260), 27 (25.7), 78(74.3)>
Regdanvimab 80
mg/kg: 51.0 (4060), 28 (25.2), 83(74.8)>
Either dosage ofintervention: 51.0
(40-60), 55(25.5), 161 (74.5)>
Placebo: 52.0 (4161), 30 (27.0), 81(73.0)
Mean>
Overall: 46>
AZD7442: NR>
Placebo: NR

Median (IQR)>
Overall: 3.0 (2-4)>

Regdanvimab 40 mg/kg:
105
Regdanvimab 80 mg/kg:
111
Either dosage ofintervention: 216
Placebo: 111

Female, %>Overall: 50>
AZD7442: NR>
Placebo: NR

NR

>
>

EMPATHY>

NCT04828161>

Streinu-Cercel et al.
2022[68]>

CT-P59
NCT04602000

Montgomery et al.
2022a[69]TACKLE>>Time to symptom onset(days)≤7 from symptom onset todosing

NC04723394

183

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Author and year, trial
identifier(s)Montgomery et al.
2022b[70]TACKLE

Number randomized>>>

Overall: 903
Tixagevimab/cilgavimab:
452
Placebo: 451

NCT04723394

Hobbs et al. 2022[71]TACKLE
NCT04723394
STAMP 2022[72]STAMPO’Brien et al. 2022[73]O’Brien et al. 2022
casirivimab/imdevimab
NCT04452318>>

Age (years)

Sex

Mean (SD)>Overall: 46.1
(15.2)>
Tixagevimab/
cilgavimab: 46.3
(15.4)>
Placebo: 45.9
(15.0)
NR

Male, female, n (%)>
Overall: 448 (50),448 (50)>
Tixagevimab/
cilgavimab: 213(47), 239 (53)>Placebo: 216 (48),235 (52)
NR

NR>

Overall: 903
Tixagevimab/cilgavimab:
452
Placebo: 451>>>

Overall: 336
Adintrevimab: 169
Placebo: 167

NR

>
>

Overall: 207
Casirivimab/imdevimab:
101
Placebo: 106

Mean (SD)>
Casirivimab/
imdevimab: 39.2
(17.7)>
Placebo: 42.5
(18.3), 11 (10.4),
39 (36.8)>

Female, male, n (%)>
Casirivimab/
imdevimab: 50(49.5), 51 (50.5%)>
Placebo: 63 (59.4),
43 (40.6)

Time to symptom onset(days)
Mean (SD)>Overall: 5.0 (1.6)>
Tixagevimab/cilgavim
ab: 4.9 (1.6)>
Placebo: 5.0 (1.6)≤7 days from onset ofsymptoms

NR[Note: Subgroup treatedwithin 3 days of symptom
onset]
Within 4 days

≥12 to <18, ≥50, n (%)>
Casirivimab/
imdevimab: 15(14.9), 31 (30.7)>
Placebo: 11(10.4), 39 (36.8)

184Confidential

Author and year, trial
identifier(s)Mazzaferri et al.
2022[74]
MANTICO
NCT05205759

Number randomized

Age (years)

Sex

Total, Delta variant, Omicron
variant>
Overall: 319, 141, 170>
Sotrovimab: 107, 43, 61>
Bamlanivimab/etesevima
b: 106, 48, 57>
Casirivimab/imdevimab:
106, 50, 52

Median (IQR) [range](Delta variant)>
Sotrovimab: 65.8
(16.4) [50-90]>
Bamlanivimab/
etesevimab: 68.6
(11.8) [50-92]>
Casirivimab/imdev
imab: 63.2 (12.0)[50-89]Male, n (%) (Delta variant)>
Sotrovimab: 22(51.16)>
Bamlanivimab/
etesevimab: 21(43.75)>
Casirivimab/
imdevimab: 26(52.00)Median (IQR) [range](Omicron variant)>
Sotrovimab: 64.2
(15) [50-90]>
Bamlanivimab/
etesevimab: 64.8
(14.6) [50-86]>
Casirivimab/imdev
imab: 65.3 (14.8)[50-86]Time to symptom onset(days)
Within 4 days

Male, n (%) (Omicron
variant)>
Sotrovimab: 36(59.02)>Bamlanivimab/
etesevimab: 30(52.63)>
Casirivimab/
imdevimab: 35(67.31)

185

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Author and year, trial
identifier(s)Portal-Celhay et al.
2022[75]

Number randomized>>

Casirivimab/imdevimab
300 mg IV: 80
Casirivimab/imdevimab
600 mg IV: 68
Casirivimab/imdevimab
1200 mg IV: 72
Casirivimab/imdevimab
2400 mg IV: 62
Casirivimab/imdevimab
600 mg SC: 75
Casirivimab/imdevimab
1200 mg SC: 73
Pooled placebo: 77>>>

Overall: 1315
Regdanvimab: 656
Placebo: 659

Schilling et al. 2022[77]>

PLATCOV>

Casirivimab/imdevimab:
40
No study drug: 45

Portal-Celhay et al. 2022
casirivimab/imdevimab
NCT04666441

>
>
>
>
>

Kim et al. 2022[76]Kim et al. 2022
regdanvimab
NCT04602000

NCT05041907

Age (years)

Sex

Mean (SD)>
Casirivimab/imdev
imab 300 mg IV:
33.8 (8.90)>
Casirivimab/imdev
imab 600 mg IV:
33.9 (9.16)>
Casirivimab/imdev
imab 1200 mg IV:
34.1 (10.51)>
Casirivimab/imdev
imab 2400 mg IV:
36.3 (9.16)>
Casirivimab/imdev
imab 600 mg SC:
33.5 (9.18)>
Casirivimab/imdev
imab 1200 mg SC:
33.5 (10.88)>
Pooled placebo:
35.1 (9.97)
Median (IQR)>
Overall: 48.0 (3859)>
Regdanvimab:
49.0 (38-59)>
Placebo: 47.0 (3758)
Median (range)>
Casirivimab/
imdevimab: 26.5
(3.7-7.8)>
No study drug: 27(20-43)

Male, female, n (%)>
Casirivimab/imdevi
mab 300 mg IV: 33(41.3), 47 (58.8)>
Casirivimab/imdevi
mab 600 mg IV: 39(57.4), 29 (42.6)>
Casirivimab/imdevi
mab 1200 mg IV:
29 (40.3), 43 (59.7)>
Casirivimab/imdevi
mab 2400 mg IV:
28 (45.2), 34 (54.8)>
Casirivimab/imdevi
mab 600 mg SC: 36(48.0), 39 (52.0)>
Casirivimab/imdevi
mab 1200 mg SC:
35 (47.9), 38 (52.1)>
Pooled placebo: 31(40.3), 46 (59.7)
Male, female, n (%)>
Overall: 674 (51.3),
641 (48.7)>
Regdanvimab: 347(52.9), 309 (47.1)>
Placebo: 327(49.6), 332 (50.4)
Male, %>
Casirivimab/imdevi
mab: 20>
No study drug: 44

Time to symptom onset(days)NR

Median (IQR)>
Overall: 4.0 (3-5)>
Regdanvimab: 4.0 (35)>Placebo: 4.0 (3-5)
Reported symptoms for no
more than 4 days

[Note: mITT population forcasirivimab/imdevimab and no
study drug were 10 and 41,
respectively]
CDC: Centers for Disease Control and Prevention; g: gram; IM: intramuscular; IQR: interquartile range; ITT: intention-to-treat; IV: intravenous; kg: kilogram;
mg: milligram; mITT: modified intention-to-treat; NA: Not applicable NR: Not reported; SC: subcutaneous; SD: standard deviation; UPMC: University ofPittsburgh Medical Center.

186

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Table 7. Results from RCTs assessing neutralizing antibodies; primary outcome(s)Author and year,
Primary efficacy outcome(s)trial identifier(s)Weinreich et al. 2020[46]Time-weighted average change from baseline in viral load at Day 7
versus placebo group, LSM (95% CI)
REGEN-COV (phase 2 portion)>
2.4 g casirivimab/imdevimab: -0.25 log10 copies/mL (0.60 to 0.10)
NCT04425629>
8.0 g casirivimab/imdevimab: -0.56 log10 copies/mL (0.91 to -0.21)

Weinreich et al. 2021[47],[48]REGEN-COV (phase 3 portion)
NCT04425629

Patients with at ≥1 COVID-19-related medically attended visit
within 29 days versus placebo group, difference (95% CI)>
2.4 g casirivimab/imdevimab: -3 percentage points (-18
to 11)>
8.0 g casirivimab/imdevimab: -3 percentage points (-18
to 11)
Proportion of patients with ≥1 COVID-19-related hospitalization or
all-cause death through Day 29>
2.4 g REGN-COV2: 18>
Placebo (2.4 g REGEN-COV2 group): 62>
Difference, % ([95% CI], p-value): 71.3 ([51.7-82.9],
p<0.0001), significant difference
Proportion of patients with ≥1 COVID-19-related hospitalization or
all-cause death through Day 29>
1.2 g REGN-COV2: 7>
Placebo (1.2g REGEN-COV2 group): 24>
Difference, % ([95% CI], p-value): 70.4 ([31.6-87.1],
p=0.0024), significant difference[Note: 8.0g REGEN-COV2 arm was discontinued at protocol
amendment and not analyzed for efficacy; demographic data areprovided in the Supplementary material]

Safety outcome(s)Patients who experienced a SAE, n (%)>
2.4 g casirivimab/imdevimab: 1 (1)>8.0 g casirivimab/imdevimab: 0 (0)>Placebo: 2 (2)Patients who experienced an AE of special
interest*, n (%)>
2.4 g casirivimab/imdevimab: 0 (0)>8.0 g casirivimab/imdevimab: 2 (2)>Placebo: 2 (2)*No SAE of special interest was reported acrossthe treatment groups
Patients who experienced an AE, n (%)>
1.2 g casirivimab/imdevimab: 59/827(7.1)>
2.4 g casirivimab/imdevimab: 142/1849(7.7)>
8.0 g casirivimab/imdevimab: 85/1012(8.4)>
Placebo: 189/1843 (10.3)
Patients who experienced a SAE, n (%)>
1.2 g casirivimab/imdevimab: 9/827 (1)>2.4 g casirivimab/imdevimab: 24/1849(1)>
8.0 g casirivimab/imdevimab: 17/1012(2)>
Placebo: 74/1843 (4)Patients who experienced a grade 3 or 4 AE, n(%)>
1.2 g casirivimab/imdevimab: 11/827 (1)>2.4 g casirivimab/imdevimab: 18/1849(1)>
8.0 g casirivimab/imdevimab: 15/1012(1)>
Placebo: 62/1843 (3)187

Confidential

Author and year,
trial identifier(s)Gupta et al. 2021[49]
COMET-ICE
NCT04545060
Gupta et al. 2022a[50]
COMET-ICE
NCT04545060

Shapiro et al. 2022[52]
COMET-TAIL
NCT04913675

Primary efficacy outcome(s)Safety outcome(s)Interim analysis:
Proportion of patients hospitalized >24 hours or death for any
cause, n (%)>
Sotrovimab: 3/291 (1)>Placebo: 21/292 (7)>RR ([95% CI], p-value): 0.15 ([0.04-0.56], p=0.002),
significant difference

Patients who experienced an AE, n (%)>
Sotrovimab: 73/430 (17)>Placebo: 85/438 (19)Final analysis:
All-cause hospitalization >24 hours for acute illness management
or death due to any cause through Day 29, n>
Sotrovimab: 6/528>
Placebo: 30/529>
RR ([95% CI], p-value): -4.53 ([-6.70 to -2.37],
p<0.001), threshold defined as P <0.2758)
Proportion of patients hospitalized for >24 hours for acutemanagement of illness due to any cause or death, n (%)>
500 mg sotrovimab IV: 5/378 (1.3)>
500 mg sotrovimab IM: 10/376 (2.7)>
The 3.5% non-inferiority margin was met. Adjusted risk
difference, % (95% CI): 1.07 (-1.25 to 3.39)

Patients who experienced a SAE, n (%)>
Sotrovimab: 7/430 (2)>Placebo: 26/438 (6)Disease-related AEs were balanced between
treatment groups
Total SAE was ~1% and was considered unrelated
to treatment

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Author and year,
trial identifier(s)Gupta et al. 2022c[53]
COMET-PEAK (Parts B and C)
NCT04779879

Primary efficacy outcome(s)Safety outcome(s)Ratio of least square geometric mean viral load AUC(D1-8) for
sotrovimab IM group vs IV group, LS geometric mean (90% CI)>
Part B: 1.04 (0.98-1.09)>
Part C: 1.02 (0.94-1.11)

Occurrence of injection site reactions, n (%)>
Part B 500 mg IV: 0 (0)>Part B 500 mg IM: 10 (12)>Part C 500 mg IV: 0 (0)>Part C 250 mg IM: 4 (5)Occurrence of grade 3 SAEs, n>Part B 500 mg IV: 1>
Part B 500 mg IM: 2>
Part C 500 mg IV: 0>
Part C 250 mg IM: 1
Occurrence of grade 4 SAEs, n>Part B 500 mg IV: 0>
Part B 500 mg IM: 2>
Part C 500 mg IV: 0>
Part C 250 mg IM: 1

Chen et al. 2020[54]BLAZE-1
NCT04427501

Mean change in viral load from baseline at Day 11 forbamlanivimab group versus placebo group, difference ([95% CI],
p-value)>
700 mg bamlanivimab: -0.2 ([-0.66 to 0.25], p=0.38), no
significant difference>
2800 mg bamlanivimab: -0.53 ([-0.98 to -0.08],
p=0.02), [assumed] significant reduction>
7000 mg bamlanivimab: 0.09 ([-0.37 to 0.55], p=0.7),
no significant differenceOccurrence of grade 5 SAEs, n>Part B 500 mg IV: 0>
Part B 500 mg IM: 0>
Part C 500 mg IV: 0>
Part C 250 mg IM: 1
Patients who experienced an AE, n (%)>
700 mg bamlanivimab: 24 (23.8)>
2800 mg bamlanivimab: 23 (21.5)>
7000 mg bamlanivimab: 22 (21.8)>
Placebo: 35 (24.5)[Note: Endpoints for hospitalization are also available in the DEF]

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Author and year,
trial identifier(s)Gottlieb et al. 2021[55]BLAZE-1
NCT04427501

Primary efficacy outcome(s)Safety outcome(s)Mean change in viral load from baseline at Day 11 forbamlanivimab groups versus placebo group, difference ([95% CI],
p-value)>
700 mg bamlanivimab: 0.09 ([-0.35 to 0.52], p=0.69),
no significant difference>
2800 mg bamlanivimab: -0.27 ([-0.71 to 0.26], p=0.21),
no significant difference>
7000 mg bamlanivimab: 0.31 ([-0.13 to 0.76], p=0.16),
no significant difference>
2800 mg bamlanivimab and 2800 mg etesevimab: -0.57([-1.00 to -0.14], p=0.01), significant difference

Patients who experienced ≥1 TEAE, n (%)>
700 mg bamlanivimab: 27 (26.7)>
2800 mg bamlanivimab: 26 (24.3)>
7000 mg bamlanivimab: 22 (21.8)>
2800 mg bamlanivimab and 2800
etesevimab: 19 (17)>Placebo arm: 42 (26.9)

Change in hospitalizations from baseline to Day 29 forbamlanivimab groups versus placebo, % ([95% CI], p-value)[No deaths reported]>
700 mg bamlanivimab: -4.8 ([-8.9 to -0.6], p=0.09), no
significant difference>
2800 mg bamlanivimab: -3.9 ([-8.4 to 0.6], p=0.21), no
significant difference>
7000 mg bamlanivimab: -3.8 ([-8.3 to 0.8], p=0.21), no
significant difference>
2800 mg bamlanivimab and 2800 etesevimab: -4.9 ([-8.9
to -0.8], p=0.49), no significant difference

Dougan et al. 2021a[56]BLAZE-1
NCT04427501
Dougan et al. 2021b[57]
BLAZE-1
NCT04427501[Note: Change in hospitalizations was not the primary endpoint
but was included here for reference]
Hospitalization rate due to COVID-19 or any cause death withbamlanivimab/etesevimab group versus placebo group by Day 28>
70%, p=0.0004; significant reduction withbamlanivimab/etesevimab group
Number of COVID-19-related hospitalizations or deaths throughstudy Day 29, n>Bamlanivimab/etesevimab: 11/518>
Placebo: 36/517>
Reduction rate: 70%, p=0.001

Patients who experienced an AE, n (%)>
Bamlanivimab/etesevimab: 69 (13.3)>
Placebo: 60 (11.6)
Patients who experienced an AE, n (%)>
Bamlanivimab/etesevimab: 69/518(13.3)>
Placebo: 60/517 (11.6)
Patients who experienced a SAE, n (%)>
Bamlanivimab/etesevimab: 7/518 (1.4)>
Placebo: 5/517 (1)190Confidential

Author and year,
trial identifier(s)Dougan et al. 2022[59]BLAZE-1
NCT04427501

Chen et al.

2022[60]

BLAZE-1
NCT04427501

Primary efficacy outcome(s)Safety outcome(s)Overall reduction in COVID-19-related hospitalization or all-cause
death by Day 29, %>Balmanivimab/etesevimab group versus placebo group:87

Patients who experienced a SAE, n (%)>
Balmanivimab/etesevimab: 6 (1.2)>
Placebo: 2 (0.8)

Proportion of patients who experienced COVID-19-related
hospitalization or all-cause death by Day 29, n (%)>
Balmanivimab/etesevimab: 4 (0.8)>
Placebo: 15 (5.8)>
Difference, % ([95% CI], p-value): -5.0 ([-8.0 to -2.1],
p<0.001)
Time to key symptom endpoints for balmanivimab/etesevimab
group versus placebo group, p-value>
Sustained symptom resolution: p=0.009>
Symptom resolution: p=0.016>
Sustained complete symptom resolution: p=0.01

Patients who experienced a TEAE, n (%)>
Balmanivimab/etesevimab: 46 (9.0)>
Placebo: 25 (9.7)

NRTime (days) to symptom improvement, median>Balmanivimab/etesevimab: 7>
Placebo: 9>
p-value: 0.009

Williams et al. 2022†[61]
BLAZE-4
NCT4634409

Proportion of patients demonstrating key symptom endpoints by
Day 11 for balmanivimab/etesevimab group versus placebogroup:>
Sustained symptom resolution: 57.8% vs 47.7%,
p=0.008>
Symptom resolution: 61.8% vs 50.8%, p=0.004>
Symptom improvement: 52.7% vs 40.7%, p=0.002
The primary endpoint was safety[Note: Endpoints for hospitalization and death by day 29 are alsoavailable in the DEF]

Patients who experienced a TEAE, n (%)>
Bebtelovimab: 20/100 (20)>Bebtelovimab/bamlanivimab/etesevimab:
8/50 (16)Patients who experienced a SAE, n (%)>
Bebtelovimab: 18/176 (10.2)>
Bebtelovimab/bamlanivimab/etesevimab:
2/176 (1.1)

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Author and year,
trial identifier(s)Davis et al. 2022[62]Davis et al. 2022
casirivimab/imdevimab
NCT04666441
Huang et al. 2021[63]
UPMC Quality Improvement Review
Committee Project ID 3282.
University of Pittsburgh Institutional
Review Board STUDY210220179

Primary efficacy outcome(s)Safety outcome(s)All 6 casirivimab and imdevimab dose groups showed comparable
virologic reduction through Day 7 versus placebo

Comparable safety for all dose groups

Number of patients with 28 hospital-free days, n (%)[No deaths]>
Casirivimab/imdevimab: 2163/2454 (88.1)>
Sotrovimab: 964/1104 (87.3)

Patients who experienced an AE, n (%)>
Casirivimab/imdevimab: 17/2163 (0.5)>
Sotrovimab: 6/1104 (0.5)

NCT04790786
Chew et al. 2021[64]ACTIV-2/A5401
NCT04518410

Detection of NP SARS-CoV-2 RNA at Day 3 (log10 copies/mL)>
Bamlanivimab 7000 mg: 2.2>
Placebo 7000 mg: 3.4o
P=0.07; significant difference>
Bamlanivimab 700 mg: 2.9>
Placebo 700 mg: 3.9o
P=0.002; significant difference[Note: Detection of NP SARS-CoV-2 RNA at Days 7, 14, and 21
were also primary endpoints]
Time (days) to improvement of all of 13 targeted COVID-19
symptoms (by self-assessment through Day 28)>
Bamlanivimab: 24>
Placebo: 20.5oDifference: 3.5, p=0.08; no significant difference[Note: Endpoints for hospitalization or death are also available in
the DEF]

Patients who experienced a SAE, n (%)>
Casirivimab/imdevimab: 7/2163 (0.2)>
Sotrovimab: 4/1104 (0.4)
Patients who experienced a grade 3 AE, n (%)>
Bamlanivimab 7000 mg: 6/48 (12.5)>
Placebo 7000 mg: 6/48 (13.0)>
Balanivimab 700 mg: 10/111 (9.0)>
Placebo 700 mg: 6/112 (5.4)
Patients who experienced a grade 2+ AE, n (%)>
Bamlanivimab 7000 mg: 18/48 (37.5)>
Placebo 7000 mg: 14/48 (30.4)>
Balanivimab 700 mg: 41/111 (36.9)>
Placebo 700 mg: 25/111 (22.3)
Patients who experienced a SAE, n (%)>
Bamlanivimab 7000 mg: 2/48 (4.2)>
Placebo 7000 mg: 4/48 (8.7)>
Balanivimab 700 mg: 4/111 (3.6)>
Placebo 700 mg: 3/111 (2.7)

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Author and year,
trial identifier(s)Chew et al. 2022[65]ACTIV-2/A5401
NCT04518410

Boucau et al. 2022[66]ACTIV-2/A5401
NCT04518410
Kumarasamy et al. 2022[67]
EMPATHY
NCT04828161

Primary efficacy outcome(s)Safety outcome(s)Detection of SARS-CoV-2 RNA from NP swabs at Days 3, 7, 14, 21,
and 28, n (%)>
Bamlanivimab (7000 mg): 8 (17.4), 11 (23.9), 24 (52.2),
32 (69.6), 34 (72.3)>
Placebo (7000 mg): 8 (18.2), 10 (23.3), 28 (66.7), 32(80.0), 33 (78.6)>
Bamlanivimab (700 mg): 8 (7.6), 13 (12.5), 35 (35.0),
66 (64.1), 70 (72.2)>
Placebo (700 mg): 7 (6.5), 17 (16), 33 (32.4), 56 (53.8),
66 (64.1)

Patients who experienced a grade 3 or higher
TEAE, n (%)>
Bamlanivimab (7000 mg): 6 (12.5)>
Placebo (7000 mg): 6 (13)>Bamlanivimab (700 mg): 12 (10.8)>
Placebo (700 mg): 7 (6.3)

Proportion of patients that were culture-positive at Days 1, 2, 3
and 7, n (%)>
Bamlanivimab: 0 (0.0), 0 (0.0), 0 (0.0), 0 (0.0)>
Placebo: 16 (41.0), 7 (17.9), 8 (21.6), 1 (2.7)
op-value of bamlanivimab group versus placebogroup at Day 1 was <0.0001, significant
difference
Participants achieving sustained clinical recovery by Day 8, %>Ensovibep 75 mg: 30>
Ensovibep 225 mg: 20>
Ensovibep 600 mg: 10>
Placebo: 10

Patients who experienced a SAE, n (%)>
Bamlanivimab (7000 mg): 2 (4.2)>
Placebo (7000 mg): 4 (8.7)>
Bamlanivimab (700 mg): 4 (3.6)>
Placebo (700 mg): 3 (2.7)
NR

Patients who experienced a TEAE, %>Pooled ensovibep: 41.7>
Placebo: 51
No SAEs were observed[Note: the primary efficacy endpoint was “time-weighted change
from baseline in log10 SARS-CoV-2 viral load in nasopharyngeal
swabs to Day 8, versus placebo”, however, this was shown withina figure in the publication and not reported clearly][Note: Endpoints for hospitalization are also available in the DEF]

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Author and year,
trial identifier(s)Streinu-Cercel et al. 2022[68]CT-P59
NCT04602000

Primary efficacy outcome(s)Safety outcome(s)Time (days) to negative RT-qPCR for regdanvimab groups versus
placebo group, median ([95% CI], p-value), significant thresholdof p=0.05>
Regdanvimab 40 mg/kg: 12.8 ([9.0-12.9], p=0.06)>
Regdanvimab 80 mg/kg: 11.9 ([8.9-12.9], p=0.21)>
Either dosage of intervention: 12.7 ([9.0-12.8], p=0.08)>
Placebo: 12.9 (12.7-13.9)

Patients who experienced a TEAE, n (%)>
Regdanvimab 40 mg/kg: 31/105 (29.5)>
Regdanvimab 80 mg/kg: 27 (24.5)>
Placebo: 34/110 (30.9)

Time (days) to Clinical Recovery up to Day 14 for regdanvimab
groups versus placebo group, median ([95% CI], p value),significant threshold of p=0.05>
Regdanvimab 40 mg/kg: 5.3 ([4.0-6.8], p=0.01)>
Regdanvimab 80 mg/kg: 6.2 ([5.5-7.9], p=0.04)>
Either dosage of intervention: 5.7 ([5.2-6.8], p=0.01)>
Placebo: 8.8 (6.8-11.6)

Montgomery et al. 2022a[69]TACKLE
NCT04723394[Note: Endpoints for hospitalization or death are also available in
the DEF]
Relative reduced risk of developing severe COVID-19 or deaththrough Day 29, %>AZD7442: 4>
Placebo: 9>
Risk reduction, % ([95% CI], p-value): 50 ([15-71], p =0.010)

Patients who experienced ≥1 grade 3 TEAE
(related to study drug), n (%)>
Regdanvimab 40 mg/kg: 1/105 (1.0)>
Regdanvimab 80 mg/kg: 0/110 (0.0)>
Placebo: 0/110 (0.0)

Patients who experienced an AE, %>AZD7442: 29>
Placebo: 36
Patients who experienced a SAE, %>AZD7442: 7>
Placebo: 12
AEs of special interest were balanced between
treatment groups[Note: These safety outcomes were also primary
endpoints]

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Author and year,
trial identifier(s)Montgomery et al.

2022b[70]TACKLE
NCT04723394

Hobbs et al. 2022[71]TACKLE
NCT04723394

STAMP 2022[72]STAMP

Primary efficacy outcome(s)Safety outcome(s)Proportion of patients with severe COVID-19 or death from any
cause through Day 29 (mITT population), n (%)>
Tixagevimab/cilgavimab: 18 (4)>Placebo: 37 (9)>RRR, % ([95% CI], p-value): 50.5 ([14.6-71.3],
p=0.0096)

Patients who experienced an AE, n (%)>
Tixagevimab/cilgavimab: 132 (29)>Placebo: 163 (36)

Incidence of death or hospitalization for COVID-19 complications
or sequalae through Day 169, n (%)>
Tixagevimab/cilgavimab: 20 (5.0)>
Placebo: 40 (9.8)>
RRR, % ([95% CI], p-value): 49.1 ([14.5-69.7],
p=0.0009 (for Tixagevimab/cilgavimab group versus
placebo group)
Incidence of hospitalization or death through Day 29, n (%)>
Adintrevimab: 8/169 (4.7)>
Placebo: 23/167 (13.8)>
Standard risk difference, % ([95% CI], p-value): -8.6%([-14.65 to -2.57], p=0.0052)>
RRR: 66%

Patients who experienced a SAE (including death),n (%)>
Tixagevimab/cilgavimab: 33 (7)>Placebo: 54 (12)Patients who experienced an AE of special
interest, n (%)>
Tixagevimab/cilgavimab: 15 (3)>Placebo: 15 (3)Patients who experienced an AE, %>Tixagevimab/cilgavimab: 38.5>
Placebo: 43.5

Occurence of AEs, including SAEs, was lower in
the adintrevimab group versus the placebo group

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Author and year,
trial identifier(s)O’Brien et al. 2022[73]O’Brien et al. 2022
casirivimab/imedevimab
NCT04452318

Mazzaferri et al. 2022[74]
MANTICO
NCT05205759

Primary efficacy outcome(s)Safety outcome(s)Proportion of participants (seronegative) who developed signs andsymptoms of COVID-19 within 14 days of a positive RT-qPCR
result at baseline or during the efficacy assessment period, n (%)>
Casirivimab/imdevimab: 29/100 (29.0)>
Placebo: 44/104 (42.3)>
Adjusted OR ([95% CI], p-value): 0.54 ([0.30-0.97], p =0.04),>
Absolute risk difference, % (95% CI): -13.3 (-26.3 to 0.3)

Patients who experienced ≥1 TEAE, n (%)>
Casirivimab/imdevimab: 52/155 (33.5)>
Placebo: 75/156 (48.1)[Note: Endpoints for hospitalization or death are also available in
the DEF]
Proportion of patients that experienced COVID-19 progression
through Day 14 (Delta variant), n (%)>
Sotrovimab: 0 (0.0)>
Bamlanivimab/etesevimab: 0 (0.0)>
Casirivimab/imdevimab: 0 (0.0)

25.8% of the casirivimab/imdevimab groupexperienced COVID-related TEAEs

NR

Proportion of patients that experienced COVID-19 progression
through Day 14 (Omicron variant), n (%)>
Sotrovimab: 0 (0.0)>
Bamlanivimab/etesevimab: 2 (3.51)>
Casirivimab/imdevimab: 0 (0.0)[Note: Data regarding emergency department visits, all-cause
mortality, duration of supplemental oxygen therapy, and rateand duration of non-invasive ventilation and mechanicalventilation are also available in the DEF]

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Author and year,
trial identifier(s)Portal-Celhay et al. 2022[75]Portal-Celhay et al. 2022
casirivimab/imdevimab
NCT04666441

Kim et al. 2022[76]Kim et al. 2022 regdanvimab
NCT04602000

Primary efficacy outcome(s)Safety outcome(s)Time-weighted average daily change from baseline in viral load
(log10 copies/mL) to Day 7 for casirivimab groups versus matchedplacebo group, LS mean difference ([95% CI], p-value)>
Casirivimab/imdevimab 300 mg IV: -0.57 ([-0.88 to 0.25], p<0.001)>
Casirivimab/imdevimab 600 mg IV: -0.66 ([-0.99 to 0.34], p<0.001)>
Casirivimab/imdevimab 1200 mg IV: -0.56 ([-0.89 to 0.24], p<0.001)>
Casirivimab/imdevimab 2400 mg IV: -0.71 ([-1.05 to 0.38], p<0.001)>
Casirivimab/imdevimab 600 mg SC: -0.56 ([-0.88 to 0.24], p<0.001)>
Casirivimab/imdevimab 1200 mg SC: -0.56 ([-0.87 to 0.24], p<0.001)

Occurrence of AEs, n>
Casirivimab/imdevimab 300 mg IV: 115>
Casirivimab/imdevimab 600 mg IV: 114>
Casirivimab/imdevimab 1200 mg IV: 116>
Casirivimab/imdevimab 2400 mg IV: 115>
Casirivimab/imdevimab 600 mg SC: 114>
Casirivimab/imdevimab 1200 mg SC:
114>
Placebo (IV): 57>
Placebo (SC): 58

Proportion of patients with disease progression up to Day 28 (ITTHigh-risk patients), n (%) [95% CI]>
Regdanvimab: 14 (3.1) [1.9-5.2]>
Placebo: 48 (11.1) [8.4-14.4]
Proportion of patients with disease progression up to Day 28 (ITT),n (%) [95% CI]>
Regdanvimab: 16 (2.4) [1.5-3.9]>
Placebo: 53 (8.0) [6.2-10.4]

Patients who experienced a TEAE, SAE, n (%):>
Casirivimab/imdevimab 300 mg IV: 10(8.7), 0 (0.0)>
Casirivimab/imdevimab 600 mg IV: 16(14.0), 0 (0.0)>
Casirivimab/imdevimab 1200 mg IV: 22(19.0), 1 (0.9)>
Casirivimab/imdevimab 2400 mg IV: 9(7.8), 1 (0.9)>
Casirivimab/imdevimab 600 mg SC: 5(4.4), 0 (0.0)>
Casirivimab/imdevimab 1200 mg SC: 12(10.5), 0 (0.0)>
Placebo (IV): 10 (7.5), 0 (0.0)>
Placebo (SC): 6 (10.3), 0 (0.0)
Patients who experienced a TEAE, n (%)>
Regdanvimab: 198 (30.4)>
Placebo: 202 (31.1)
Patients who experienced a grade ≥3 TEAE, n (%)>
Regdanvimab: 61 (9.4)>
Placebo: 69 (10.6)
Patients who experienced a TESAE, n (%)>
Regdanvimab: 4 (0.6)>
Placebo: 1 (0.2)

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Author and year,
trial identifier(s)Schilling et al. 2022[77]
PLATCOV
NCT05041907

Primary efficacy outcome(s)Safety outcome(s)Time to viral clearance for casirivimab/imdevimab group versus nostudy drug group>
52.3% faster (95% CI: -7.0% to 115.1%)

Patients who experienced any grade ≥3 AE, n>Casirivimab/imdevimab: 0>
No study drug: 2
Patients who experienced a SAE, n>Casirivimab/imdevimab: 0>
No study drug: 2*Events were grade 2 or higher hypersensitivity reactions or infusion-related reactions. †Results for the double-blinded low-risk population for Williams et al.
2022 are not presented here but can be found in the DEF.
AE: adverse event; CI: confidence interval; DEF: data extraction form; COVID: Coronavirus disease; COVID-19: Coronavirus disease 2019; g: grams; ITT:
intention-to-treat; IV: intravenous; kg: kilogram; LS: least squares; LSM: least squares mean; mg: milligram; mL: milliliter; NP: nasopharyngeal; OR: odds ratio;
RNA: ribonucleic acid; RR: relative risk; RRR: relative risk ratio; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; SAE: severe adverse
event; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SC: subcutaneous; TEAE: treatment emergent adverse event; TESAE: treatment emergent
serious adverse event; TRAE: treatment-related adverse event.

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Table 8. RCTs assessing interferons (interferon lambda)
Author and year
Source
Title
Report type
Trial identifier(s)PhaseFeld et al. 2021[78]The BMJPeginterferon lambda for the treatment of
Journal article
Feld et al. 2021 peginterferon
2
MAGIC-WHOoutpatients with COVID-19: a phase 2,
lambdaplacebo-controlled randomized trial
NCT04354259
Jagannathan et al.
The BMJPeginterferon Lambda-1a for treatment of
Journal article
Jagannathan et al. 2021
2
2021[79]
MAGIC-WHOoutpatients with uncomplicated COVID-19: apeginterferon Lambda-1a
randomized placebo-controlled trial
NCT04331899
BMJ: British Medical Journal; COVID-19: Coronavirus disease 2019; MAGIC: Making GRADE the Irresistible Choice; WHO: World Health Organization.
Table 9. Study characteristics of RCTs for interferons (interferon lambda)
Author and year,
Intervention(s) andPatient characteristics
trial identifier(s)comparator
enrollment,
location
Feld et al. 2021[78]>Peginterferon>
Individuals with SARSlambda: SC injection,
CoV-2 infection
Feld et al. 2021
180 μg single dose
confirmed by NP swab,
peginterferon lambda
within 7 days of>Placebo: SC injection
symptom onset (or firstof saline placebo,
NCT04354259
positive test if
single dose
asymptomatic)
18/05/2020-04/09/2020>
Patients were excluded if
hospitalization was
CanadarequiredPrimary (efficacy)
endpoint(s)>Proportion ofindividuals with anegative midturbinate swab for
SARS-CoV-2 at
Day 7

Secondary endpoint(s)

>
>

>
>
>

Time to undetectable
SARS-CoV-2 RNA
Quantitative changein
SARS-CoV-2 RNAover time
Anti-SARS-CoV-2 IgG
antibody positivity
Incidence andseverity of adverse
eventsThe proportion ofpatients admitted tohospital by Day 14[Complete list of secondary
endpoints outlined in the
appendix]

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Author and year,
trial identifier(s)enrollment,
location
Jagannathan et al.
20216[79]Intervention(s) andcomparator>

Patient characteristics

Primary (efficacy)
endpoint(s)Secondary endpoint(s)Adults (aged 18-65>
Time to first of>Time to alleviation ofyears) RT-PCR positive
two consecutive
all symptoms, definedfor SARS-CoV-2 within
negativeas the first day where
Jagannathan et al. 2021
72 hours from swab tooropharyngeal
no symptoms werepeginterferon Lambdathe time of enrollment
tests for SARSreported>
1a
CoV-2 by RT-PCR>
Symptomatic individuals>
SARS-CoV-2
were eligible given theoropharyngeal viral
NCT04331899
presence of mild to
RNA levels over timemoderate symptoms>
SARS-CoV-2
24/04/2020-17/07/2020
without signs oforopharyngeal viral
respiratory distressRNA area under the
US>
Asymptomatic individuals
curve
were eligible if infection>
Incidence of
was initial diagnosis of
emergency
SARS-CoV-2 infection
department visits or>
Excluded criteria
hospitalizations within
included current or
28 days of initiation
imminent hospitalization,of treatment
respiratory rate >20
breaths per minute, androom air oxygen
saturation <94%
IgG: Immunoglobulin G; mL: milliliter; NP: nasopharyngeal; RNA: ribonucleic acid; RT-PCR: reverse transcription-polymerase chain reaction; SARS-CoV-2:
severe acute respiratory syndrome coronavirus 2; SC: subcutaneous; US: United States; μg: microgram.
Peginterferon
lambda: SC injection,
180 μg (0.45 mL),
single dose
Placebo: SC injectionof saline placebo(0.45 mL), single
dose

>

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Table 10. Patients baseline characteristics for RCTs for an interferon (interferon lambda)
Author and year, trial
Number randomized
Age (years)
Sex
identifier(s)Feld et al. 2021[78]Median (IQR)
Female, n (%)>
Peginterferon>
Peginterferon>
Peginterferon
lambda: 30
Feld et al. 2021
lambda: 48 (30lambda: 18 (60)>Placebo: 30
peginterferon lambda
53)>
Placebo: 17 (57)>Placebo: 39 (33NCT04354259
55)
Jagannathan et al.
Median (range)
Female, n (%)>
Overall: 1202021[79]>
Overall: 36 (18>Overall: 50 (41.7)>
Peginterferon
71)>
Peginterferon
lambda: 60
Jagannathan et al. 2021>
Peginterferon
lambda: 24 (40.0)>
Placebo: 60
peginterferon Lambda-1a
lambda arm: 37>
Placebo: 26(18-66)(43.3)
NCT04331899>
Placebo arm: 34(20-71)
IQR: interquartile range; NR: not reported; SD: Standard Deviation.

Time to symptom onset (days)
Mean (SD)>
Peginterferon lambda: 4.3(1.7)>
Placebo: 4.7 (1.7)
Median (IQR)>
Overall: 5 (3-6)>
Peginterferon lambda: 4 (36)>Placebo: 5 (3-5)

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Table 11. Results from RCTs assessing interferons (interferon lambda); primary outcome(s)Author and year,
Primary efficacy outcome(s)trial identifier(s)Feld et al. 2021[78]Undetectable SARS-CoV-2 RNA for peginterferon lambda group versus placebogroup at Day 7, OR ([95% CI], p-value)
Feld et al. 2021>
2.32 ([0.74-7.81], p=0.15), no significant difference
peginterferon lambda
Undetectable SARS-CoV-2 RNA for peginterferon lambda group versus placebo
NCT04354259
group at Day 7 after adjusting for baseline viral load, OR ([95% CI], pvalue)>
4.12 ([1.15 to 16.73], p=0.029), significant increase

Safety outcome(s)Patients who experienced an AE, n (%)>
Peginterferon lambda: 2 (7)>Placebo: 1 (3)Patients who experienced a SAE, n (%)>
Peginterferon lambda: 1 (3)>Placebo: 1 (3)Undetectable SARS-CoV-2 RNA for peginterferon lambda group versus placebogroup at Day 7 for patients with baseline viral load ≥108 copies per mL, OR([95% CI], p-value)>
6.25 ([1.49 to 31.06], p=0.012), significant increase
Jagannathan et al.
2021[79]
Jagannathan et al. 2021
peginterferon Lambda1a[Note: Endpoints for hospitalization or death are also available in the DEF]
Viral shedding cessation for peginterferon lambda group versus placebo group,aHR ([95% CI], p-value)>
0.81 ([0.56-1.19], p=0.29), no significant difference[Note: Endpoints for hospitalization are also available in the DEF]

Patients who experienced an AE, n (%)>
Peginterferon lambda: 25 (42)>Placebo: 21 (35)Patients who experienced a SAE, n (%)>
Peginterferon lambda: 2 (3)>Placebo: 2 (3)NCT04331899
AE: adverse event; aHR: adjusted hazard ratio; BMJ: British Medical Journal; CI: confidence interval; DEF: data extraction form; OR: odds ratio; RNA: ribonucleic
acid; SAE: serious adverse event; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Table 12. RCT assessing the H2 antagonist, famotidine
Author and year
SourceTitle
Brennan et al.
2022[80]OVID

COVID-19: Coronavirus disease 2019.

Oral famotidine versus placebo in non-hospitalized patientswith COVID-19: a randomized, double-blind, data-intense,
phase 2 clinical trial

Reporttype
JournalarticleTrial identifier(s)PhaseBrennan et al. 2022
famotidine
NCT04724720

2

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Table 13. Study characteristics of the RCT assessing famotidine for the treatment of COVID-19
Author and year,
Intervention(s) andPatient characteristics
Primary (efficacy)
trial identifier(s)comparators
endpoint(s)enrollment, location
Brennan et al.
Famotidine and placebo
Patients with a laboratory
Time to symptom2022[80](microcrystalline
confirmed SARS-CoV-2 test
resolution (by Day 28)
cellulose)less than 72 hours prior to
Brennan et al. 2022
randomization and at least
famotidine
three symptoms of moderate
severity
NCT04724720

Secondary endpoint(s)The impact of earlier symptom
resolution of famotidine on an individual
symptom level

01/2021-04/2021
US
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; US: United States.
Table 14. Patient baseline characteristics in RCTs of famotidine for the treatment of COVID-19
Author and year, trial
Number randomized
Age (years)
Sex
identifier(s)Brennan et al. 2022[80]Mean (SD)Male, female, n (%)>
Overall: 55>
Overall: 35 (20)>Overall: 29 (36.4),>
Famotidine: 27
Brennan et al. 2022 famotidine
35 (63.3)>
Famotidine: 35>
Placebo: 28>
Famotidine: 10(18)
NCT04724720(37), 17 (63)>Placebo: 31.5 (13)>Placebo: 13(35.7), 18 (64.3)
IQR: interquartile range; SD: standard deviation.

Time to symptom onset(days)Median (IQR)>
Overall: 4 (2)>Famotidine arm: 4(3)>
Placebo arm: 4 (2)203Confidential

Table 15. Results from RCT assessing famotidine for the treatment of COVID-19
Author and year, trial
Primary efficacy outcome(s)identifier(s)Brennan et al. 2022[80]Time (days) to 50% symptom resolution by study Day 28, estimated time
(95% CI)
Brennan et al. 2022 famotidine>
Famotidine: 8.2 (7-9.8)>
Placebo: 11.4 (10.3-12.6)
NCT04724720
Time to symptom resolution by Day 28 famotidine group versus placebogroup>
ITT population: p=0.4 (0.05 threshold)>PP population: p=0.3 (0.05 threshold)

Safety outcome(s)Patients who experienced an AE, n>Famotidine: 3>
Placebo: 2
Patients who experienced a SAE, n>Famotidine: 3>
Placebo: 2[Note: Endpoints for hospitalization or death are also available in the DEF]
AE: adverse event; CI: confidence interval; DEF: data extraction form; ITT: intention-to-treat; PP: per-protocol; SAE: serious adverse event.
Table 16. RCTs assessing steroids (budesonide)
Author and year
Source
Title
Report type
Ramakrishnan et
OVID
Inhaled budesonide in the treatment of early
Journal article
al. 2021[81]
COVID-19 (STOIC): a phase 2, open-label,randomized controlled trial
Yu et al. 2021a[82]
NIH guidelines
Inhaled budesonide for COVID-19 in people at
Journal article
higher risk of adverse outcomes in the(pre-print)
community: interim analyses from the PRINCIPLE
trial
Yu et al. 2021b[83]
OVID
Inhaled budesonide for COVID-19 in people at
Journal article
high risk of complications in the community in the(published)
UK (PRINCIPLE): a randomized, controlled, openlabel, adaptive platform trial
COVID-19: Coronavirus disease 2019; NIH: National Institutes of Health; NR: not reported; UK: United Kingdom.

Trial identifier(s)STOIC
NCT04416399

Phase
2

PRINCIPLE trial
ISRCTN86534580

NR [Appears
to be phase3]

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Table 17. Study characteristics of RCTs for steroids (budesonide)
Author and year,
Intervention(s) andPatient characteristics
trial identifier(s)comparator
enrollment,
location
Ramakrishnan et al. 2021[81]

>

STOIC
NCT04416399
16/07/2020-09/12/2020
UK>

Budesonide: dry
powder inhaler
at a dose of 400
μg peractuation; twopuffs BID; total
dose 1600 μg
daily
Usual care
(symptomatic
treatment
according to
NHS advice)>>

Adults (aged ≥18
years) withsymptoms of
COVID-19 (newonset cough andfever or anosmia,
or both) within 7
days
Patient requiring
hospitalization attime of study
consent were
excludedPrimary (efficacy)
endpoint(s)>COVID-19related urgent
care visits
includingemergency
department or
hospitalization

Secondary endpoint(s)

>
>
>
>

Self-reported time tosymptom resolution
Viral symptoms measured
by the CCQ and the FLUPro
Blood oxygen saturation andbody temperature
SARS-CoV2 viral load

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Author and year,
trial identifier(s)enrollment,
locationYu et al. 2021a[82]Intervention(s) andcomparator>

Budesonide plus
usual care:
Budesonide
inhaled 800 μg
BID for 14 days
Usual care
(undefined but
likely focused on
management ofsymptoms, as
per UK National
Health Service(NHS) practice)

Patient characteristics>

People (aged ≥65
years, or ≥50 years
with comorbidities)
in the community
with ongoing
symptoms from
PCR-confirmed orsuspected COVID19 which started
within the past 14
days
Exclusion criteria
included being
currently
hospitalized or
admitted to hospitaland already taking
inhaled or systemic
corticosteroids

Primary (efficacy)
endpoint(s)Within 28 days of
randomization:>
Time to firstreportedrecovery>Hospitalization
or death
related to
COVID-19

Secondary endpoint(s)>Binary outcome of earlysustained recovery
PRINCIPLE trial>
Daily rating of how wellparticipants feel
ISRCTN86534580 [trial does not>
Time to initial alleviation of
appear on clinicaltrials.gov]>
symptoms>
Time to sustained alleviation
27/11/2020-25/03/2021 [cutof symptoms
off date for presented data]>
Time to initial reduction ofseverity of symptoms
UK>
Contacts with health service>>
Hospital assessment without[83]
Yu et al. 2021b
admission>
Oxygen administration
PRINCIPLE trial>
ICU admission>
Mechanical ventilation
ISRCTN86534580>
Adherence to study
treatment
27/11/2020-31/03/2021>
WHO-5 Wellbeing Index>
Reports of new householdUKinfections[Full list of secondary outcomeslisted within supplementary
appendix]
BID: twice daily; CCQ: Common Cold Questionnaire; COVID-19: Coronavirus disease 2019; FLUPro: InFLUenza Patient Reported Outcome; ICU: intensive care
unit; NHS: National Health Service; PCR: polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; WHO: World HealthOrganization; UK: United Kingdom; μg: microgram.

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Table 18. Patients baseline characteristics for RCTs for steroids (budesonide)
Author and year, trial
Number randomized
Age (years)
identifier(s)Ramakrishnan et al.
Mean (range)>
Budesonide:2021[81]>
Budesonide: 44 (197071)>
Usual care: 69
STOIC>
Usual care: 46 (1979)
NCT04416399
Yu et al. 2021a[82]<65 years, ≥65 years, n (%)>
Budesonide:>
Budesonide: 277
1032
PRINCIPLE trial(34.4), 528 (65.6)>
Usual care:>
Usual care: 456
1943
ISRCTN86534580 [trial(41.5), 644 (58.5)
does not appear on[in COVID-positive analysis
clinicaltrials.gov]
population]

Sex

Time to symptom onset (days)

Female, n (%)>
Budesonide: 39 (56)>
Usual care: 41 (59)Median (IQR)>
Budesonide: 3 (2-5)>
Usual care: 3 (2-4)

Male, n (%)>
Budesonide: 390(48.4)>
Usual care: 528(48.0)[in COVID-positive analysis
population]Median (IQR)>
Budesonide: 6.0 (4.0-9.0)>
Usual care: 6.0 (4.0-9.0)[in COVID-positive analysis
population]

Mean (SD), <65 years n (%),
≥65 years n (%)
Female, male, n (%)>
Budesonide:>
Budesonide: 64.7
PRINCIPLE trial>
Budesonide: 429
1073(7.3), 297 (36), 536(52), 404 (48)(64)>
Usual care:
ISRCTN86534580>
Usual care: 63.8>
Usual care: 586 (52),1988(7.8), 475 (42), 651
540 (48)(58)
COVID: Coronavirus disease; IQR: interquartile range; NR; not reported; SD: standard deviation.
Yu et al. 2021b[83]207Confidential

Table 19. Results from RCTs assessing steroids (budesonide); primary outcome(s)Author and year,
Primary efficacy outcome(s)trial identifier(s)Ramakrishnan et al.
Rate of hospitalization for budesonide group versus usual care group, difference2021[81](95% CI)>
0.131 (0.043-0.218)
STOIC>
p=0.004; significant reduction difference
NCT04416399

Proportion of patients with symptom resolution at Day 14 for budesonide groupversus usual care group, difference (95% CI)>
0.10 (-0.04 to 0.24)>
p=0.166; no significant difference

Yu et al. 2021a[82]Benefit in time (days) to first reported recovery for budesonide group vs usual caregroup, median (95% BCI)>
3.011 (1.124-5.410)>
probability of superiority = 0.999*; significant improvement

PRINCIPLE trial
ISRCTN86534580 [trial
does not appear on
clinicaltrials.gov]
Yu et al. 2021b[83]
PRINCIPLE trial
ISRCTN86534580

Safety outcome(s)Patients who experienced an AE, n (%)>
Budesonide: 5 (7)>Usual care: NR

Patients who experienced a SAE, n (%)>
Budesonide: 2/70 (7)>Usual care: NR

Estimated benefit in patients hospitalized or dead at Day 28 for budesonide groupvs usual care group, % (95% BCI)>
2.1 (-0.7 to 4.8)>
probability of superiority = 0.928*; not significant
Time (days) to first reported recovery (outpatient cohort), median (95% BCrI)>
Budesonide: 11.8 (10.0-14.1); probability of superiority >0.999*>
Usual care: 14.7 (12.3-18.0); probability of superiority >0.999*>
HR/OR: 1.21 (1.08-1.36); probability of superiority >0.999*
Patients hospitalized or dead at Day 28 (outpatient cohort), (%)>
Budesonide: 6.8>
Usual care: 8.8>
Estimated benefit, % (95% BCI): 2 (-0.2 to 4.5)>
HR/OR: 0.75 (0.55-1.03); p=0.963*Predefined superiority threshold of 0.975

AE: adverse event; BCI: Bayesian credible interval; BCrI: Bayesian credible interval; CI: confidence interval; HR: hazard ratio; NR: not reported; OR: odds ratio;
SAE: serious adverse event.

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Table 20. RCTs assessing a selective serotonin reuptake inhibitor (fluvoxamine)
Author and year
SourceReport title
Lenze et al. 2020[84]
OVID
Fluvoxamine vs Placebo and Clinical Deterioration in
Outpatients with Symptomatic COVID-19
Seo et al. 2022[85]OVID
Fluvoxamine Treatment of Patients with Symptomatic
COVID-19 in a Community Treatment Center: A
Preliminary Result of Randomized Controlled Trial
Reis et al. 2022[86],[87]OVID
Effect of early treatment with fluvoxamine on risk ofemergency care and hospitalization among patientswith COVID-19: the TOGETHER randomized, platformclinical trial
Bramante et al.
OVID
Randomized Trial of Metformin, Ivermectin, and2022[88]
Fluvoxamine for Covid-19
McCarthy et al.
OVID
Fluvoxamine for Outpatient Treatment of COVID-19: A
2022[89]
Decentralized, Placebo-controlled, Randomized,
Platform Clinical Trial
COVID-19: Coronavirus disease 2019.

Report type
Journal article
Journal article
Journals article

Journal article
Journal article(pre-print)

Trial identifier(s)STOP COVID trial
NCT04342663
Seo et al. 2022
fluvoxamine
NCT04711863
TOGETHER
NCT04727424

Phase
2

COVID-OUT
NCT04510194
ACTIV-6
NCT04885530

3

2
3

3

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Table 21. Study characteristics of RCTs for a selective serotonin reuptake inhibitor (fluvoxamine)
Trial report,
Intervention(s) and comparator
Patient characteristics
Primary (efficacy)
trial identifier(s)endpoint(s)enrollment,
location
Lenze et al.
Clinical deterioration within>
Fluvoxamine: 50 mg first>
Adult outpatients
2020[84]
15 days of randomization;
dose; two days at 100 mg
living in the
BID as tolerated; 100 mg
community (aged defined as both:
STOP COVID trial>
Shortness of
three times daily as tolerated≥18 years) withbreath or
through Day 15
SARS-CoV-2,
NCT04342663
hospitalization for
confirmed by PCR>
Matched placebo: Same as
shortness oftesting
intervention
10/04/2020breath or>
Symptomatic
05/08/2020
pneumonia
within 7 days of>
Oxygen saturation
the first dose ofUSless than 92% on
study medication
room air or need>Excludedfor supplemental
characteristics
oxygen to achieve
includedoxygen saturation
hospitalization,of 92% or
oxygengreater)saturation >92%,
and requiring
home oxygen

Secondary
endpoint(s)

>
1.
2.
3.
4.
5.
6.

>

>

Clinical deterioration ona Likert-type scale
Oxygen saturation <92%
but no supplemental
oxygen requirement
Oxygen saturation <92%plus supplemental oxygen
requirement
2 plus hospitalization
related to dyspnea or
hypoxia
3 plus ventilator support
needed for <3 days
3 plus ventilator support
needed for ≥3 days
Death
The number of days
requiring supplemental
oxygen, hospitalization,or ventilator support
Symptomatic severity
during the 15 days ofthe trial using acontinuous scale of eachpatient’s most severebaseline symptom on an
11-point scale

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Trial report,
trial identifier(s)enrollment,
location
Seo et al. 2022[85]Seo et al. 2022
fluvoxamine
NCT04711863
15/01/202108/02/2021

Intervention(s) and comparator>>

Fluvoxamine: Oraladministration, 50 mg on Day
1 followed by 100 mg BID for
approximately 10 days
Matched placebo(ursodeoxycholate): Same asintervention

Patient characteristics>>

South Korea>

Patients withmild symptoms
associated with
COVID-19
admitted to acommunity
treatment center
Onset ofsymptoms
consistent with
COVID-19 within
7 days ofrandomization
Had a laboratory
confirmed SARSCoV-2 test within
72 hours of
randomization

Primary (efficacy)
endpoint(s)Definition of clinicaldeterioration:>
Decrease inoxygen saturation(SpO2 <94%) on
room air>Supplemental
oxygen required
to maintain anoxygen saturation≥94%>
Aggravation ofpneumonia withdyspnea: clinicallydevastating
condition judged
by clinician plus
increased
infiltration ofchest X-ray or
minute respiratory
rate over 25>
WHO Clinical
Progression ≥4
includingintubation anddeath)

Secondary
endpoint(s)>All the categories ofclinical deterioration
described as primary
endpoints and days toclinical deterioration

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Trial report,
trial identifier(s)enrollment,
location
Reis et al. 2022[86],[87]

TOGETHER
NCT04727424
02/06/202009/09/2021(enrollment for the
fluvoxamine groupbegan on20/01/2021)
BrazilIntervention(s) and comparator>>

Fluvoxamine: Oraladministration, 100 mg BID
for 10 days
Matched placebo: Same asintervention

Patient characteristics

>

OR

>

Outpatients withan acutecondition
consistent with
COVID-19(beginning within
7 days ofscreening)
Positive rapid
test for SARSCoV-2 done at
the time ofscreening with apositive test
within 7 days ofsymptom onset

Primary (efficacy)
endpoint(s)

>

OR

>

Medical admission
to a hospitalsetting due to
COVID-19-related
illness defined as
COVID-19
emergency setting
visits withparticipantsremaining underobservation for
more than 6
hours

Secondary
endpoint(s)NR

Referral to further
hospitalization
due to theprogression of
COVID-19 within
28 days of
randomization

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Trial report,
trial identifier(s)enrollment,
location
Bramante et al.
2022[88]

Intervention(s) and comparator>

COVID-OUT
NCT04510194
30/12/202028/01/2022

>

US

>

>
>

>

Metformin active: Metformin
and placebo, metformin andivermectin, or metformin andfluvoxamineoMetformin: Oraladministration, increase
dose over 6 days to 1500
mg/day for 14 days
Metformin control: Placeboalone, ivermectin alone, or
fluvoxamine aloneoMatched placebo
Ivermectin active: Metformin
and ivermectin or ivermectinaloneoIvermectin: Oraladministration, 390-470µg/kg/day for 3 days
Ivermectin control: Placeboalone or metformin aloneoMatched placebo
Fluvoxamine active:
Metformin and fluvoxamine or
fluvoxamine aloneoFluvoxamine: Oraladministration, 50 mg
twice daily for 14 days
Fluvoxamine control: Placeboalone or metformin aloneoMatched placebo

Patient characteristics>>

Patients (aged30-85 years)
with a BMI
associated withoverweight orobesity
Proof of SARSCoV-2 infection
within the past 3days and an
onset ofsymptoms within
7 days before
randomization

Primary (efficacy)
endpoint(s)>Severe COVID-19
through 14 days,
defined ascomposite ofhypoxemia,
emergency
department visit,
hospitalization, or
death

Secondary
endpoint(s)>>Daily symptom severity
Drug discontinuations

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Trial report,
trial identifier(s)enrollment,
location
McCarthy et al.
2022[89]
ACTIV-6
NCT04885530
06/08/202127/05/2022

Intervention(s) and comparator>>

Fluvoxamine: Oraladministration, 50 mg dailyfor 10 days
Placebo: Oral administrationfor 10 days

Patient characteristics>

Patients (aged≥30 years) withconfirmed SARSCoV-2 infection≤10 days, andexperiencing ≥2
COVID-19
symptoms for ≤7days from time ofconsent

Primary (efficacy)
endpoint(s)>Secondary
endpoint(s)Time to recovery,
defined as thethird of 3
consecutive days
without symptoms

>
>
>
>

Hospitalization or deathby Day 28
Time unwell
COVID-19 Clinical
Progression Scale score
on Days 7, 14, and 28
Mortality, urgent or
emergency care visit, or
hospitalization throughDay 28US
BID: twice daily; BMI: body-mass index; COVID: Coronavirus disease; COVID-19: Coronavirus 2019; kg: kilogram; mg: milligram; NR: not reported; PCR:
polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SpO2: peripheral capillary oxygen saturation; US: United States;
WHO: World Health Organization; µg: microgram.
Table 22. Patients baseline characteristics for RCTs for a selective serotonin reuptake inhibitor (fluvoxamine)
Author and year, trial
Number randomized
Age (years)
Sex
identifier(s)Lenze et al. 2020[84]Mean (IQR)
Female, n (%)>
Fluvoxamine:>
Fluvoxamine: 46>
Fluvoxamine: 56 (70)80
STOP COVID trial(35-58)>
Placebo: 72>
Placebo: 53 (74)>Placebo: 45 (36-54)
NCT04342663
Seo et al. 2022[85]Median (IQR)
Male, n (%)>
Fluvoxamine:>
Fluvoxamine: 54>
Fluvoxamine: 18
26
Seo et al. 2022
(44.0-60.3)(69.2)>
Placebo: 26
fluvoxamine>
Placebo: 51.5 (42.0>
Placebo: 13 (50)59.3)
NCT04711863

Time to symptom onset (days)
Median (IQR)>
Fluvoxamine: 4 (3-5)>
Placebo: 4 (3-5)
Median (IQR)>
Overall: 1 (0-1)

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Author and year, trial
identifier(s)Reis et al. 2022[86],[87]TOGETHER

Number randomized>>

Fluvoxamine:
741
Placebo: 756

NCT04727424

Bramante et al.
2022[88]
COVID-OUT
NCT04510194

>
>
>
>
>
>

McCarthy et al. 2022[89]ACTIV-6
NCT04885530>>>

Metformin
active: 663
Metformin
control: 660
Ivermectin
active: 410
Ivermectin
control: 398
Fluvoxamine
active: 334
Fluvoxamine
control: 327
Overall: 1288
Fluvoxamine:
674
Placebo: 614

IQR: interquartile range; NR: not reported.

Age (years)

Sex

Time to symptom onset (days)<50, ≥50, not specified, n(%)>
Fluvoxamine: 379(51), 327 (44), 46(6)>
Placebo: 368 (49),328 (43), 49 (6)n (%)

Median (IQR)>
Metformin active: 46(38-55)>
Metformin control:
45 (37-55)>
Ivermectin active:
46 (39-55)>
Ivermectin control:
45 (37-56)>
Fluvoxamine active:
46 (38-53)>
Fluvoxamine control:
43 (37-55)
Median (IQR)>
Overall: 47.0>
Fluvoxamine: 47.0
(37.0-56.8)>
Placebo: 48.0 (39.058.0)

Female, n (%)>
Metformin active: 359(54.1)>
Metformin control:
382 (57.9)>
Ivermectin active:
216 (52.7)>
Ivermectin control:
226 (56.8)>
Fluvoxamine active:
170 (50.9)>
Fluvoxamine control:
188 (57.5)
Female, male, prefer not toanswer, n (%)>
Overall: 734 (56.99),
551 (42.78), 3 (0.23)>
Fluvoxamine: 387(57.42), 286 (42.43),
1 (0.15)>
Placebo: 347 (56.51),
265 (43.16), 2 (0.33)>>

Fluvoxamine: Female:409 (55%) Male:332(45%)
Placebo: Female: 453(60%) Male: 303(40%)

0-3 days, 4-7 days, unspecified, n(%)>
Fluvoxamine: 328 (44),239 (32), 174 (23)>Placebo: 310 (41), 267(35), 179 (24)
Mean (SD), ≤4 days, n (%)>
Metformin active: 4.8(1.9), 298 (45.6)>
Metformin control: 4.8(1.9), 305 (47.5)>
Ivermectin active: 4.6(1.9), 199 (49.0)>
Ivermectin control: 4.8(1.8), 174 (44.5)>
Fluvoxamine active: 5.0(2.2), 147 (44.5)>
Fluvoxamine control: 4.7(1.8), 146 (45.3)
Mean (range)>
Overall: 4 (2-5)>
Fluvoxamine: 4 (2-5)>
Placebo: 4 (2-5)

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Table 23. Results from RCTs assessing a selective serotonin reuptake inhibitor (fluvoxamine); primary outcome(s)Trial report,
Primary efficacy outcome(s)Safety outcome(s)trial identifier(s)Lenze et al. 2020[84]Absolute difference in proportions with clinical deterioration for fluvoxamine
Patients who experienced a SAE, ngroup versus placebo group (95% CI, survival analysis for clinical>Fluvoxamine: 1
STOP COVID trial
deterioration using a log-rank test)>
Placebo: 6>
8.7 (1.8-16.4)
NCT04342663>
p=0.009; significantly lower with fluvoxamine group versus placebo
Patients who experienced a “other” AE, ngroup>
Fluvoxamine: 11>
Placebo: 12[Note: Clinical deterioration was ranked using the WHO ordinal scale for
COVID-19 trials, which includes hospitalization]
Seo et al. 2022[85]Clinical deterioration (absolute difference is a difference in proportions), n (%) Occurrence of drug related AEs linked totermination of treatment, n>Fluvoxamine: 2/26 (7.7%), p>0.99
Seo et al. 2022 fluvoxamine>
Fluvoxamine: 10>
Placebo: 2/26 (7.7%), p>0.99>
Placebo: 1>
Difference ([95% CI], p-value): 0 ([-17.37 to 17.37], p>0.99)
NCT04711863
Reis et al. 2022[86],[87]Proportion of primary outcome events and RR of hospitalization defined as
Patients who experienced a TEAE (Grade 1,
either retention in a COVID-19 emergency setting or transfer to tertiary
2, 3, 4, 5), n (%)
TOGETHER
hospital due to COVID-19 for patients allocated fluvoxamine versus placebo, n>Fluvoxamine: 20 (3), 72 (10), 38(%)(5), 21 (3), 18 (2)NCT04727424>
ITT analysis:>Placebo: 11 (1), 81 (11), 50 (7), 20oFluvoxamine: 79/741 (11)(3), 26 (3)oPlacebo: 119/756 (16)o
RR (95% BCI): 0.68 (0.52-0.88); probability of superiority:
99.8%*>
mITT analysis:oFluvoxamine: 78/740 (11)oPlacebo: 115/752 (15)oRR (95% BCI): 0.69 (0.53-0.90); probability of superiority:
99.7%*Surpassed prespecified superiority threshold of 97·6% (risk difference 5.0%)

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Trial report,
trial identifier(s)Bramante et al. 2022[88]
COVID-OUT
NCT04510194

McCarthy et al. 2022[89]ACTIV-6

Primary efficacy outcome(s)Safety outcome(s)Rate of severe COVID-19 through Day 14 (mITT population), n (%)>
Metformin active: 154 (23.6)>
Metformin control: 179 (27.4)oAdjusted OR for active group versus control group ([95%CI], p-value): 0.84 ([0.66-1.09], p=0.19)>
Ivermectin active: 105 (25.8)>
Ivermectin control: 96 (24.6)oAdjusted OR for active group versus control group ([95%CI], p-value): 1.05 ([0.76-1.45], p=0.78)>
Fluvoxamine active: 79 (24.0)>
Fluvoxamine control: 80 (24.9)oAdjusted OR for active group versus control group ([95%CI], p-value): 0.94 ([0.66-1.36], p=0.75)
Time to recovery (mITT population), median (IQR)>
Fluvoxamine: 12 (12-13)>
Placebo: 13 (12-13)

Patients who experienced totalinterruption/discontinuation of treatment, n(%)>
Metformin active: 201 (30.3)>
Metformin control: 164 (24.8)>
Ivermectin active: 92 (22.4)>
Ivermectin control: 156 (26.9)>
Fluvoxamine active: 117 (35.0)>
Fluvoxamine control: 156 (26.9)

Patients who experienced an AE, n (%)>
Fluvoxamine: 32 (5.2)>
Placebo: 35 (6.2)

NCT04885530

Patients who experienced a SAE, n (%)>
Fluvoxamine: 3 (0.49)>
Placebo: 5 (0.88)
AE: adverse event; BCI: Bayesian credible interval; CI: confidence interval; COVID-19: Coronavirus 2019; ITT: intention-to-treat; IQR: interquartile range;mITT: modified intention-to-treat; OR: odds ratio; RR: relative risk; SAE: serious adverse event; TEAE: Treatment emergent adverse event.
Table 24. RCTs assessing the serine protease inhibitor, camostat mesylate
Author and year
SourceReport title
Report type
Trial identifier(s)Phase
Chupp et al. 2022[90]OVID
A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial Journal article
Chupp et al. 2022
2of Oral Camostat Mesylate for Early Treatment of COVID-19
camostat mesylate
NCT04724720
Outpatients Showed Shorter Illness Course and Attenuationof Loss of Smell and Taste
Jilg et al. 2022a[91]CROI
A randomized controlled trial of camostat in outpatients with
Conference
CAMELOT
22022
COVID-19
abstract
NCT04583592
Jilg et al. 2022b[92]
CROI
Camostat is not effective for mild-moderate COVID-19 in a
Conference
ACTIV-2/A5401
2
2022
phase 2 Trial of ACTIV-2
abstract
NCT04518410
Tobback et al.
OVID
Efficacy and safety of camostat mesylate in early COVID-19
Journal article
Tobback et al. 2022
2
2022[93]
disease in an ambulatory setting: a randomized placebocamostat mesylate
controlled phase II trial
NCT04625114
COVID: Coronavirus disease; COVID-19: Coronavirus 2019; CROI: Conference on Retroviruses and Opportunistic Infections; RCT: Randomized controlled trial.

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Table 25. Study characteristics of RCTs assessing camostat mesylate for the treatment of COVID-19
Author and year,
Intervention(s) andPatient characteristics
Primary (efficacy)
trial identifier(s)comparators
endpoint(s)enrollment, location
Chupp et al. 2022[90]>Camostat mesylate:>Patients with a first>
Reduction of 4-day
Oral administration,
positive RT-PCR for
log10 NP swab viral
Chupp et al. 2022 camostat
camostat mesylate
COVID-19 within 3load by 0.5 log10mesylatecompared to
200 mg 4 times adays before
placebo
day for 7 days
enrollment with at
NCT04353284
least one>
Matching placebo
compatible
06/2020-04/2021
COVID-19 symptom
US
Jilg et al. 2022a[91]>

CAMELOT
NCT04583592
08/11/2020-31/03/2021
US>

Camostat mesylate:
Oral administration,
two 100 mg tablets(200 mg total) taken
four times daily for
14 days, plus SOC
Placebo plus SOC>

Patients (aged ≥18
years) withlaboratory
confirmed mild or
moderate COVID19 infection (SpO2>94% at screening)with ≥1 risk factors
for severe illness>

Hospitalization ordeath within 28
days

Secondary endpoint(s)

>

>

>

Change in log10 NP viralload from baseline(Day 0), Day 2 andDay 6 postrandomization
COVID-19 PRO daily
self-scoring tool
(FLUpro) (symptom
severity scoring
system)Positivity for SARSCoV-2 by PCR on midnasal turbinate swabs
on Days 7 and 15
compared to baseline[Note: An extensive list can befound on clinicaltrials.gov]

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Author and year,
trial identifier(s)enrollment, location
Jilg et al. 2022b[92]
ACTIV-2/A5401
NCT04518410

Intervention(s) andcomparators>>

Camostat mesylate: Oraladministration, 200 mg
every 6 hours for 7 days
Placebo

Patient characteristics

>
>
>

US

>

Laboratory
confirmed
COVID-19 infection
Treatment ≤7 daysof symptom onset
One or more
symptom within 24
hours ofparticipating
Oxygen levels of≥92% obtained at
rest

Primary (efficacy)
endpoint(s)

>

>

>

>

Tobback et al. 2022[93]>Tobback et al. 2022
camostat mesylate
NCT04625114
04/11/2020-06/2021>

Camostat mesylate:
Oral administration,
three 100 mg
tablets, 3 times daily
for 5 days
Placebo: Oraladministration, 3tablets, 3 times daily
for 5 days>

Patients (aged ≥18
years) withconfirmed COVID19 infection by RTPCR showing Ctvalue below 30

COVID-19 symptom
duration (Phase 2)[Time Frame: Up toDay 28]Quantification of
SARS-CoV-2 RNA(Phase 2) [Day 3, 7,
and 14]
Proportion ofparticipants with
new AE ≥ Grade 3(Phases 2 & 3)
[Through Day 28]
Cumulative
incidence of death
due to any cause or
hospitalization due
to any cause (Phase3) [Through Day
28][Note: reported onclinicaltrials.gov but notwithin abstract]>
Change in theshedding of the
SARS-CoV-2 virus
as measured by Ct
obtained from NP
swabs on Days 1
and 5

Secondary endpoint(s)NR[Note: An extensive list can befound on clinicaltrials.gov]>>

Time to clinicalimprovement
SafetyBelgium
AE: adverse event; COVID-19: Coronavirus 2019; CROI: Conference on Retroviruses and Opportunistic Infections; Ct: cycle threshold; FLUPro: InFLUenza Patient
Reported Outcome; mg: milligram; NP: nasopharyngeal; NR: not reported; PRO: patient reported outcome; RNA: ribonucleic acid; RT-PCR: reverse transcriptionpolymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOC: standard of care; SpO2: peripheral capillary oxygen saturation;
US: United States.

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Table 26. Patient baseline characteristics of RCTs assessing camostat mesylate for the treatment of COVID-19
Author and year, trial
Number randomized
Age (years)
Sex
identifier(s)Chupp et al. 2022[90]Mean (range)
Female, n (%)>
Overall: 70>
Overall: 44.1 (20.6>
Camostat: 35
Chupp et al. 2022 camostat>
Total: 28 (40)78.2)>
Placebo: 35
mesylate>
Camostat: 44.1>
Camostat: 13 (37.1)(23.2-78.2)>
Placebo: 15 (42.9)
NCT04353284>
Placebo: 44.1 (20.669.4)
Jilg et al. 2022a[91]Mean (SD)
Female, n (%)>
Camostat: 194>
Camostat: 52 (17)>Camostat: 108>
Placebo: 101
CAMELOT(55.7)>
Placebo: 51 (18)>Placebo: 61 (60.4)
NCT04583592
Jilg et al. 2022b[92]MedianFemale, %>Overall: 215>
Overall: 37>
Overall: 54>
Camostat: 108
ACTIV-2/A5401>
Camostat: NR>
Camostat: NR>
Placebo: 107>
Placebo: NR>
Placebo: NR
NCT04518410
Tobback et al. 2022[93]Median (IQR)
Female, n (%)>
Overall: 96>
Overall: 40 (25-53)>
Overall: 49 (54.4)>
Camostat: 66
Tobback et al. 2022 camostat>
Camostat: 38 (25>Camostat: 33 (54.1)>
Placebo: 30
mesylate
53)>
Placebo: 16 (55.2)>
Placebo: 37 (22-51)
NCT04625114
IQR: interquartile range; SD: Standard Deviation.

Time to symptom onset
The mean time fromsymptom onset until
enrollment was notprospectively determined but
was generally in the 2-to-3day range
76% were randomized ≤5days from symptom onset

47% were randomized ≤5days from symptom onset

Median (IQR), days>
Overall: 3 (1-4)>
Camostat: NR>
Placebo: NR

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Table 27. Results from RCTs assessing camostat mesylate for the treatment of COVID-19
Author and year, trial
Primary efficacy outcome(s)identifier(s)Chupp et al. 2022[90]Reduction in viral load at Day 4 (log10)>
Camostat: -2.0
Chupp et al. 2022 camostat>
Placebo: -2.8mesylate>
Difference in means ([95% CI], p-value): 0.74 ([-0.03 to
1.51], p = 0.06)
NCT04353284
Jilg et al. 2022a[91]
CAMELOT
NCT04583592
Jilg et al. 2022b[92]
ACTIV-2/A5401
NCT04518410

Tobback et al. 2022[93]Tobback et al. 2022 camostat
mesylate

Hospitalization/death at Day 28, %>Camostat: 5.3>
Placebo: 6.1>
No significant difference
Days to symptom improvement, median (IQR)>
Camostat: 9 (5-20)>
Placebo: 9 (6-19)>
No significant differences in the proportion of participants withNP SARS-CoV-2 RNA[Note: Endpoints for hospitalization or death are also available in the
DEF]
Difference in the mean change in Ct between Day 1 and 5 for camostat
group versus placebo group>
1.183 (p=0.511)

Safety outcome(s)Patients who experienced an AE, n (%)>
Camostat: 11/35 (31.4)>
Placebo: 6/35 (17.1)
Patients who experienced a SAE, n (%)>
Camostat: 1/35 (0.03)>
Placebo: 1/35 (0.03)
Patients who experienced an AE, %>Camostat: 8.7>
Placebo: 13.1
Patients who experienced a ≥ Grade 3 AE, %>Camostat: 7.4>
Placebo: 6.5>
No significant difference

Patients who experienced an AE, n (%)>
Camostat: 59 (96.7)>
Placebo: 23 (79.3)

Discontinuation of treatment, n (%)>
Camostat: 5 (7.6)>
Placebo: 1 (3.3)
AE: adverse event; CI: confidence interval; Ct: cycle threshold; DEF: data extraction form; IQR: interquartile range; NP: nasopharyngeal; RNA: ribonucleic acid;
SAE: serious adverse event; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
NCT04625114

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Table 28. RCTs assessing anti-inflammatory therapies
Author and year
SourceReport title
Dorward et al.
2022[94]

OVID

Tardif et al. 2021[95]

OVID

Colchicine for COVID-19 in the community(PRINCIPLE): a randomized, controlled, adaptive
platform trial

Colchicine for community-treated patients with COVID19 (COLCORONA): a phase 3, randomized, doubleblinded, adaptive, placebo-controlled, multicenter trial
Audemard-Verger et
OVID
Efficacy and safety of anakinra in adults presenting
al. 2022[96]deteriorating respiratory symptoms from COVID-19: A
randomized controlled trial
COVID-19: Coronavirus 2019; NR: Not Reported.

Reporttype
JournalarticleTrial identifier(s)

Phase
NR

Journalarticle

PRINCIPLE
ISRCTN86534580 [trial does
not appear on
clinicaltrials.gov]
COLCORONA
NCT04322682

JournalarticleANACONDA
NCT04364009

3

3

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Table 29. Study characteristics of RCTs for anti-inflammatory therapies
Author and year, trial
Intervention(s) andPatient characteristics
identifier(s)comparator
enrollment,
location
Dorward et al.
>
Colchicine: Inhaled>
Patients (aged ≥652022[94]
colchicine 500 μg
years, or 50 to 65 years
daily plus usualwith comorbidities) with
PRINCIPLE
care for 14 days
ongoing symptoms from
PCR-confirmed COVID>
Usual care: Usual
ISRCTN86534580 [trial
19 or suspected COVIDcare or usual caredoes not appear on
19, which started withinplus otherclinicaltrials.gov]
14 days of the study
interventions for 14
days
02/04/202026/05/2021
UK

Primary (efficacy)
endpoint(s)>>Time to firstself-reported
recovery(defined as thefirst instancethat participant
reports feelingrecovered)
Admission tohospital/death
related to
COVID-19,
within 28 days

Secondary endpoint(s)

>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>

Binary outcome of earlysustained recovery
Daily rating of how wellparticipants feelTime to initial alleviation ofsymptoms
Time to sustained
alleviation of symptoms
Time to initial reduction ofseverity of symptoms
Worsening of symptoms
Contacts with healthcare
service
Hospital assessment
without admission
Oxygen administration
ICU admission
Mechanical ventilation
Adherence to study
treatment
WHO-5 Wellbeing Index
Serious adverse events
All-cause death or urgent,
non-elective hospital
admission
Reports of new household
infections[Full list of secondary outcomeslisted within supplementary
appendix]223

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Author and year, trial
identifier(s)enrollment,
location
Tardif et al. 2021[95]Intervention(s) andcomparator>

COLCORONA
NCT04322682
23/03/202022/12/2020
US, Brazil, Canada,
Greece, South Africa,
Spain

>

Colchicine: Oraladministration, 0.5
mg colchicine BID
for the first 3 days
and then once dailyfor 27 days
thereafterPlacebo: Orally
administration, BID
for the first 3 days
and then once per
day for 27 days
thereafter[Note: Study medication wasdelivered at thepatient’s house within 4hours of enrollment]

Patient characteristics

>

>

>
>

Patients (aged ≥40years) who received adiagnosis of COVID-19
within 24 h ofenrollment
Not currently being
treated in hospital andnot under immediate
consideration for
hospital treatment oradmission
Presented ≥1 high-risk
criteria
The diagnosis of COVID19 was made by local
laboratories using PCR
testing on a NP swab
specimen:oDiagnosis was also
accepted as an
epidemiological linkwith a household
member who
received a positive
NP test result forpatients withsymptoms
compatible with
COVID-19, or by aclinical algorithm ina symptomaticpatient without anobvious alternativecause, as per official
guidelines

Primary (efficacy)
endpoint(s)>Death orhospital
admission
because of
COVID-19
infection in the
30 days after
randomization

Secondary endpoint(s)

>
>
>
>
>

Death
Hospitalization for COVID19
The need for mechanicalventilation in the 30 days
after randomization
Pneumonias and otherserious adverse events
Non-serious adverse events

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Author and year, trial
identifier(s)enrollment,
location
Audemard-Verger et
al. 2022[96]Intervention(s) andcomparator

Patient characteristics

Primary (efficacy)
endpoint(s)Secondary endpoint(s)>Anakinra plus>
Patients (aged ≥18>
Treatment>
Treatment success assessedoSOC: IV
years) with confirmed
success at Day
with the WHO Clinicaladministration, 400
SARS-CoV-2 infection,
14, defined as
Progression Scale, NEWS,ANACONDA
mg/day (100 mg
confirmed with RT-PCR
a patient being
and biological parameters,
every 6 hours) for 3
and/or typical chest or
alive and not
at Days 3, 10, 14 and 28
NCT04364009
days, then 200
computed tomographic
requiring either>
Overall survival
mg/day (100 mg
scan of COVID-19of the>Time to hospital discharge,
27/04/2020-6/10/2020
every 12 hours) for
pneumonia and required
following:
ICU admission, ventilatory
7 days - total
oxygen therapy
invasive
support, and oxygen supply
Franceduration of 10 days
mechanicalwithdrawal over the 28-dayof treatment
ventilation orfollow-up
extracorporeal>oSOC: including>
Safetymembrane
antiviral drugs,
oxygenationhydroxychloroquine,
corticosteroids,
anticoagulants,
hydration, nutrition,
extra-renal
purification, oxygentherapy andvasopressive drugs
BID: twice daily; COVID-19: Coronavirus 2019; ICU: intensive care unit; IgG: Immunoglobulin G; mg: milligram; NEWS: National Early Warning Score; NP:
nasopharyngeal; oSOC: optimized standard of care; PCR: polymerase chain reaction; RNA: ribonucleic acid; RT-PCR: reverse transcription-polymerase chain
reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; UK: United Kingdom; US: United States; WHO: World Health Organisation; μg:
microgram.

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Table 30. Patients baseline characteristics for RCTs for anti-inflammatory therapies
Author and year, trial
Number randomized
Age (years)
Sex
identifier(s)Dorward et al. 2022[94]Mean (SD)
Female, male, other, n (%)>
Overall: 2293>
Overall: 60.5>
Overall: 1,216 (53.9), 1039>
Colchicine: 212
PRINCIPLE(10.2)(46.1), 1 (0.0)>
Usual care:>
Colchicine: 48.5>
Colchicine: 98 (47.6), 107
2081
ISRCTN86534580 [trial does
(13.2)(51.9), 1 (0.5)
not appear on>
Usual care: 61.7>
Usual care: 1,118 (54.5),
clinicaltrials.gov](9.0)
932 (45.5), 0 (0.0)
Tardif et al. 2021[95]
COLCORONA
NCT04322682>>>

Audemard-Verger et al.
2022[96]>>

ANACONDA>

Overall: 4488
Colchicine:
2235
Placebo: 2253
Overall: 71
Anakinra plus
oSOC: 37
oSOC: 34

Mean (IQR)>
Overall: NR>
Colchicine: 53.0
(47.0-61.0)>
Placebo: 54.0
(47.0-61.0)
Mean (SD)>Overall: NR>
Anakinra plus
oSOC: 71 (15)>oSOC: 70 (14)Time to symptom onset(days)Median (IQR)>
Overall: 6.0 (4.09.0)

Female, n (%)>
Overall: NR>
Colchicine: 1238 (55.4)>
Placebo: 1183 (52.5)

NR

Female, n (%)>
Overall: NR>
Anakinra plus oSOC: 9 (24)>oSOC: 10 (29)Median (IQR)>
Overall: NR>
Anakinra plus
oSOC: 9 (7-11)>
oSOC: 9 (7-11)

NCT04364009
IQR: Interquartile range; NR: Not reported; oSOC: optimized standard of care; SD: standard deviation.

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Table 31. Results from RCTs assessing anti-inflammatory therapies
Author and year, trial
Primary efficacy outcome(s)identifier(s)Dorward et al. 2022[94]
PRINCIPLE
ISRCTN86534580 [trial does
not appear on
clinicaltrials.gov]

Tardif et al. 2021[95]
COLCORONA
NCT04322682

Audemard-Verger et al.
2022[96]
ANACONDA
NCT04364009

Days to first reported recovery, median>Colchicine: 15>
Usual care: 14>
Benefit ([95% BCI], p-value): 1.14 ([-1.86 to 5.21], p=0.241)
Patients hospitalized or dead at Day 28, n (%)>
Colchicine: 6/156 (3.8)>
Usual care: 4/133 (3.0)>
OR, % ([95% BCI], p-value): -0.4 ([-2.7 to 2.4], p=0.714)
oPrespecified superiority threshold 0.99; therefore,
insignificant
Odds of composite endpoint (mortality or hospitalization) by Day 30 withcolchicine group versus placebo group, odds ([95% CI], p-value)>
0.79 (]0.61-1.03], p=0.081)o
not significant [however, significant in subgroup withconfirmed diagnosis of COVID-19]
Odds of mechanical ventilation with colchicine group versus placebo group,
odds (95% CI)>
0.53 (0.25-1.09)
Patients with treatment success at Day 14, n (%)>
Anakinra plus oSOC: 26 (70)>oSOC: 31 (91)>
Risk difference, % ([95% CI], p-value): -21 ([-39 to -2],
p=0.027)

Safety outcome(s)Patients who experienced a SAEs, n>
Colchicine: 1>
Usual care: 1

Patients who experienced a TRAE, n (%)
Colchicine: 532 (24.2)
Placebo: 344 (15.5)
Patients who experienced a SAEs, n (%)
Colchicine: 108 (4.9)
Placebo: 139 (6.3)
Patients who experienced ≥1 AE, n (%)>
Anakinra plus oSOC: 32 (87)>oSOC: 22 (65)>p=0.016

Patients who experienced ≥1 SAE, n (%)>
Anakinra plus oSOC: 19 (51)>oSOC: 18 (53)>p=0.89
AE: adverse event; BCI: Bayesian confidence interval; CI: confidence interval; COVID-19: Coronavirus 2019; oSOC: optimized standard of care; OR: odds ratio;
SAE: serious adverse event; TRAE: treatment-related adverse event.

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Table 32. RCTs assessing antiparasitic (nitazoxanide)
Author and year
SourceReport title
Rocco et al. 2021[97]
OVID
Early use of nitazoxanide in mild COVID-19
disease: randomized, placebo-controlled trial
Rossignol et al. 2021[98]clinicaltrials.gov

Rossignol et al. 2022[99]

OVID

Mehdat et al. 2022[100]OVID

COVID-19: Coronavirus 2019.

Early treatment with nitazoxanide preventsworsening of mild and moderate COVID-19 andsubsequent hospitalization
A randomized double-blind placebo-controlled
clinical trial of nitazoxanide for treatment of mild or
moderate COVID-19
Sofosbuvir/ledipasvir in combination or
nitazoxanide alone are safe and efficient
treatments for COVID-19 infection: A randomized
controlled trial for repurposing antivirals

Report type
Journal article
Journal article(pre-print)
Journal article(published)
Journal article

Trial identifier(s)Rocco et al. 2021
nitazoxanide
NCT04552483
Rossignol et al. 2021
nitazoxanide
NCT04486313
Rossignol et al. 2022
nitazoxanide
NCT04486313
Mehdat et al. 2022
nitazoxanide andsofobuvir/ledipasvir
NCT04498936

Phase
2
3
3
4

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Table 33. Study characteristics of RCTs for antiparasitic (nitazoxanide)
Trial report,
Intervention(s) andPatient characteristics
trial identifier(s)comparator
enrollment,
location
Rocco et al. 2021[97]>Nitazoxanide: Oral>
Consecutive adult patientsadministration, 500(aged ≥18 years) who
Rocco et al. 2021
mg (20 mg/mL, 25
presented with clinicalnitazoxanidemL) taken three
symptoms of COVID-19
times a day for 5(defined for the purposes of
NCT04552483
days
this trial as dry cough, fever
and/or fatigue) of no longer>
Placebo: Oral
08/06/2020-20/08/2021
than 3 days’ duration
administration, colormatched, 25 mL three
Braziltimes daily
Rossignol et al.
>
Nitazoxanide: Oral>
Outpatients (aged ≥12 years)
2021[98]
administration, twopresenting within 72 hours of
300 mg tablets (600
onset of symptoms of mild or
Rossignol et al. 2021
mg per dose) withmoderate COVID-19
nitazoxanide
food BID, for 5 days>
Minimum symptom>
Placeborequirements were:
NCT04486313
o
At least two respiratory
symptom domains (head,
18/08/2020-08/01/2021
throat, nose, chest,
cough) with a score of ≥2
US and Puerto Ricoas determined by scoring
the FLUpro questionnaire
Rossignol et al.
administered at screening
2022[99](only one domain scorerequired to be ≥2 if pulse
Rossignol et al. 2022
rate ≥90 beats pernitazoxanide
minute)OR
NCT04486313oRespiratory rate ≥16breaths per minute), withno improvement in overall
symptom severity fromthe prior day
Mehdat et al.
>
Sofosbuvir/ledipasvir>
Patients (aged ≥18 years)
2022[100]plus SCT: Oral
with a COVID-19 diagnosis
administration, 400
based on positive RT-PCR
mg (sofosbuvir) andtesting for SARS-CoV-2 NP
90 mg (ledipasvir)
swab

Primary (efficacy)
endpoint(s)>Complete
symptom
resolution after
5 daysSecondary endpoint(s)

>
>
>
>

Reduction in viralload on NP swab
specimens
Improvement inlaboratory
parameters
Incidence of
hospital admission
Adverse events>

Time from thefirst dose tosustained
response(TSR), ameasure ofmeaningful
within-subjectchange insymptoms>

The rate ofprogression tosevere COVID-19
illness>

Confirmed viralclearance byserial RT-PCR
testing on NP
swab

>
>
>

Mortality
ICU admission
Development ofserious adverse
events229

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Trial report,
trial identifier(s)enrollment,
location
Rocco et al. 2021[97]Intervention(s) andcomparator

Patient characteristics

Primary (efficacy)
endpoint(s)Secondary endpoint(s)>Nitazoxanide: Oral>
Consecutive adult patients>
Complete>
Reduction in viraladministration, 500(aged ≥18 years) who
symptomload on NP swab
Rocco et al. 2021
mg (20 mg/mL, 25
presented with clinicalresolution after
specimensnitazoxanidemL) taken three
symptoms of COVID-19
5 days>
Improvement intimes a day for 5(defined for the purposes oflaboratory
NCT04552483
days
this trial as dry cough, feverparameters
and/or fatigue) of no longer>
Placebo: Oral>
Incidence of
08/06/2020-20/08/2021
than 3 days’ duration
administration, colorhospital admission
matched, 25 mL three>
Adverse events
Braziltimes daily
Mehdat et al. 2022
daily, plus SCT, for 14
nitazoxanide anddays
sofobuvir/ledipasvir>
Nitazoxanide plus
SCT: Oral
NCT04498936
administration, 500
mg four times daily,
07/2020-10/2021
plus SCT, for 14 days>
SCT: Oral
Egyptadministration for 14
days
BID: twice daily; COVID-19: Coronavirus 2019; FLUPro: InFLUenza Patient-Reported Outcome; ICU: intensive care unit; mg: milligram; mL: milliliter; NP:
nasopharyngeal; PaO2/FiO2: the ratio of arterial oxygen partial pressure to fractional inspired oxygen; RT-PCR: reverse transcriptionpolymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SCT: standard care treatment; SpO2:
peripheral capillary oxygen saturation; TSR: time to sustained response; US: United States.

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Table 34. Patients baseline characteristics for RCTs for antiparasitic (nitazoxanide)
Author and year, trial
Number randomized
Age (years)
identifier(s)Rocco et al. 2021[97]n (%)>
Nitazoxanide: 238>
Nitazoxanide:>
Placebo: 237
Rocco et al. 2021o
18-39 years: 115
nitazoxanide(59)
o40-59 years: 68
NCT04552483(35)
o60-77 years: 11 (6)>Placebo:o
18-39 years: 113(57)
o40-59 years: 74(37)o60-77 years: 11 (6)Rossignol et al. 2021[98]Median (IQR)>
Overall: 379>
Overall: 40.0 (27.0>
Nitazoxanide: 184
Rossignol et al. 2021
51.0)>
Placebo: 195
nitazoxanide>
Nitazoxanide: 38.0
(26.0-50.5)
NCT04486313>
Placebo: 42.0 (29.051.0)
Rossignol et al. 2022[99]SexTime to symptom onset

Male, n (%)>
Nitazoxanide: 101(52)>
Placebo: 83 (42)Median (IQR), days>
Nitazoxanide: 5(4-5)>
Placebo: 5 (4-5)

Male, n (%)>
Overall: 165 (43.5)>
Nitazoxanide: 83(45.1)>
Placebo: 82 (42.1)

Mean (SD), hours>
Overall: 43.6
(15.56)>
Nitazoxanide:
42.7 (15.25)>
Placebo: 44.6
(15.83)

Male, female, n (%)>
Sofosbuvir/ledipasvir
plus SCT: 32 (45.7),
38 (54.3)>
Nitazoxanide plus
SCT: 27 (35.1), 50(64.9)>
SCT: 41 (56.2), 32(43.8)

NR

Rossignol et al. 2022
nitazoxanide
NCT04486313
Mehdat et al. 2022[100]Mehdat et al. 2022
nitazoxanide andsofobuvir/ledipasvir
NCT04498936>>>

Sofosbuvir/ledipasvir
plus SCT: 70
Nitazoxanide plus
SCT: 77
SCT: 73

Mean (SD)>
Sofosbuvir/ledipasvir
plus SCT: 45.04 (8.14)>
Nitazoxanide plus SCT:
44.32 (8.43)>
SCT: 45.35 (5.59)

IQR: Interquartile range; SCT: standard care treatment; SD: Standard deviation.

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Table 35. Results from RCTs assessing antiparasitic (nitazoxanide)
Trial report,
Primary efficacy outcome(s)trial identifier(s)Rocco et al. 2021[97]Rate of complete resolution of symptoms (dry cough, fever, and fatigue) did not
significantly differ between the nitazoxanide and placebo after 5 days of therapy
Rocco et al. 2021
(p=0.277)
nitazoxanide
Proportion of patients with complete symptom resolution (dry cough, fever, andfatigue) after 5 days of therapy
NCT04552483>
Nitazoxanide: 135>
Placebo: 146>
p=0.277; no statistical difference

Rossignol et al. 2021[98]Rossignol et al. 2021
nitazoxanide
NCT04486313
Rossignol et al. 2022[99]Rossignol et al. 2022
nitazoxanide
NCT04486313
Mehdat et al. 2022[100]Mehdat et al. 2022
nitazoxanide andsofobuvir/ledipasvir

NP swab RT-PCR viral load log10 copies/mL>
Nitazoxanide: 3.63>
Placebo: 4.13>
p=0.006; patients with nitazoxanide had significantly lower viral load
than patients with placebo
Time (days) from the first dose to sustained response in all patients, median(IQR)>
Nitazoxanide: 13.28 (6.26 to >21)>
Placebo: 12.35 (7.18 to >21)>p=0.88; no statistical differenceTime (days) from the first dose to sustained response with nitazoxanide in themild subgroup, median (IQR)>
Nitazoxanide: 10.3 (6.2 to >21)>
Placebo: 13.4 (7.4 to >21)>p=0.10; no statistical difference[Note: Endpoints for hospitalization or death are also available in the DEF]
Proportion of patients with confirmed viral clearance at Days 5, 8, 11, 14, %> Sofosbuvir/ledipasvir plus SCT: 42.90, 70.00, 80.00, 85.71> Nitazoxanide plus SCT: 0.00, 2.60, 32.47, 36.63> SCT: 0.00, 1.37, 15.07, 16.44

Safety outcome(s)Patients who experienced an AE, n (%)>
Nitazoxanide arm: 60 (30.9)>
Placebo arm: 60 (30.3)>
p=0.913; no significant difference
Patients who experienced a SAE, n (%)>
Nitazoxanide arm: 1 (0.5)>
Placebo arm: 1 (0.5)>
p=0.999; no significant difference

Patients who experienced an AE, n (%)>
Nitazoxanide: 63 (13.3)>
Placebo: 75 (16.2)
Patients who experienced a SAE, n>Nitazoxanide: 2>
Placebo: 7

NR

NCT04498936
AE: adverse event; DEF: data extraction form; IQR: interquartile range; mL: milliliter; NP: nasopharyngeal; NR: not reported; RT-PCR: reverse transcriptionpolymerase chain reaction; SAE: serious adverse event; SCT: standard care treatment.

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Bias assessment
The quality of each publication included in the SLR was assessed using the Cochrane risk of bias assessment tool (RoB2) for
randomized trials.84 A total of 86 publications were assessed for bias.

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別添 6： QOL 値の詳細
Health-related quality-of-life studies
Vignettes utilised in the de novo utility study
Description S1: Baseline (pre-infection)••

The patient does not have COVID-19.
The patient has an underlying health condition that makes them more likely
to get severely ill from COVID-19. You do not need to consider the impact of
this underlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S2: Outpatient (mild)

•
•
•
•
•
•

•
•
•
•
•
•
•

The patient has COVID-19.
The patient is not in hospital.
The patient is not using any devices that supply extra oxygen to the lungs.
The patient has a normal breathing rate and is not out of breath.
The patient has a normal heart rate at rest.
The patient has a fever – their body temperature is over 38°C. They feelhotter than usual (particularly on their chest and back), have chills and areshivery.
The patient has a dry cough and is coughing more than they usually do.
The patient feels extremely tired and finds daily activities (such as walking up
the stairs, getting out of bed, daily chores) difficult.
The patient has a headache that is moderately to severely painful, feels‘pulsing’, ‘pressing’, or ‘stabbing’, occurs across both sides of the head andlasts more than three days.
The patient’s muscles are sore, particularly their shoulders and legs. The area
feels sore to the touch and can prevent the patient from carrying out dailytasks without pain.
The patient has lost their sense of smell, they are unable to smell as theyusually would, including strongly scented things like coffee or flowers.
The patient has a blocked, stuffy, or bunged-up feeling in their nose.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S3: Outpatient (moderate)

•
•
•
•
•
•
•

The patient has COVID-19.
The patient is not in hospital.
The patient is not using any devices that supply extra oxygen to the lungs.
The patient experiences shortness of breath on exertion, for example, when
walking up the stairs.
The patient has a high heart rate at rest.
The patient has a fever – their body temperature is over 38°C. They feelhotter than usual (particularly on their chest and back), have chills and areshivery.
The patient has a dry cough and is coughing more than they usually do.
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•
•
•
•
•
•

The patient feels extremely tired and finds daily activities (such as walking up
the stairs, getting out of bed, daily chores) difficult.
The patient has a headache that is moderately to severely painful, feels‘pulsing’, ‘pressing’, or ‘stabbing’, occurs across both sides of the head andlasts more than three days.
The patient’s muscles are sore, particularly their shoulders and legs. The area
feels sore to the touch and can prevent the patient from carrying out dailytasks without pain.
The patient has lost their sense of smell, they are unable to smell as theyusually would, including strongly scented things like coffee or flowers.
The patient has a blocked, stuffy, or bunged-up feeling in their nose.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S4: General hospital ward (severe)

•
•
•
•
•
•

•
•
•
•
•

The patient has COVID-19.
The patient is in hospital on a general ward.
The patient is using a device in which oxygen is delivered through a tube
through the nose, allowing the air into their lungs.
The patient is short of breath at rest.
The patient’s heart rate is very high.
The patient has a fever – their body temperature is over 38°C. They feelhotter than usual (particularly on their chest and back), have chills and areshivery.
The patient has a dry cough and is coughing more than they usually do.
The patient feels extremely tired and finds daily activities (such as walking up
the stairs, getting out of bed, daily chores) difficult.
The patient is withdrawn and less responsive to the world around them, they
forget to go to the toilet when they need to and stop eating and drinking.
The patient’s muscles are sore, particularly their shoulders and legs. The area
feels sore to the touch and can prevent the patient from carrying out dailytasks without pain.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S5: High dependency unit (severe)

•
•
•
•
•

The patient has COVID-19.
The patient is using supplemental oxygen through a face mask.
The patient is in a high dependency unit of a hospital, where patients arecared for more extensively than a general ward, but not to the point ofintensive care.
The patient is short of breath at rest.
The patient’s heart rate is very high.

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•
•
•
•
•
•

The patient has a fever – their body temperature is over 38°C. They feelhotter than usual (particularly on their chest and back), have chills and areshivery.
The patient has a dry cough and is coughing more than they usually do.
The patient feels extremely tired and finds daily activities (such as walking up
the stairs, getting out of bed, daily chores) difficult.
The patient is withdrawn and less responsive to the world around them, they
forget to go to the toilet when they need to and stop eating and drinking.
The patient’s muscles are sore, particularly their shoulders and legs. The area
feels sore to the touch and can prevent the patient from carrying out dailytasks without pain.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S6: ICU (critical)

•
•
•
•
•

•
•

The patient has COVID-19, they cannot breathe on their own and will die if nottreated.
The patient is in an intensive care unit in a hospital.
The patient has a breathing tube inserted into their windpipe to allow amachine to breathe for them.
The patient is unable to breathe on their own.
The patient has multi-organ dysfunction/failure of more than 1 of the following
organ systems: respiratory (lungs), cardiovascular (heart and blood vessels),
kidney, liver, and/or central nervous systems (brain and spinal cord) andrequires organ support.
The patient is unconscious.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S7: Recovered (no long-term sequelae)••

The patient has had COVID-19 and has now recovered without any long-term
health issues.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.

Description S8: Recovered (long-term sequelae)••

The patient has had COVID-19 and is now suffering from long-term healthissues as a result.
The patient has an underlying health condition that makes them more likely to
get severely ill from COVID-19. You do not need to consider the impact of thisunderlying health condition on the patient’s health, only that this condition
makes the patient more likely to get severely ill from COVID-19.
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The patient feels extremely tired and finds daily activities (such as walking up
the stairs, getting out of bed, daily chores) difficult.
The patient is short of breath and feels as though they cannot get enough air
in their lungs. They find it difficult to inhale and exhale. They have a tightchest.
The patient’s muscles and/or joints are sore, particularly their shoulders andlegs. The area feels sore to the touch and can prevent the patient fromcarrying out daily tasks without pain.

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