ISSN 2759-6478 (Online)
Academic Technology Assessment Group (ATAG) Reports
2024;2(2)Cost-effectiveness evaluationof molnupiravir for coronavirus
disease 2019

Yuta Suzuki1), Michi Sakai2), Munenobu Kashiwa2,3),
Ryo Iketani1), Tomomi Maeda2,4), Yasuhiro Morii1),
Satomi Kojima2), Eri Hoshino1,5), Takeru Shiroiwa1),
Kojiro Shimozuma2,6), Takashi Fukuda1)
1)Center for Outcomes Research and Economic Evaluation, National Institute of
Public Health2)Comprehensive Unit for Health Economic Evidence Review and Decision Support(CHEERS), Research Organization of Science and Technology, Ritsumeikan University
3)
Faculty of Pharmacy, Institute of Medical Pharmaceutical and Health Sciences,
Kanazawa University
4)
Graduate School of Health Management, Keio University
5)
Division of Policy Evaluation, Department of Health Policy, Research Institute, National Center for Child Health and Development
6)
Division of Health Policy and Management, Department of Biomedical Sciences,
College of Life Sciences, Ritsumeikan University

Center for Outcomes Research and Economic Evaluation for Health (C2H)

ISSN 2759-6478 (Online)
Academic Technology Assessment Group (ATAG) Reports
2024;2(2)SARS-CoV-2 による感染症に対するモルヌピラビルの費用対効果評価

鈴木 裕太 1), 酒井 未知 2), 柏 宗伸 2,3), 池谷 怜 1),
前田 知美 2,4), 森井 康博 1), 小嶋 智美 2), 星野 絵里 1,5),
白岩 健 1), 下妻 晃二郎 2,6), 福田 敬 1)

国立保健医療科学院 保健医療経済評価研究センター
立命館大学 総合科学技術研究機構 医療経済評価・意思決定支援ユニット(CHEERS)3)金沢大学 医薬保健研究域薬学系
4)
慶應義塾大学大学院 健康マネジメント研究科
5)
国立研究開発法人国立成育医療研究センター 政策科学研究部 政策評価研究室
6)
立命館大学 生命科学部 生命医科学科 医療政策・管理学研究室
1)
2)

保健医療経済評価研究センター（C2H）

目次
Abstract………………………………………………………………………………………………………………………… 5
抄録…………………………………………………………………………………………………………………………… 6
略語表………………………………………………………………………………………………………………………… 7
0. 分析枠組み………………………………………………………………………………………………………………… 8
1. 諸外国の医療技術評価機関における評価結果………………………………………………………………………… 9
1.1 評価結果の概要………………………………………………………………………………………………………… 9
1.2 製造販売業者による諸外国の医療技術評価機関における評価報告のレビュー………………………………… 11
1.3 公的分析における参考事項…………………………………………………………………………………………… 11
1.4 その他の海外医療技術評価機関の報告における参考事項………………………………………………………… 14
2. 追加的有用性の評価……………………………………………………………………………………………………… 15
2.1 公的分析におけるシステマティックレビュー……………………………………………………………………… 15
2.1.1 公的分析が設定したリサーチクエスチョン…………………………………………………………………… 15
2.1.2 実施の流れ………………………………………………………………………………………………………… 15
2.1.3 臨床研究の組み入れ基準や除外基準…………………………………………………………………………… 15
2.1.4 使用したデータベース…………………………………………………………………………………………… 16
2.1.5 使用した検索式…………………………………………………………………………………………………… 16
2.1.6 検索結果…………………………………………………………………………………………………………… 18
2.1.7 臨床試験の概要…………………………………………………………………………………………………… 19
2.2 製造販売業者によるシステマティックレビューと公的分析におけるレビュー結果の概要…………………… 26
2.2.1 製造販売業者によるシステマティックレビューについて…………………………………………………… 26
2.2.2 製造販売業者の実施したシステマティックレビューとの結果の差異について…………………………… 26【製造販売業者の提出資料 ( システマティックレビュー ) に対するレビュー結果】…………………………………… 27
2.3 製造販売業者による追加的有用性評価と公的分析におけるレビュー結果の概要……………………………… 28
2.3.1 製造販売業者による追加的有用性評価………………………………………………………………………… 28
2.3.2 公的分析におけるレビュー結果………………………………………………………………………………… 28
2.4 追加的有用性の有無に関する評価………………………………………………………………………………… 45【製造販売業者の提出資料 ( 追加的有用性 ) に対するレビュー結果】…………………………………………………… 45
3. 費用対効果の評価………………………………………………………………………………………………………… 46
3.1.1 標準治療と比較した費用効果分析の概要……………………………………………………………………… 46
3.1.2 標準治療群と比較した費用効果分析に対する見解…………………………………………………………… 47

ATAG. Rep. 2024;2(2)33.2 レビュー結果による再分析の必要な箇所の有無…………………………………………………………………… 47
3.3 実施が必要な再分析の概要…………………………………………………………………………………………… 48
3.3.1 再検討が必要な分析手法やパラメータなど ( 主要な [ 結果への影響が大きい ] もの )…………………… 48
3.3.2 再検討が必要な分析手法やパラメータなど (3.3.1 以外のもの )…………………………………………… 48
3.4 主要な点 ( 結果に与える影響が大きい点 ) についての再分析の内容…………………………………………… 48
3.4.1 費用最小化分析の実施…………………………………………………………………………………………… 48【具体的な再分析の内容】…………………………………………………………………………………………………… 48
3.5 3.4 以外に検討が必要な点における再分析の内容………………………………………………………………… 48
4. 分析結果…………………………………………………………………………………………………………………… 49
4.1 再分析における基本分析の結果……………………………………………………………………………………… 49
4.1.1 再分析における基本分析の増分費用…………………………………………………………………………… 49
4.1.2 費用効果分析を実施する場合に、増分費用効果比に影響を与えうる要因………………………………… 49
4.2 再分析における感度分析の結果……………………………………………………………………………………… 50
4.3 再分析におけるシナリオ分析の結果………………………………………………………………………………… 50
4.4 分析結果の解釈………………………………………………………………………………………………………… 50
4.5 価格調整率の重み……………………………………………………………………………………………………… 50
5. 参考文献…………………………………………………………………………………………………………………… 51

4ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Abstract
The academic technology assessment group (ATAG) reviewed a report on molnupiravir’ s additional benefits and cost-effectiveness compared to standard of care (SoC) in adults with coronavirus disease 2019
(COVID-19) who are at an increased risk of progression to severe COVID-19 (except adults with severe

COVID-19). The report was submitted by the manufacturer of molnupiravir (MSD). This report summarizes
the results of a review and reanalysis conducted by the ATAG. When evaluating the additional benefits of molnupiravir over the SoC, the manufacturer provided data from the MOVe-OUT trial. The manufacturer insistedon the additional benefits of molnupiravir over SoC based on the MOVe-OUT trial’ s findings, which indicatedthat molnupiravir had a statistically significant effect on the incidence of hospitalization or death at day 29
compared with placebo. The ATAG observed that the MOVe-OUT trial was conducted in unvaccinated adults
infected with the delta, gamma, and mu variants of SARS-CoV-2. Given that the main variant of SARS-CoV-2
is Omicron and COVID-19 vaccination has become widespread in Japan, the generalizability of the study results is limited. Therefore, the ATAG proposed that the evaluation should follow the PANORAMIC trial (conducted in the U.K., University of Oxford) for vaccinated adults infected with omicron variants. However, owing
to differences in the definition of risk factors for progression to severe COVID-19 and the SoC in Japan versus
the U.K., the PANORAMIC trial included participants who were not defined as having risk factors in Japanand those who were treated with other medications indicated for the treatment of COVID-19. Therefore, theATAG evaluated the treatment effect of molnupiravir after extracting adults who met the Japanese definitionof risk factors for progression to severe COVID-19 and the SoC in Japan from the PANORAMIC study. The
post-hoc analysis of the PANORAMIC trial demonstrated that the odds ratio for hospitalization or death was
1.053 (95% confidence interval: 0.775–1.396), and the difference in event rate was not significant between themolnupiravir plus usual care group and the usual care group. Based on these results, the ATAG could not determine that molnupiravir had additional benefits for hospitalization or death. Clinical experts have suggested
that molnupiravir may have additional benefits for older adults based on the results of the subgroup analysis
by age; however, the available evidence is limited, and further data are required to establish these benefits.
The manufacturer conducted a cost-effectiveness analysis using a decision-tree model representing the acutephase of COVID-19 and a Markov model representing the post-acute phase of COVID-19. As molnupiravir did
not exhibit additional benefits over the SoC, the ATAG conducted a cost-minimization analysis, revealing thatmolnupiravir increased costs by JPY 94,312. In conclusion, for adults with COVID-19 at an increased risk ofprogression to severe COVID-19, the results of the ATAG analysis suggest that the ICER for molnupiravir compared with SoC is likely to indicate equivalent effectiveness and cost increase from the perspective of publichealthcare payers in Japan.

keywords: m
 olnupiravir, COVID-19, cost-effectiveness analysis, health technology assessment

ATAG. Rep. 2024;2(2)5

抄録
公的分析は、モルヌピラビルの製造販売業者 (MSD 株式会社）より提出された、SARS-CoV-2 による感染症(COVID-19) 患者における、標準療法に対するモルヌピラビルの追加的有用性及び経済評価に関する報告について
レビューを行った。本報告書ではその結果と、公的分析が実施した再分析の内容を要約している。まず追加的有用性の評価に際して、製造販売業者は、COVID-19 患者を対象とした抗ウイルス薬、中和抗体薬、免疫抑制・調節薬のランダム化比較試験に関するシステマティックレビューを実施し、このうち、重症化リスク因子を有する
COVID-19 患者を対象とした MOVe-OUT 試験が追加的有用性評価の主たるエビデンスとして用いられた。製造販売業者は、この MOVe-OUT 試験における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患者の割合で、優越性が検証されたことからモルヌピラビルが追加的有用性を有すると主張した。公的分析では、製造販売業者が追加的有用性評価の主な根拠とした MOVe-OUT 試験はデルタ株、ミュー株、及びガンマ株等の環境下における新型コロナワクチン未接種者を対象とした臨床試験であり、主な流行株はオミクロン株であったことに加えて、新型コロナワクチン接種が普及している本邦の臨床実態と状況が異なると考えられた。そのため、英国でオミクロン株環境下において、ワクチン接種者を対象として実施された PANORAMIC試験を中心にモルヌピラビルの追加的有用性評価を行った。ただし PANORAMIC 試験には、本邦においては必ずしも重症化リスク因子を有すると定義されない症例や、モルヌピラビル使用時に他の抗ウイルス薬等を併用した症例が含まれていた。そこで、本邦における重症化リスク因子の定義や標準治療の内容に合致した症例のみを抽出した上で、モルヌピラビルの評価を行った。その結果、標準治療に対するモルヌピラビルの入院又は死亡におけるオッズ比は 1.053 (95% 信頼区間：0.775 to 1.396) であったことから、公的分析ではモルヌピラビルは比較
対照技術に対して追加的有用性を有すると判断できないと評価した。製造販売業者は COVID-19 の発症から急性期治療終了までの分析期間は決定樹モデル、その後の分析期間 ( 生涯 ) はマルコフモデルにより表現し、費用効
果分析を実施した。モルヌピラビルの有効性パラメータ ( 入院、入院患者の重症化及び死亡に対する効果 ) には、
MOVe-OUT 試験のデータが用いられていた。公的分析ではモルヌピラビルは比較対照技術に対して追加的有用性を有すると判断できないと評価したことから、治療効果に群間差を設定せず、治療費用を比較する費用最小化分析を実施した。その結果、モルヌピラビルは比較対照技術に対して 94,312 円の費用増加であった。以上より、公的分析の結果は、本邦における公的医療の立場において、標準治療に対してモルヌピラビルは「効果が同等 ( あ
るいは劣り )、かつ費用が高い」の区間に所属する可能性が高いことを示唆した。
キーワード：モルヌピラビル、COVID-19、費用効果分析、医療技術評価

6
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

略語表
略語
AE
ASMR
CADTH
CI
EMA
FDA
HAS
ICER
IQWiG
IQR
MSAC
MTA
NICE
PBAC
QALY
RCT
SAE
SR
SMC
SMR
STA
OR
RR
RRR

正式表記
Adverse Event
Amelioration du Service Médical Rendu
Canadian Agency for Drugs and Technologies in HealthConfidence Interval
The European Medicines Agency
Food and Drug Administration
Haute Autorité de Santé
Incremental Cost-Effectiveness Ratio
Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen
Interquartile Range
Medical Services Advisory Committee
Multiple Technology Appraisal
National Institute for Health and Care Excellence
Pharmaceutical Benefits Advisory Committee
Quality-Adjusted Life Year
Randomized Controlled Trial
Serious Adverse Event
Systematic Review
Scottish Medicines Agency
Service Médical Rendu
Single Technology Appraisal
Odds Ratio
Risk Ratio
Relative Risk Reduction

ATAG. Rep. 2024;2(2)70. 分析枠組み
対象品目名は「モルヌピラビル(ラゲブリオカプセル200 mg)」で、製造販売業者はMSD株式会社である。
モルヌピラビルは、SARS-CoV-2による感染症(COVID-19)を対象とした抗ウイルス薬であり、2022年8月10日の中央社会保険医療協議会総会において、費用対効果評価の対象品目に指定された。モルヌピラビ
ルの市場規模予測は138億円で、費用対効果評価の区分はH1(市場規模が100億円以上)に該当する。モルヌピラビルに係る分析枠組みは、2022年11月25日の費用対効果評価専門組織を経て、表0-1の通り設定された。
表 0-1 評価対象技術に関する分析枠組みの概要
分析対象集団(複数可)分析対象集団を設定した理由(適宜記載)
比較対照技術名

比較対照技術を選定した理由

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。

標準治療*(評価対象技術：モルヌピラビル＋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

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、分析の実施が困難である。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。

「公的医療の立場」以外の分析
有(その詳細:の有無
効果指標としてQALY以外を使用(該当せず)
する場合、その指標と理由
その他(該当せず)

8
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院)

無1. 諸外国の医療技術評価機関における評価結果
1.1

評価結果の概要

諸外国の医療技術評価機関におけるモルヌピラビルの評価結果を調査し、製造販売業者による報告と比較した。諸外国における評価の概要は表1-1-1~1-1-3に要約した。
表 1-1-1 主要国における評価の一覧表
国名

評価結果

機関名

製造販売業者

公的分析

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()

モルヌピラビルに関するMTAが実施されていたものの、製造販売業者からのアピールに応じて新たなSTAを実施し、その結論が出るまで最終ガイダンス
は公表しないことで合意した。

イギリス

NICE
SMC

該当なし

左記に同じ

フランス

HAS

該当なし

左記に同じ

ドイツ

IQWiG

該当なし

左記に同じ

カナダ

CADTH 該当なし

左記に同じ

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))/

条件つき推奨(償還される対象に条件が付されている)

表 1-1-2 各国における費用対効果評価実施の有無
国名
イギリス

機関名

評価結果の有無
製造販売業者

公的分析

NICEあり/ なし/ 評価中(ドラフトあり/なし)/不明

MTAについてFinal draft guidanceが存在するが、最終ガイダンスとしては公表しないこととされている。

SMCあり/ なし/ 評価中/不明

あり/ なし/ 評価中/不明

フランス

HAS

あり/ なし/ 評価中/不明

あり/ なし/ 評価中/不明

カナダ

CADTH あり/ なし/ 評価中/不明

あり/ なし/ 評価中/不明

オーストラリア PBACあり/ なし/ 評価中/不明あり(結果は非公表)

ATAG. Rep. 2024;2(2)9表 1-1-3-1 イギリス(NICE)におけるMTAによる費用対効果評価結果の詳細
製造販売業者
国名

イギリス

機関名

NICE

公的分析

評価結果のURLなど https://www.nice.org.uk/guidance/indevelopment/GID-TA11297(1)
評価対象技術評価結果

モルヌピラビル

左記に同じ

N/A(MTA評価中）

MTAの結果に対しては製造販売業者によるアピールが認められ、最終ガイダンスを出さずに改めてSTAを実施することとなった。

条件付き推奨の場合
N/A(MTA評価中）は、その条件の詳細

N/A

評価対象疾患SARS-CoV-2 による感染症

重症化リスク因子を有する軽症のCOVID-19 患者

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
左記に同じ
回 800mgを 1 日 2 回、5 日間経口投与する。

比較対照

標準治療

主要な増分費用効果
N/A(MTA評価中）
比の値

左記に同じ
• Assessment report
標準治療に対する相対的な治療効果に対し、ネット
ワークメタアナリシスから得られた点推定値、 95%信頼区間の上限、 95%の下限をそれぞれ当てはめて推計されたICERは以下の通りであった。
- 点推定値: £13,684/QALY- 95%信頼区間の上限: £9,825/QALY- 95%信頼区間の下限: £69,786/QALY• Draft guidanceCommittee’ s preferred assumptionsを 置 い た 状 況
で、モルヌピラビルのICERは治療効果の設定に対して鋭敏に変動したが、£30,000/QALYを超える可能性が高いことが示された。

10
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

表 1-1-3-2 オーストラリア(PBAC)における費用対効果評価結果の詳細
製造販売業者

公的分析

国名オーストラリア

機関名

PBAC

評価結果のURLなど

https://www.pbs.gov.au/publication/factsheets/covid-19-treatments/Factsheet-lagevrio-molnupiravir-July-2023.pdf(2)

評価対象技術モルヌピラビル

左記に同じ

評価結果

推奨

条件付き推奨以下に該当する軽症から中等症のCOVID-19 患者に対して推奨
- 70 歳以上(無症状陽性者を含む。また他の重症化リ
スク因子は必要としない)のもの- 50 歳以上で 2 つ以上の重症化リスク因子を有するも以下に該当する場合推奨の- 70 歳以上(無症状陽性者を含む）- 30 歳以上の先住民で 1 つ以上の重症化リスク因子を
条件付き推奨の場合 - 50 歳以上で複数の重症化リスク因子を有する軽症者有するものは、その条件の詳細 - 30 歳以上の先住民で複数の重症化リスク因子を有す- 18 歳以上で中等症から重症の免疫抑制状態のもの
る軽症者- 18 歳以上で過去にCOVID-19 で入院しており、その- 18 歳以上で中等症～重症の免疫抑制状態の軽症者
後再感染したもの
またPBACは、PANORAMIC試験の結果をふまえ、ニルマトレルビル/リトナビルが禁忌または適切でない
場合にモルヌピラビルを考慮すべきとしている。
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
左記に同じ
回 800mgを 1 日 2 回、5 日間経口投与する。

比較対照

標準治療

主要な増分費用効果
N/A(評価中）
比の値

1.2

左記に同じ

左記に同じ
具体的な値は確認できないが、PBACの推奨は、製造販売業者が提案した価格でのモルヌピラビルの費用対効果に基づくとされている。

製造販売業者による諸外国の医療技術評価機関における評価報告のレビュー

諸外国の医療技術評価機関の評価報告について、公的分析におけるレビューの結果、製造販売業者の報告内容といくつかの相違が認められたが、最新の情報の反映によること等が理由として考えられた。
1.3

公的分析における参考事項

諸外国の医療技術評価機関や公的機関の報告において、公的分析の参考となりうる項目を下記に列挙した。
<NICE>(1)
MTAの概要⃝NICEでは、重症化リスク因子を有する軽症のCOVID-19患者を分析対象集団として、カシリビマブ/
イムデビマブ、モルヌピラビル、ニルマトレルビル/リトナビル、レムデシビル、ソトロビマブ、チ
キサゲビマブ/シルガビマブのMTAが実施された。

ATAG. Rep. 2024;2(2)11⃝Assessment groupの報告によると、標準治療と比較したときのICERはニルマトレルビル/リトナ
ビルが最も小さく、モルヌピラビルを含むその他の薬剤はニルマトレルビル/リトナビルに対してdominatedであった。
⃝Final draft guidanceでは、重症化リスク因子を有する軽症のCOVID-19患者の治療薬として、ニルマ
トレルビル/リトナビルを推奨している。モルヌピラビル、カシリビマブ/イムデビマブ、レムデシビ
ル、ソトロビマブ、チキサゲビマブ/シルガビマブは非推奨と記述されている。
モルヌピラビルの治療効果⃝Assessment groupは、ネットワークメタアナリシスの手法を用いて各薬剤の治療効果を評価した。
モルヌピラビルに関しては、対象集団の大部分がワクチン等で免疫を獲得しており、かつオミクロン
株流行下で行われたPANORAMIC試験を含めて解析が実施されており、入院または死亡に関するリス
ク比は0.80(95% CI: 0.56 to 1.15)、
全死亡に関するリスク比は0.27(95% CI: 0.09 to 0.82)と推計された。
⃝PANORAMIC試 験 に お い て モ ル ヌ ピ ラ ビ ル が 標 準 治 療 に 対 す る 優 越 性 を 示 し て い な い こ と をCommitteeは指摘しているが、重症化リスク因子の定義として最も確実性の高いエビデンスであると考えられるDepartment of Health and Social CareのMcInnes報告(3)に基づくハイリスク集団に比較すると、PANORAMIC試験の対象集団は重症化リスクがより低いことも認識している。
⃝そこでCommitteeは、英国の実臨床の状況を反映し、McInnes報告に基づくハイリスク集団を含む
OpenSAFELYのデータを参照した。このデータは入院率や死亡率に対するモルヌピラビルの限定的な有用性を示しており、ネットワークメタアナリシスやPANORAMIC試験の結果を支持していた。
⃝モルヌピラビルによる入院または死亡リスクの減少効果は不確かであり、これを正当化するためには強固なエビデンスが必要であるとCommitteeは結論付けた。
現在のendemic期における過去に行われた臨床試験の一般化可能性⃝NICEにおける評価時点で懸念される主要な変異型はオミクロン株であったものの、薬剤の効果を評価した臨床試験のほとんどが、それよりも前の株を対象としていることをCommitteeは指摘しており、臨床専門家も、過去に行われた臨床試験のデータを外挿することは誤解を招くものであると述べている。
⃝Committee並びに臨床専門家は、臨床的なエビデンスをどのように現在のendemic期に外挿するかを検討すべきであると指摘しており、一般化可能性に関する主要な懸念事項として、以下のものを挙げていた。
- 自然免疫とワクチンによる集団免疫の変化- ウイルスの病原性の変化

12ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

- ウイルスに関する知識が深まることによるサポーティブケアの有効性の増大- その他pandemic期との状況の差異⃝経済評価モデルでは上述の懸念事項を可能な限り考慮したが、これら懸念事項と治療効果には交互作用が存在しうるため、臨床試験が示す薬剤の効果は依然として一般化可能性を欠く可能性があるとCommitteeは考えた。また、臨床試験が入院率や死亡率の高い時期に行われたものであるた
め、この交互作用は薬剤が有効であることを示す方向に働く可能性がある。したがってCommitteeは、
pandemic期に観察された治療効果はベストサポーティブケアの変化やワクチン接種率の向上によってendemic期では減じるものであると結論付けた。
Appeal panelにおける議論⃝製造販売業者のアピールが認められた主な事項は以下の通りである。
- モルヌピラビルの治療効果の評価において、PANORAMIC試験が重視され、その解釈の助けとして
特定のreal world evidence(OpenSAFELY)が参照されたが、そのプロセスが不透明であること- scopeで定義された入院率及び死亡率以外のアウトカムについても精査すべきであること⃝製造販売業者のアピールが認められなかった事項は以下の通りである。
- PANORAMIC試験が対象とした集団は、McInnes報告におけるハイリスク集団を15%程度しか含んでおらず、一般化可能性に課題があること(PANORAMIC試験では、免疫不全患者のサブグループ
解析が実施されており、これによっても有意な差が認められなかったこと等が説明されている)- 経済評価において、ネットワークメタアナリシスから得られた治療効果の点推定値、 95%信頼区間の上限及び下限をそれぞれ適用することでICERを推計すること(単純な方法ではあるものの、
PANORAMIC試験と他の試験の異質性を考慮すると、このような幅での評価は妥当である等の説明がなされている)⃝以上の製造販売業者のアピールの結果、新たなSTAを実施し、その結論が出るまで最終ガイダンスは公表しないことで合意した。
<PBAC>(2)⃝2022年2月、PBACは、製造販売業者が提案した価格でのモルヌピラビルの費用対効果に基づきつつ、
モルヌピラビルを、条件に合致する酸素吸入を必要としない軽症から中等症のCOVID-19患者に対して推奨した。
⃝2022年11月には、PANORAMIC試験を考慮して、ニルマトレルビル/リトナビルが禁忌または適切ではない場合のみ、モルヌピラビルによる治療を検討すべきであると提言した。
⃝PBACは、モルヌピラビルに関する新たなエビデンスを考慮し、Pharmaceutical Benefits SchemeのATAG. Rep. 2024;2(2)13アクセス条件を引続き検討する予定である。
1.4

その他の海外公的機関の報告における参考事項

2023年6月にEMA(4)による評価が公表されたため、この情報を追加した。
<EMA>(4)⃝EMAは、酸素投与を受けていない、重症化リスク因子を有する成人のCOVID-19患者におけるモルヌ
ピラビルの臨床的有用性が証明されていないとして、モルヌピラビルの販売承認の取下げを勧告した。
製造販売業者は再審査請求の後、再審査終了前に販売承認を取下げた。
⃝EMAの評価において、下記が勧告の根拠となった。
- MOVe-OUT試験では、IA3/4(事前に計画された中間解析)までの時点のper protocol populationにおいて、 29日目までの入院または死亡の発生におけるモルヌピラビルの優越性が示された(群間差, -5.6%; 95% CI, -9.8

to -1.5)。一方、IA3/4後のper protocol populationでは、入院または死亡の発生に群間差が認められなかった(群間差, 0.0%; 95% CI, -3.3 to 3.3)。すなわち、モルヌピラビ
ルの治療効果に関する一貫した結果が示されておらず、MOVe-OUT試験はモルヌピラビルの有効性を証明していない。またMOVe-OUT試験において、モルヌピラビル群における29日目までの入院または死亡の発生は、IA3/4までの時点で5.7%、IA3/4後で4.2%であった。一方、プラセボ群はIA3/4までの時点で11.3%、IA3/4後で4.2%に低下していた。したがってIA3/4までの時点を対象として示されたモルヌピラビルの有効性は、リスクが高いより早期のpandemic期におけるワクチン
未接種者を対象として観察されており、現在のヨーロッパの集団に対して外挿することはできないという懸念がある。
- さらに、ヨーロッパの状況に結果を外挿することができると考えられるPANORAMIC試験は、入院または死亡の発生におけるモルヌピラビルの優越性を示していない。
- その他、 3件のインドで行われた非盲検ランダム化比較試験のデータも参考情報として提出されたが、ヨーロッパにおける一般化可能性や評価項目の性質からモルヌピラビルの有効性を裏付けるためには不十分である。
- リアルワールドデータに基づく研究はモルヌピラビルの有効性を支持するものの、ランダム化の欠如によるコントロールできないバイアスが懸念される。したがって、これらの研究はMOVe-OUT試験で認められた結果の一貫性の欠如に対する懸念を覆す根拠とするには十分でない。

14
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

2. 追加的有用性の評価
2.1

公的分析におけるシステマティックレビュー

COVID-19患者におけるモルヌピラビルの追加的有用性を検討するために、ランダム化比較試験(RCT)を対象としたシステマティックレビュー (SR)を実施した。
2.1.1

公的分析が設定したリサーチクエスチョン

公的分析が設定したリサーチクエスチョンを表2-1-1に示す。
表 2-1-1 公的分析によるシステマティックレビューのリサーチクエスチョン
項目

2.1.2

内容

対象集団

COVID-19 患者

介入

モルヌピラビル

比較対照

標準治療

アウトカム

有効性、安全性

研究デザイン

RCT

文献検索期間指定なし(検索実施時点である 2023 年 6 月まで)

実施の流れ

文献検索では、医学情報サービス・文献検索の専門家が、疾患名、薬剤名、研究デザイン、検索対
象期間等の条件を組合わせて検索式を構築した。論文のアブストラクトに基づくスクリーニング、追加的有用性評価に用いる論文を特定する作業は、 2名の独立したレビューアーが盲検下にて実施した。
論文の採否は事前に設定した組み入れ基準、除外基準に従い判定した。レビューアー間の不一致等は、両者の協議により解消した。最終的に特定されたランダム化比較試験の概要を要約し整理し、最後に特定された文献の批判的吟味をおこなった。
2.1.3

臨床研究の組み入れ基準や除外基準

SR の主な組み入れ基準と除外基準を以下に示す。
表 2-1-3 適格基準
組み入れ基準除外基準

対象集団

COVID-19 患者

左記以外

介入

ラゲブリオ/モルヌピラビル

左記以外

比較対照

標準治療

ラゲブリオ/モルヌピラビル以外の抗ウイルス薬

アウトカム

有効性、安全性

左記以外

研究デザイン

第II相または第III相RCT

左記以外

文献の種類

原著論文

レビュー、レター、会議録、臨床試験登録

言語

英語、日本語

左記以外

ATAG. Rep. 2024;2(2)152.1.4

使用したデータベース

SRには、PubMed、Embase/Embase Preprints、Cochrane Central Register of Controlled Trials(CENTRAL)、医中誌webを用いた。
2.1.5

使用した検索式

SR の検索式を表2-1-5-1~表2-1-5-4に示す。
表 2-1-5-1 PubMedに対して用いた検索式
通番

検索式

結果数

#1

"LitCGeneral"[Filter]

365,030#2"molnupiravir"[Supplementary Concept] OR "molnupiravir"[Title/Abstract] OR "EIDD 2801"[Title/Abstract] OR "lagevrio"[Title/Abstract] OR "MK 4482"[Title/Abstract]#3#1 AND #2#4"Randomized Controlled trial"[Publication Type] OR "random*"[Text Word] OR "placebo"[Text Word]#5#3 AND #4#6#5 NOT ("animals"[MeSH Terms] NOT "humans"[MeSH Terms])

567
534
1,726,934
57
56

最終検索日

2023/6/6

件数

56

表 2-1-5-2 Embaseに対して用いた検索式
通番

検索式

結果数

s1

((EMB.EXACT.EXPLODE("Severe acute respiratory syndrome coronavirus 2")) OR (EMB.EXACT.EXPLODE("coronavirus disease 2019")) OR ab("covid19" OR "covid 19" OR "covid-19" OR "sars-cov-2" OR"sars cov 2" OR "sarscov2" OR "severe acute respiratory syndrome coronavirus" OR "2019-ncov") OR ti("covid19" OR "covid 19" OR "covid-19" OR "sars-cov-2" OR "sars cov 2" OR "sarscov2" OR "severe acuterespiratory syndrome coronavirus" OR "2019-ncov"))

410,055

s2

EMB.EXACT("molnupiravir") OR ab("molnupiravir" OR "EIDD 2801" OR "EIDD-2801" OR "lagevrio" OR"MK 4482") OR ti("molnupiravir" OR "EIDD 2801" OR "EIDD-2801" OR "lagevrio" OR "MK 4482")s3

S2 AND S1

s4(EMB.EXACT.EXPLODE("randomized controlled trial") OR ab(random*) OR ab(placebo) OR ti(random*)
OR ti(placebo))s5(S4 AND S3) not (rtype.exact("Conference Abstract" OR "Note" OR "Erratum"))

16
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

988
2,170,01655
最終検索日2023/6/6

件数55

表 2-1-5-3 CENTRALに対して用いた検索式
通番

検索式

結果数

#1

MeSH descriptor: [COVID-19] explode all trees

4,374

#2

MeSH descriptor: [SARS-CoV-2] explode all trees

2,282

#3

("severe acute respiratory syndrome coronavirus" OR "sars-cov" OR "sars cov" OR "sarscov"):ti,ab,kw OR("covid19" OR "covid 19" OR "covid-19" OR "2019-ncov"):ti,ab,kw

16,181#4#1 OR #2 OR #3

16,615#5(molnupiravir):ti,ab,kw OR ("lagevrio"):ti,ab,kw OR ("EIDD 2801" OR "EEIDD-2801"):ti,ab,kw OR ("MK4482" OR "MK-4482"):ti,ab,kw

80#6#4 AND #5

74

in CENTRAL

73
最終検索日

2023/6/6

件数

73

表 2-1-5-4 医中誌Webに対して用いた検索式
通番

検索式

結果数

#1

SARSコロナウイルス-2/TH or COVID-19/TH or COVID-19/AL or (コロナ/TA and DT=2020:2023)#2"Molnupiravir"/TH or "molnupiravir"/TA or "EIDD 2801"/TA or "EIDD-2801"/TA or "EIDD2801"/TA or "lagevrio"/TA or "MK 4482"/AL or "MK-4482"/TA or "MK4482"/TA or "モルヌピラビル"/TA or "ラゲブリオ"/TA

50,52799#3#1 and #2

97#4#3 and (ランダム化比較試験/TH or ランダム/TA or 無作為/TA or RCT/TA or radom*/TA or プラセボ/TA or
RD=ランダム化比較試験,準ランダム化比較試験)

3

最終検索日

2023/6/6

件数

3

ATAG. Rep. 2024;2(2)172.1.6

検索結果

SRの結果、COVID-19を対象としたRCTの原著論文を8件特定した。この内、第II相RCTはAGILE(5)、NCT04405570 (6)、第III相RCTはMOVe-OUT 2報 (7, 8)、MOVe-OUTのサブグループ解析 (9)、PANORAMIC (10)、CTRI/2021/07/034588 (11)、ChiCTR2200056817 (12)であった (図2-1-6)。臨
床試験の概要を、表2-1-7-1~表2-1-7-8に示す。

Identification

データベースから特定した件数(n=187)[PubMed (n=56)、
Embase (n=55)、
CENTRAL (n=73)、
医中誌Web (n=3)]↓

Screening

重複除外後の件数 (n=116)→↓
スクリーニング件数 (n=116)→

除外件数 (n=105)→

除外件数 (n=3)↓
Eligibility

適格性評価の対象件数 (n=11)

Included

RCT (n=8)[第II相臨床試験:
AGILE CST-2 (n=1)、
NCT04405570 (n=1)、
第III相臨床試験:
MOVe-OUT (n=3)、
PANORAMIC (n=1)、
CTRI/2021/07/034588 (n=1)、
ChiCTR2200056817 (n=1)]↓

図 2-1-6 フローチャート

18
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

2.1.7

臨床試験の概要
表 2-1-7-1 臨床試験の概要

試験名

AGILE CST-2

書誌情報

Khoo SH, FitzGerald R, Saunders G, Middleton C, Ahmad S, Edwards CJ, et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK(AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis.
2023;23(2):183-95.(5)臨床試験登録情報

NCT04746183

試験を実施した場所

イギリス

試験の登録期間2020 年 11 月～ 2022 年 3 月

対象集団

軽症～中等症のCOVID-19 外来患者

適格基準

•18 歳以上
•症状発現から 5 日以内•コントロール不良の慢性疾患がない

主な除外基準•妊婦または授乳中•重度の慢性腎臓病または透析患者•肝機能不全または腎機能障害•入院、酸素投与、人工呼吸器等の介入を必要とする呼吸器疾患

介入方法の詳細

モルヌピラビル(800mg1 日 2 回 5 日間経口投与)＋標準治療(n=90)

比較対照の詳細

プラセボ＋標準治療 (n=90)

試験デザイン

第II相、多施設共同、無作為化比較試験

盲検化法

二重盲検

主要評価項目ランダム化からPCR陰性までの時間

主な副次的評価項目•29 日目まで死亡率•29 日目まで入院率•安全性、等

有効性

モルヌピラビル群 (n=90)、プラセボ群 (n=90)
ランダム化からPCR陰性までの時間の中央値 (95% CI):
モルヌピラビル群： 8 日 (8 to 9) VS プラセボ群： 11 日 (10 to 11)
HR 1.30 (95% CI： 0.92 to 1.71)
29 日目までの入院:
モルヌピラビル群： 0% VS プラセボ群： 4%
29 日目までの死亡:
モルヌピラビル群： 0% VS プラセボ群： 0%

安全性グレード 3 以上AE：
モルヌピラビル群： 1% VS プラセボ群： 3%
グレード 3 以上SAE：
モルヌピラビル群： 0% VS プラセボ群： 1%

日本人集団における有効性

NA

日本人集団における安全性

NA

ATAG. Rep. 2024;2(2)19表 2-1-7-2 臨床試験の概要
試験名

Fischer 2022

書誌情報

Fischer WA, 2nd, Eron JJ, Jr., Holman W, Cohen MS, Fang L, Szewczyk LJ, et al. A phase 2a clinical
trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance andelimination of infectious virus. Sci Transl Med. 2022;14(628):eabl7430.(6)

臨床試験登録情報

NCT04405570

試験を実施した場所

米国試験の登録期間2020 年 6 月～ 2021 年 1 月

対象集団

軽症～中等症のCOVID-19 外来患者

適格基準

•SARS-CoV-2 のワクチン接種•18 歳以上
•症状発現から 7 日以内

主な除外基準記載なし

介入方法の詳細•モルヌピラビル 200mg 1 日 2 回 5 日間 (n=23)•モルヌピラビル 400mg 1 日 2 回 5 日間 (n=62)•モルヌピラビル 800mg 1 日 2 回 5 日間 (n=55)

比較対照の詳細プラセボ (n=62)

試験デザイン

第IIa相、多施設共同、無作為化比較試験

盲検化法

二重盲検

主要評価項目•ウイルスRNAクリアランスまでの時間•グレード 3 以上のAE

主な副次的評価項目

患者報告のCOVID-19 の重症度
患者報告の症状持続時間

有効性

モルヌピラビル 800mg群 (n=55)、プラセボ群 (n=62)
ウイルスRNAクリアランスまでの時間 (中央値、95% CI):
モルヌピラビル 800mg群:14.0 日 (13.0-14.0 ）VS
プラセボ群:15.0 日 (15.0-27.0) p= 0.013

安全性グレード 3 以上のAE:
モルヌピラビル 800mg 群: 7.3% VSプラセボ群: 8.1%

日本人集団における有効性

NA

日本人集団における安全性

NA

20
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

表 2-1-7-3 臨床試験の概要
試験名

MOVe-OUT

書誌情報

Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V,
et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med.
2022;386(6):509-20.(7)臨床試験登録情報

NCT04575597

試験を実施した場所

日本を含まない 20 か国試験の登録期間2021 年 5 月～ 2021 年 11 月

対象集団

軽症～中等症のCOVID-19 外来患者

適格基準

• 18 歳以上• 症状発現から 5 日以内• 1 つ以上のCOVID-19 症状を有する• 重症化リスク因子を有する (60 歳以上、活動性のがん、慢性腎臓病、慢性閉塞性肺疾患、BMI≧ 30、
重篤な心疾患、糖尿病)

主な除外基準• 48 時間以内にCOVID-19 による入院の可能性がある• 透析患者またはeGFR<30 mL/min/1.73 ㎡• 妊婦• 重度の好中球減少症(好中球絶対数<500/ mL)• 血小板数<100,000/μL• SARS-CoV-2 のワクチン接種

介入方法の詳細

モルヌピラビル 800 ㎎ 1 日 2 回 5 日間 (n=716)

比較対照の詳細プラセボ (n=717)

試験デザイン

第III相、多施設共同、無作為化比較試験

盲検化法

二重盲検

主要評価項目• mITT集団(無作為化後、モルヌピラビルまたはプラセボを 1 回以上投与され、初回投与前に入院していない集団)における 29 日目までの入院または死亡• AE

主な副次的評価項目• 29 日目までのWHO 11-point Clinical Progression Scale• 患者報告のCOVID-19 の兆候及び症状

有効性

29 日目までの入院または死亡:
中間解析:
モ ル ヌ ピ ラ ビ ル 群: 7.3% (28/385) VSプ ラ セ ボ 群: 14.1% (53 /377) 群 間 差 -6.8 (95% CI: -11.3 to-2.4)、p=0.001
Post-hoc:
モルヌピラビル群: 6.8% (48/709) VSプラセボ群: 9.7% (68 /699) 群間差 -3.0 (95% CI: -5.9 to -0.1)、
p=0.001

安全性

Post-hoc AE発生割合:
モルヌピラビル群: 30.4% (216/710) VSプラセボ群: 33.0% (231/701)

日本人集団における有効性

NA

日本人集団における安全性

NA

ATAG. Rep. 2024;2(2)21表 2-1-7-4 臨床試験の概要
試験名

MOVe-OUT

書誌情報

Johnson MG, Puenpatom A, Moncada PA, Burgess L, Duke ER, Ohmagari N, et al. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial. Ann Intern Med. 2022;175(8):1126-34.(8)臨床試験登録情報
試験を実施した場所
試験の登録期間
対象集団
適格基準
主な除外基準MOVe-OUTと同じ(表 2-1-7-3 と同じ)介入方法の詳細比較対照の詳細
試験デザイン
盲検化法
主要評価項目•安全性評価の対象集団におけるベースラインから 29 日目までのCRP濃度、及びSpO2 の平均変化量•mITT集団における呼吸介入の使用、及び急性期治療の受診

主な副次的評価項目

記載なし
安全性評価の対象集団(モルヌピラビル群 n=710、プラセボ群 n=701)におけるベースラインから 29 日
目までのCRP濃度の平均変化量:
モルヌピラビル群: –14.69 VSプラセボ群: –12.32
安全性評価の対象集団におけるベースラインから 29 日目までのSpO2 の平均変化量:
モルヌピラビル群: 0.76 VSプラセボ群: 0.69

有効性

mITT集団(モルヌピラビル群 n=709、プラセボ群 n=699)における呼吸介入の使用:
プラセボ群に対するモルヌピラビル群のRRR:
34.3% (95% CI:4.3 to 54.9)
mITT集団における急性期治療の受診:
プラセボ群に対するモルヌピラビル群のRRR (95% CI):
32.1% (4.4 to 51.7)

安全性

NA

日本人集団における有効性

NA

日本人集団における安全性

NA

22
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

表 2-1-7-5 臨床試験の概要
試験名

MOVe-OUT

書誌情報

Johnson MG, Strizki JM, Brown ML, Wan H, Shamsuddin HH, Ramgopal M, et al. Molnupiravir forthe treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial. Infection. 2023:1-12.(9)臨床試験登録情報

NCT04575597

試験を実施した場所

MOVe-OUTと同じ(表 2-1-7-3 と同じ)試験の登録期間

同上

対象集団

免疫不全者で、軽症～中等症のCOVID-19 外来患者

適格基準

MOVe-OUTと同じ

主な除外基準同上

介入方法の詳細

モルヌピラビル 800mgを 1 日 2 回 5 日間 (N=24)

比較対照の詳細

プラセボを 1 日 2 回 5 日間 (N=31)

試験デザイン

MOVe-OUTと同じ

盲検化法

同上

主要評価項目同上

主な副次的評価項目•29 日目までのWHO 11-point Clinical Progression Scale•患者報告のCOVID19 の兆候及び症状

有効性

モルヌピラビル群 (n=31)、プラセボ群 (n=24)
29 日目までの入院または死亡:
モルヌピラビル群: 22.6%VSプラセボ群: 8.3%
群間差 -14.2 (95% CI: -33.5 to 6.6)

安全性

AE発生割合:モルヌピラビル群: 45.2% VSプラセボ群: 25.0%

日本人集団における有効性

NA

日本人集団における安全性

NA

ATAG. Rep. 2024;2(2)23表 2-1-7-6 臨床試験の概要
試験名

PANORAMIC

書誌情報

Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus
usual care versus usual care alone as early treatment for adults with COVID-19 at increased riskof adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.
Lancet. 2023;401(10373):281-93.(10)

臨床試験登録情報

ISRCTN30448031

試験を実施した場所

イギリス

試験の登録期間2022 年 3 月～ 2022 年 4 月

対象集団

軽症～中等症のCOVID-19 外来患者

適格基準

•18 歳以上
•症状発現から 5 日以内•1 つ以上のCOVID-19 症状を有する•50 歳以上、あるいは 18 歳以上で合併症を有する(免疫抑制、慢性腎臓病、慢性閉塞性肺疾患、BMI≧
35、慢性心疾患、慢性血管疾患、慢性肝疾患、糖尿病、慢性神経疾患、重度の学習障害、重度の精神疾患、ダウン症、固形臓器、骨髄、幹細胞移植患者、ケアホーム入居者、その他臨床的に脆弱と判断された患者)

主な除外基準•妊婦または授乳中介入方法の詳細

モルヌピラビル 800mg1 日 2 回 5 日間＋標準治療 (n=12,529)

比較対照の詳細

標準治療 (n=12,525)

試験デザイン

多施設共同、無作為化比較試験

盲検化法

非盲検

主要評価項目•28 日目までの入院または死亡

主な副次的評価項目•患者報告の症状回復までの時間•医療、または福祉サービスの利用•安全性
モルヌピラビル群 (n=12,529)、標準治療群 (n=12,525)
28 日目までの入院または死亡:
モルヌピラビル群 1% VS 標準治療 1%
OR: 1.06 (95% CI:0.81 to 1.41)

有効性

患者報告の初回回復までの時間 (中央値、IQR):
モルヌピラビル群 9 日(5-23) VS 標準治療群 15 日(7-未到達)
OR: 1.36 (95% CI:1.32 to 1.40)
NHS111 サービスの利用:
モルヌピラビル群 5% VS標準治療群 6%
OR: 0·72 (95% CI:0·64 to 0·80)

安全性

SAE発生割合:モルヌピラビル群 0.4%

日本人集団における有効性

NA

日本人集団における安全性

NA

24
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

VS 標準治療群 0.3%

表 2-1-7-7 臨床試験の概要
試験名Sinha 2022

書誌情報

Sinha S, N K, Suram VK, Chary SS, Naik S, Singh VB, et al. Efficacy and Safety of Molnupiravir in
Mild COVID-19 Patients in India. Cureus. 2022;14(11):e31508.(11)

臨床試験登録情報

CTRI/2021/07/034588

試験を実施した場所

インド

試験の登録期間2021 年 5 月～ 2021 年 8 月

対象集団

軽症のCOVID-19 外来患者

適格基準

•18 歳以上 60 歳以下•症状発現から 5 日以内

主な除外基準•中等度から重度のCOVID-19 (SpO2 ≦ 93％、または呼吸数≧ 24 回/分)
•重度の肝疾患•活動性のC型肝炎、B型肝炎•HIV•急性膵炎、慢性膵炎の既往•重度の腎障害、または腎代替療法を継続的に受けている

介入方法の詳細

モルヌピラビル (800mg1 日 2 回 5 日間)＋標準治療 (n=608)

比較対照の詳細

標準治療 (n=610)

試験デザイン

第III相、多施設、無作為化比較試験

盲検化法

非盲検

主要評価項目•14 日目までの入院•AE

主な副次的評価項目

記載無し

有効性

モルヌピラビル群(n=608)、標準治療群(n=610)
14 日目までの入院:
モルヌピラビル群 1.48% VS 標準治療群 4.26%
群間差 -2.78(95% CI: -4.65 to -0.90)、p=0.0053

安全性

AE発生割合:モルヌピラビル群 4.8% VS 標準治療群

日本人集団における有効性

NA

日本人集団における安全性

NA

2.6%

ATAG. Rep. 2024;2(2)25表 2-1-7-8 臨床試験の概要
試験名

Zou 2022

書誌情報

Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G, et al. Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial. Front Pharmacol.
2022;13:939573.(12)

臨床試験登録情報

ChiCTR2200056817

試験を実施した場所

中国

試験の登録期間2022 年 3 月～ 2022 年 3 月

対象集団

軽症～中等症のCOVID-19 外来患者

適格基準

•18 歳以上 80 歳以下•症状発現から 5 日以内

主な除外基準•重度の嘔吐やそれ以外の理由によって経口治療が困難•妊婦または授乳中•抗体療法、血漿療法、SARS-CoV-2 に対するその他の治験薬の治療歴

介入方法の詳細

モルヌピラビル (800mg1 日 2 回 5 日間)＋標準治療 (n=76)

比較対照の詳細

標準治療 (n=31)

試験デザイン

第III相、無作為化比較試験

盲検化法

非盲検

主要評価項目

ウイルスRNA消失までの時間

主な副次的評価項目

5 日、7 日、10 日目におけるSARS-CoV-2 ウイルス陰性化

有効性

モルヌピラビル群 (n=76)、標準治療群 (n=31)
ウイルスRNA消失までの時間の中央値 (95% CI):
モルヌピラビル群 9 日(7 to 9) VS 標準治療群 10 日 (9 to 11)
p=0.0092

安全性グレード 3 以上のAE発生割合:
モルヌピラビル群 0% VS 標準治療群 0%

日本人集団における有効性

NA

日本人集団における安全性

NA

2.2

製造販売業者によるシステマティックレビューと公的分析におけるレビュー結果の概要

2.2.1

製造販売業者によるシステマティックレビューについて

製造販売業者は、COVID-19外来患者を対象とし、比較対照技術はモルヌピラビル含む抗ウイルス薬、中和抗体薬、免疫抑制・調節薬の薬物療法を対象とした幅広い条件でSRを実施した。費用対効
果評価専門組織で決定された分析枠組みにおける分析対象集団は「重症化リスク因子を有するSARSCoV-2 による感染症(COVID-19)患者」であったが、製造販売業者のSRでは外来患者に限定したリサー
チクエスチョンの設定が行われていた。一方で、介入については分析枠組みよりも広くエビデンスの検索が行われていた。製造販売業者のSRは必ずしも分析枠組みと合致するものではなかったが、追加的有用性の評価に重要な論文はすべて含まれていた。
2.2.2

製造販売業者の実施したシステマティックレビューとの結果の差異について⃝製造販売業者によるSRの結果、COVID-19患者を対象とした抗ウイルス薬、中和抗体薬、免疫抑制・調節薬の薬物療法のRCTの原著論文等を86件(60試験)特定した。このうち、モルヌピラビル

26
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

と標準治療を比較した第II相RCTとして、AGILE CST-2試験、NCT04405570を特定した。第III相
RCTは、MOVe-OUT試 験、CTRI/2021/07/034588、ChiCTR2200056817を 特 定 し た。SR終 了 後にPANORAMIC試験を特定した。
⃝公的分析のSRにおいても第II相RCTとして、AGILE CST-2試験とNCT04405570が特定され、第III
相RCTとして、MOVe-OUT試験、PANORAMIC試験、ChiCTR2200056817が特定された。
⃝また、製造販売業者は2020年1月から2022年12月までの期間を対象として、SRを実施した。一方、
公的分析では、2023年6月までの期間を分析対象としたために、製造販売業者が実施したSR以降に出版された原著論文として、新たに、MOVe-OUTのサブグループ解析(9)、CTRI/2021/07/034588の原著論文(11)を特定した。
⃝なお、CTRI/2021/07/034588は製造販売業者によるSRにおいて、学会抄録として特定されていた。
⃝また、モルヌピラビル(ラゲブリオカプセル200mg)の添付文書における用法及び用量に関連する
注意として、「SARS-CoV-2による感染症の症状が発現してから速やかに投与を開始すること。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」とされている。公的分析が特定したNCT04575584、jRCT2031200404、及びEUCTR2020-003367-26-GBは下記原著論文の臨床試験登録情報であり、症状発現から6日目以降に投与を開始した患者が研究参加者に含まれている臨床試験であった。そのため、当該3件はモルヌピラビルの追加的有用性評価に適していないと考えられた。
Arribas, José R, Bhagani S, Lobo SM, Khaertynova I, Mateu L, et al. Randomized trial ofmolnupiravir or placebo in patients hospitalized with Covid-19. NEJM Evidence. 2022;1(2).
【製造販売業者の提出資料 ( システマティックレビュー ) に対するレビュー結果】
システマティックレビューの結果は、製造販売業者の提出したものと□完全に一致している。

■

おおむね一致し、追加的有用性の評価に重要な論文はすべて含まれている。

□

結果に解離があり、追加的有用性評価に重要な文献が欠けている。

□

その他(

)

ATAG. Rep. 2024;2(2)

27

2.3

製造販売業者による追加的有用性評価と公的分析におけるレビュー結果の概要

2.3.1

製造販売業者による追加的有用性評価

製造販売業者は、下記を根拠として、モルヌピラビルは標準治療に対して追加的有用性を有すると主張した。
⃝COVID-19外来患者におけるモルヌピラビルの有効性を、入院又は死亡を主要アウトカムとして評価したRCTは、MOVe-OUT試験とPANORAMIC試験に限られる。しかし、 2試験の異質性、例数の偏りを考慮すると2試験の統合は不適切である。
⃝PANORAMIC試験の対象集団において重症化リスク因子(合併症)の保有割合が69%であったこと、
標準治療群に中和抗体やレムデシビルの使用が許容されていたことから、当該試験において、入院又は死亡リスクに関してモルヌピラビルの優越性を証明することは、困難であった。
⃝MOVe-OUT第Ⅲ相試験の中間解析の結果、主要評価項目である無作為化29日目までの入院又は死亡の患者割合は、モルヌピラビル群7.3%、プラセボ群14.1%、群間差は-6.8%(95% CI：-11.3 to-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示された。
⃝MOVe-OUT第Ⅲ相試験において、モルヌピラビルの安全性は、標準治療と同程度であった。AE発
生割合は、モルヌピラビル群30.4%、プラセボ群33.0%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%、プラセボ群2.9%であった。
⃝MOVe-OUT試験の有効性評価の結果は、重症化リスクを有するCOVID-19外来患者を対象に、無治療に対するモルヌピラビルの有効性を評価した観察研究によって支持された。米国退役軍人保険のデータベースを用いたTarget Trial Emulation法による有効性評価(13)の結果、 30日目までの入院又は死亡割合は、モルヌピラビル群2.7%、無治療群3.8%、RRは0.72(95% CI：0.64 to 0.79)と、
MOVe-OUT試験で示されたHR 0.69(95% CI：0.48 to 1.01)とMOVe-OUT試験の結果に近かった。
2.3.2

公的分析におけるレビュー結果

公的分析のSRで特定された臨床試験において、入院又は死亡を主要評価項目とした第III相臨床試 験 は、MOVe-OUT試 験、PANORAMIC試 験、 及 びCTRI/2021/07/034588の3試 験 で あ っ た。 しかし、製造販売業者が追加的有用性の主な根拠としたMOVe-OUT試験はデルタ株、ミュー株、及びガンマ株等の環境下における新型コロナワクチン未接種者を対象とした臨床試験であった。また、
CTRI/2021/07/034588も同様に、研究実施期間からデルタ株、ミュー株、及びガンマ株等の環境下において実施された臨床試験であった。しかし、公的分析期間中における主な流行株はオミクロン株であったことに加えて、新型コロナワクチン接種率(1回以上接種)が8割を超えていたことから(14)、
当該2試験は本邦の臨床実態とは状況が異なることが考えられた。そのため、公的分析では、オミク

28ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

ロン株環境下において、ワクチン接種者を対象として実施されたPANORAMIC試験を中心にモルヌピ
ラビルの追加的有用性評価を行うこととした。
ただし本邦と英国において、主に用いられる重症化リスク因子の定義や標準治療の内容等が異なることに起因して、PANORAMIC試験には、本邦においては必ずしも重症化リスク因子を有すると定義されない症例や、モルヌピラビル使用時に他の抗ウイルス薬や中和抗体薬等を併用した症例が含まれていた。本品目の評価において、この重症化リスク因子の定義や標準治療の内容の違いが考慮されないまま評価を進めることには課題があると考えられた。そのため、PANORAMIC試験の著者(PANORAMIC Trial Collaborative Group)へ問い合わせを行い、本邦における重症化リスク因子の定義や標準治療の内容に合致した症例のみを抽出した上で、モルヌピラビルの評価を行うこととした。
具体的に実施した解析手順及び結果を下記に示す(別添1参照)。なお、症例抽出後の統計学的解析等
は全てPANORAMIC試験原著論文において実施された方法に準じた。
重症化リスク因子の定義に関する扱い(基本分析)
PANORAMIC試験の適格基準は、 50歳以上あるいは特定の合併症を有するCOVID-19患者であり、本邦において主に用いられる定義に照らし合わせると、必ずしも重症化リスク因子を有すると定義されない症例が含まれていた。そのため、公的分析期間での最新版であった新型コロナウイル
ス感染症(COVID-19)診療の手引き・第10.0版における重症化リスク因子の定義に基づき、それらのリスク因子を有する症例のみを抽出した(表2-3-2-1)。新型コロナウイルス感染症(COVID-19)診療の手引き・第10.0版における重症化リスク因子の定義は、アメリカ疾病予防管理センターにおける定義に基づいて、重症化リスク因子をエビデンスレベルが高(Higher Risk[conclusive])から低(Mixed
Evidence[inconclusive: no conclusions can be drawn from the evidence])に分類していた。本解析
では、エビデンスレベルが高(Higher Risk[conclusive])に該当する重症化リスク因子を有する症例のみを抽出した。なお、各重症化リスク因子の定義方法はPANORAMIC試験において用いられた方法に準じた。

ATAG. Rep. 2024;2(2)29表 2-3-2-1 重症化リスク因子の定義(基本分析)
Risk factor

Diagnostic criteria or definition

Older adults aged ≥ 65 years

Aged ≥ 65 years

AsthmaFrom free text and collected under lung disease.

Cancer (Hematologic malignancies)

From free text only. Mentions “blood cancer”.

Cerebrovascular disease

From free text, mentions “stroke” or “cerebral aneurysm”

Chronic kidney disease (People receiving dialysis)

Collected as “long term kidney disease”, not clear if receiving dialysis. Havecounted anyone who has this checked.

Bronchiectasis

Collect “long term lung disease (including chronic obstructive pulmonary
disease (COPD), cystic fibrosis or asthma requiring at least daily use of inhalers)” .

COPD (Chronic obstructive pulmonary disease)Collected as lung disease

Interstitial lung disease

Collected as lung disease

Pulmonary embolism

Collected as lung disease

Pulmonary hypertension

Collected as lung disease

Cirrhosis

Collected as liver diseaseNon-alcoholic fatty liver disease

Collected as liver disease

Alcoholic liver disease

Collected as liver disease

Autoimmune hepatitis

Collected as liver disease

Cystic fibrosis

Collected as lung disease

Diabetes mellitus, type 1

Collected as diabetes, not separated by type.

Diabetes mellitus, type 2

Collected as diabetes, not separated by type.

Down syndrome

Down syndrome

Heart conditions (such as heart failure, coronary
Defined as long term heart or vascular diseaseartery disease, or cardiomyopathies)
HIV (Human immunodeficiency virus)

Comes under weakened immune system or free text mentions HIV

Mood disorders, including depression

Collected under severe mental health disorder

Schizophrenia spectrum disorders

Free text mentions “Schizoaffective disorder” or collected under

Neurologic conditions limited to dementia

Collected as long term neurological disease (including dementia, stroke,
epilepsy).

Obesity

Defined as BMI ≥ 35 kg/㎡

Primary immunodeficiencies

Collected as weakened immune system due to a condition you were bornwith or due to disease or treatment (e.g. sickle cell, HIV, cancer, chemotherapy)

Smoking, current and former

Current only

Solid organ or blood stem cell transplantation

Collected as transplant

Use of corticosteroids or other immunosuppressive
Free text mentions “steroids” or “immunosuppressant”
medications

30
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

標準治療に関する扱い(基本分析)
PANORAMIC試験では、モルヌピラビル使用時に他の抗ウイルス薬や中和抗体薬等を併用した症例が含まれていた。そのため、モルヌピラビル使用時に下記薬剤を併用していた症例を除外した(表2-3-2-2)。
表 2-3-2-2 モルヌピラビル以外のCOVID-19 治療薬(基本分析)
Remdesivir

Tixagevimab/cilgavimab

Any other neutralizing antibody for COVID-19

Nirmatrelvir/ritonavir

Tocilizumab

Any other immunosuppressive medications for
COVID-19

Ensitrelvir

Baricitinib

Favipiravir

Casirivimab/imdevimab

Dexamethasone

Ivermectin

Sotrovimab

Any other antiviral medications for COVID-19

ATAG. Rep. 2024;2(2)31解析結果(基本分析)
重症化リスク因子を有する症例の抽出とモルヌピラビル以外のCOVID-19治療薬を併用した症例を除外した結果、 18,274例(モルヌピラビル群:9,120例及び標準治療群:9,154例)が解析対象となった(図2-3-2-1)。本解析対象における平均年齢は56.8歳、男性7,683例(42.0%)であった(図2-3-2-2)。

PANORAMIC study participants (n=25,708)(12,774 molnupiravir plus usual care group + 12,934 usual care group)↓↓→

Excluded
Adults without any risk factors for severe COVID-19(n=7380)→

Excluded
Adults using other COVID-19 medications (n=54)
Remdesivir (n=0)
Nirmatrelvir/ritonavir (n=5)
Ensitrelvir (n=0)
Casirivimab/imdevimab (n=0)
Sotrovimab (n=0)
Tixagevimab/cilgavimab (n=0)
Tocilizumab (n=0)
Baricitinib (n=0)
Dexamethasone (n=1)
Any other antiviral medications for COVID-19(n=2)
Any other neutralizing antibody for COVID-19(n=46)
Any other immunosuppressive medications for
COVID-19 (n=0)
Favipiravir (n=0)
Ivermectin (n=0)

Adults with risk factors for severe
COVID-19(n=18328)↓↓
Eligible participants(n=18,274)

図 2-3-2-1 解析対象者選定のフローチャート(基本分析)

32
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Age, mean(SD) [min,max]

Molnupiravir plus
usual care
(N=9120)56.9 (14.4)[18.0 to 99.0]

Usual Care
(N=9154)

Overall(N=18274)

56.7 (14.7)[18.0 to 98.0]

56.8 (14.5)[18.0 to 99.0]5267 (57.8%)
3851 (42.2%)
2 (0.0%)2.0 (2.0 to 2.0) [0.0
to 7.0]4.0 (3.0 to 5.0) [1.0to 29.0]7163 (78.5%)

5319 (58.1%)
3832 (41.9%)
3 (0.0%)N/A

0 (0.0%)10586 (57.9%)7683 (42.0%)
5 (0.0%)2.0 (2.0 to 2.0) [0.0
to 7.0]4.0 (3.0 to 5.0) [1.0to 29.0]7163 (39.2%)

8589 (94.2%)
257 (2.8%)
150 (1.6%)
54 (0.6%)70 (0.8%)8596 (93.9%)318 (3.5%)
138 (1.5%)52 (0.6%)50 (0.5%)

17185 (94.0%)575 (3.1%)
288 (1.6%)
106 (0.6%)
120 (0.7%)

256 (2.8%)537 (5.9%)1115 (12.2%)

271 (3.0%)573 (6.3%)
1108 (12.1%)

527 (2.9%)1110 (6.1%)
2223 (12.2%)

1488 (16.3%)

1463 (16.0%)

2951 (16.1%)

5577 (61.2%)
37 (0.4%)

5582 (61.0%)
35 (0.4%)11159 (61.1%)
72 (0.4%)

43 (0.5%)56 (0.6%)

99 (0.5%)67 (0.7%)

66 (0.7%)

133 (0.7%)623 (6.8%)
1810 (19.8%)2108 (23.1%)
2442 (26.8%)
2137 (23.4%)
4267 (46.8%)

633 (6.9%)
1780 (19.4%)2157 (23.6%)
2439 (26.6%)2145 (23.4%)
4161 (45.5%)1256 (6.9%)3590 (19.6%)4265 (23.3%)
4881 (26.7%)
4282 (23.4%)
8428 (46.1%)

985 (10.8%)1427 (15.6%)
1838 (20.2%)

930 (10.2%)1466 (16.0%)
1833 (20.0%)

1915 (10.5%)2893 (15.8%)3671 (20.1%)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting
receipt of medication*, median(IQR)
Days from start of symptoms to taking
medication*, median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70
and clinically extremely vulnerable
Aged ≥65 and <70 and not clinicallyextremely vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinicallyextremely vulnerable or in an at risk group
Aged ≥55 and <60 and not clinicallyextremely vulnerable or in an at risk group
Aged ≥50 and <55 and not clinicallyextremely vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
23
4
5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3

N/A

図 2-3-2-2 PANORAMIC試験から抽出した症例の背景因子(基本分析)

ATAG. Rep. 2024;2(2)334(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Moderate problem
Major problem
Loss of smell or taste, n(%)
No problem
Minor problem
Moderate problem

Molnupiravir plus
usual care
(N=9120)2248 (24.6%)
2590 (28.4%)
32 (0.4%)
8412 (92.2%)9015 (98.8%)

Usual Care
(N=9154)

Overall(N=18274)

2238 (24.4%)2640 (28.8%)47 (0.5%)9064 (99.0%)

4486 (24.5%)5230 (28.6%)
79 (0.4%)
8412 (46.0%)
18079 (98.9%)

67 (0.7%)
369 (4.0%)
8361 (91.7%)
218 (2.4%)
105 (1.2%)
787 (8.6%)

72 (0.8%)329 (3.6%)
8440 (92.2%)
223 (2.4%)
90 (1.0%)799 (8.7%)

139 (0.8%)698 (3.8%)
16801 (91.9%)
441 (2.4%)
195 (1.1%)
1586 (8.7%)4011 (44.0%)
3289 (36.1%)
1585 (17.4%)
235 (2.6%)

3948 (43.1%)
3393 (37.1%)
1577 (17.2%)
236 (2.6%)

7959 (43.6%)
6682 (36.6%)
3162 (17.3%)
471 (2.6%)853 (9.4%)
3251 (35.6%)
3672 (40.3%)1344 (14.7%)

836 (9.1%)
3254 (35.5%)3694 (40.4%)1370 (15.0%)

1689 (9.2%)6505 (35.6%)
7366 (40.3%)2714 (14.9%)2501 (27.4%)
3051 (33.5%)2724 (29.9%)844 (9.3%)

2384 (26.0%)
3295 (36.0%)2649 (28.9%)
826 (9.0%)4885 (26.7%)
6346 (34.7%)
5373 (29.4%)
1670 (9.1%)

7361 (80.7%)1339 (14.7%)
380 (4.2%)
40 (0.4%)

7340 (80.2%)1381 (15.1%)
371 (4.1%)
62 (0.7%)

14701 (80.4%)2720 (14.9%)751 (4.1%)
102 (0.6%)7414 (81.3%)
1237 (13.6%)
380 (4.2%)
89 (1.0%)7476 (81.7%)
1249 (13.6%)
358 (3.9%)
71 (0.8%)14890 (81.5%)
2486 (13.6%)
738 (4.0%)
160 (0.9%)6379 (69.9%)1791 (19.6%)
614 (6.7%)

6567 (71.7%)
1686 (18.4%)
600 (6.6%)

12946 (70.8%)3477 (19.0%)1214 (6.6%)

図 2-3-2-2 PANORAMIC試験から抽出した症例の背景因子(基本分析) 続き

34
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir plus
usual care
(N=9120)336 (3.7%)

Usual Care
(N=9154)

Overall(N=18274)301 (3.3%)

637 (3.5%)

No problem
Minor problem
Moderate problem
Major problem

1912 (21.0%)3630 (39.8%)2718 (29.8%)860 (9.4%)

2015 (22.0%)3570 (39.0%)2734 (29.9%)835 (9.1%)

3927 (21.5%)7200 (39.4%)
5452 (29.8%)
1695 (9.3%)

No problem
Minor problem
Moderate problem
Major problem

5820 (63.8%)2286 (25.1%)
855 (9.4%)
159 (1.7%)

5748 (62.8%)
2373 (25.9%)864 (9.4%)
169 (1.8%)

11568 (63.3%)4659 (25.5%)
1719 (9.4%)
328 (1.8%)

No problem
Minor problem
Moderate problem
Major problem

7311 (80.2%)1329 (14.6%)
417 (4.6%)
63 (0.7%)7280 (79.5%)1410 (15.4%)
417 (4.6%)
47 (0.5%)

14591 (79.8%)2739 (15.0%)
834 (4.6%)
110 (0.6%)

No problem
Minor problem
Moderate problem
Major problem

383 (4.2%)
3449 (37.8%)4160 (45.6%)1128 (12.4%)

381 (4.2%)
3521 (38.5%)
4138 (45.2%)1114 (12.2%)

764 (4.2%)
6970 (38.1%)
8298 (45.4%)2242 (12.3%)

No problem
Minor problem
Moderate problem
Major problem

3990 (43.8%)3428 (37.6%)
1541 (16.9%)
161 (1.8%)4052 (44.3%)
3481 (38.0%)1464 (16.0%)
157 (1.7%)8042 (44.0%)6909 (37.8%)3005 (16.4%)
318 (1.7%)1004 (11.0%)4242 (46.5%)
3277 (35.9%)
597 (6.5%)
5.1 (1.7) [0.0 to
10.0]937 (10.2%)4352 (47.5%)3291 (36.0%)
574 (6.3%)
5.1 (1.7) [0.0 to
10.0]1941 (10.6%)8594 (47.0%)6568 (35.9%)
1171 (6.4%)
5.1 (1.7) [0.0 to
10.0]1245 (13.7%)4489 (49.2%)
1376 (15.1%)
1156 (12.7%)
580 (6.4%)
274 (3.0%)2848 (31.2%)

1236 (13.5%)4368 (47.7%)1409 (15.4%)1309 (14.3%)
547 (6.0%)285 (3.1%)
3010 (32.9%)2481 (13.6%)
8857 (48.5%)2785 (15.2%)
2465 (13.5%)1127 (6.2%)
559 (3.1%)
5858 (32.1%)

Major problem
Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean(SD) [min,max]People in household, n(%)
0
1
2
3
4
5
Taking inhaled corticosteroids, n(%)

図 2-3-2-2 PANORAMIC試験から抽出した症例の背景因子(基本分析) 続き

ATAG. Rep. 2024;2(2)35Primary Care

Taking inhaled corticosteroids for COVID,

Clinical
Trials Unitn(%)

Molnupiravir plus
usual care
(N=9120)159 (1.7%)

Usual Care
(N=9154)

Overall(N=18274)

143 (1.6%)302 (1.7%)

Monoclonal antibodies for COVID, n(%)
0 (0.0%)0 (0.0%)0 (0.0%)Comorbidities
PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0
Lung disease 2989 (32.8%)3161 (34.5%)
6150 (33.7%)
Heart disease 993 (10.9%)952 (10.4%)
1945 (10.6%)
4.3 NUMBER ANALYSED
Kidney disease 222 (2.4%)
253 (2.8%)475 (2.6%)
Liver disease 158 (1.7%)
143 (1.6%)
301 (1.6%)
Neurologicaldisease423(4.6%)
432(4.7%)
855 (4.7%)
Of the 18274 participants included in the subgroup analysis 17754 (97.2%) had
data collected
Learning
disability
33(0.4%)
27(0.3%)
60(0.3%)
on hospitalisation/death and so could be included in the primary analysis. 17334 (94.9%)
Down's syndrome' 24 (0.3%)
29 (0.3%)
53 (0.3%)
completed any diaries or calls and so could be included in the secondary analysis.
Diabetes 1473 (16.2%)
1507 (16.5%)2980 (16.3%)
Weakened immune system 1110 (12.2%)
1055 (11.5%)2165 (11.8%)
Transplant recipient 50 (0.5%)60 (0.7%)
110 (0.6%)
Obesity1957(21.5%)
1932(21.1%)
3889 (21.3%)
4.4 PRIMARY ANALYSES
Mental illness 196 (2.1%)
220 (2.4%)
416 (2.3%)
Hypertension 2285 (25.1%)2303 (25.2%)
4588 (25.1%)
4.4.1 PRIMARY OUTCOME
Other vulnerability 1886 (20.7%)
1883 (20.6%)3769 (20.6%)*Median and interquartile range presented for non-normally distributed variables.

The primary outcome is defined as all cause unplanned hospitalisation or death fromrandomisation to
28 daysPANORAMIC試験から抽出した症例の背景因子(基本分析)
follow-up. Data is derived from participant daily diaries,
phone calls,
図 2-3-2-2
続きand routine electronic data. If a primary endpoint is reported from any data source then thisoutcome is counted as “yes”. If the participant has completed 28 days follow-up and is not
hospitalised or is lost to follow-up but has been checked against routine electronic data and本解析対象者において、モルヌピラビルの標準治療に対する主要評価項目(入院又は死亡)のオッズ
no hospitalisation or death is found then this outcome is coded “no”. An odds ratio<1 suggests
比は1.053 (95% CI：0.775 to 1.396)であった(図2-3-2-3)。サブグループ解析の結果は図2-3-2-4に示
fewer hospitalisations/deaths in the Molnupiravir arm. The results show probability ofす。
superiority below 0.5, indicating no benefit of Molnupiravir compared to Usual Care.
TABLE 8 PRIMARY OUTCOME

Hospitalization or death
DeathsHospitalizations*OR < 1 favours molnupiravir

Molnupiravir plus
usual care
(N=9120)92/8932 (1.0%)
3/893290/8932 (1.0%)

Usual care
(N=9154)

Estimated treatment
effect (95% BCI)

87/8822 (1.0%)
5/8822
85/8822 (1.0%)

1.053 (0.775 to 1.396)
Not estimable
1.055 (0.773 to 1.413)

図 2-3-2-3 主要評価項目の結果(基本分析)

36
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Probabilityofsuperiority
0.39190.3963

図 2-3-2-4 主要評価項目のサブグループ解析結果(基本分析)

ATAG. Rep. 2024;2(2)

37

感度分析
新型コロナウイルス感染症(COVID-19)診療の手引き・第10.0版は公的分析期間中である2023年8月に公表されたものであるが、前版である第9.0版から第10.0版に更新に際して、当該資料内における重症化リスク因子の定義が大きく変更された。分析枠組み決定時(2022年11月)では、第8.1版における重症化リスク因子の定義が臨床現場で用いられていた可能性があったことを考慮して(第8.1版と第9.0版では重症化リスク因子の定義に差異はない)、第8.1版及び第9.0版における重症化リスク因子の定義を適用させた場合の解析を感度分析として実施した(別添2参照)。
重症化リスク因子の定義と標準治療に関する扱い(感度分析)
感度分析として、新型コロナウイルス感染症(COVID-19)診療の手引き・第8.1版及び第9.0版における重症化リスク因子の定義に基づき、それらのリスク因子を有する症例のみを抽出した(表2-3-23)。なお、各重症化リスク因子の定義方法はPANORAMIC試験において用いられた方法に準じた。また、標準治療に関する扱いは基本分析での解析方法に準じた(表2-3-2-2)。
表 2-3-2-3 重症化リスク因子の定義(感度分析)
Risk factor

Diagnostic criteria or definition

Older adults aged ≥ 65 years

Aged ≥ 65 years

Cancer or chemotherapy

Free text field mentions “cancer” . Only current cancers included.

Chronic respiratory disease

Self-reported long term lung disease (including chronic obstructive pulmonary disease(COPD), cystic fibrosis or asthma requiring at least daily use of inhalers)

Chronic kidney disease

Self-reported long term kidney disease

Diabetes

Self-reported diabetes

Hypertension(high blood pressure)Self-reported high blood pressure

Chronic heart or vascular disease

Self-reported long term heart or vascular disease

StrokeSelf-reported long term neurological disease (including dementia, stroke, epilepsy) or
free text mentions stroke

Obesity

BMI ≥ 35 kg/㎡

Current smoker

Current smoker

Solid organ, bone marrow and stem Self-report have had a transplant (e.g. kidney, liver, heart, lung, bone marrow or stem
cell transplant recipients
cells)
Immunosuppression

Self-reported weakened immune system due to a condition you were born with or due todisease or treatment (e.g. sickle cell, HIV, cancer, chemotherapy)

HIV infection

Collected under immunosuppression

38
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

解析結果(感度分析)
重症化リスク因子を有する症例の抽出とモルヌピラビル以外のCOVID-19治療薬を併用した症例を除外した結果、 16,134例(モルヌピラビル群:8,088例及び標準治療群:8,046例)が解析対象となった(図2-3-2-5)。本解析対象の背景因子は図2-3-2-6に示す。

PANORAMIC study participants (n=25,708)(12,774 Molnupiravir plus usual care group + 12,934 usual care group)↓↓→

Adults with risk factors for severe
COVID-19(n=16188 )↓→Excluded
Adults without any risk factors for severe COVID-19(n= 9520)a

Excluded
Adults using other COVID-19 medications (n=54)b
Remdesivir (n=0)
Nirmatrelvir/ritonavir (n=5)
Ensitrelvir (n=0)
Casirivimab/imdevimab (n=0)
Sotrovimab (n=0)
Tixagevimab/cilgavimab (n=0)
Tocilizumab (n=0)
Baricitinib (n=0)
Dexamethasone (n=1)
Any other antiviral medications for COVID-19 (n=2)
Any other neutralizing antibody for COVID-19 (n=46)
Any other immunosuppressive medications for COVID19 (n=0)
Favipiravir (n=0)
Ivermectin (n=0)↓

Eligible participants(n=16134)

図 2-3-2-5 解析対象者選定のフローチャート(感度分析)

ATAG. Rep. 2024;2(2)39Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=8088)
59.2 (13.4)[18.0 to 99.0]

Usual Care

Overall(N=8046)59.2 (13.6)[18.0 to 98.0](N=16134)59.2 (13.5)[18.0 to 99.0]4452 (55.0%)3634 (44.9%)
2 (0.0%)2.0 (2.0 to 2.0)4450 (55.3%)
3595 (44.7%)
1 (0.0%)N/A

8902 (55.2%)
7229 (44.8%)
3 (0.0%)2.0 (2.0 to 2.0)

4.0 (3.0 to 5.0)

N/A

4.0 (3.0 to 5.0)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receipt of
medication*, median(IQR)
Days from start of symptoms to taking medication*,
median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
23
4
5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
36434 (79.5%)6434 (39.9%)7628 (94.3%)
233 (2.9%)
117 (1.4%)
53 (0.7%)
57 (0.7%)7573 (94.1%)
269 (3.3%)
105 (1.3%)
53 (0.7%)
46 (0.6%)

15201 (94.2%)
502 (3.1%)
222 (1.4%)
106 (0.7%)103 (0.6%)

256 (3.2%)
537 (6.6%)1115 (13.8%)271 (3.4%)
573 (7.1%)
1108 (13.8%)

527 (3.3%)1110 (6.9%)
2223 (13.8%)1488 (18.4%)

1463 (18.2%)

2951 (18.3%)4545 (56.2%)
37 (0.5%)4474 (55.6%)
35 (0.4%)

9019 (55.9%)
72 (0.4%)

43 (0.5%)56 (0.7%)

99 (0.6%)

67 (0.8%)66 (0.8%)

133 (0.8%)623 (7.7%)
1698 (21.0%)
1861 (23.0%)2084 (25.8%)
1822 (22.5%)3680 (45.5%)633 (7.9%)
1660 (20.6%)
1898 (23.6%)2063 (25.6%)
1792 (22.3%)
3585 (44.6%)

1256 (7.8%)3358 (20.8%)3759 (23.3%)
4147 (25.7%)3614 (22.4%)
7265 (45.0%)835 (10.3%)1250 (15.5%)
1659 (20.5%)808 (10.0%)1265 (15.7%)
1629 (20.2%)1643 (10.2%)2515 (15.6%)
3288 (20.4%)

図 2-3-2-6 PANORAMIC試験から抽出した症例の背景因子(感度分析)

40
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Current smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Moderate problem
Major problem
Loss of smell or taste, n(%)
No problem
Minor problem
Moderate problem

Molnupiravir
plus usual care
(N=8088)
2011 (24.9%)2305 (28.5%)
28 (0.3%)
7495 (92.7%)
7994 (98.8%)

Usual Care

Overall(N=8046)
1967 (24.4%)
2340 (29.1%)
37 (0.5%)
7974 (99.1%)(N=16134)
3978 (24.7%)4645 (28.8%)65 (0.4%)
7495 (46.5%)
15968 (99.0%)

54 (0.7%)
290 (3.6%)7440 (92.0%)
210 (2.6%)
94 (1.2%)
787 (9.7%)

48 (0.6%)
249 (3.1%)
7464 (92.8%)
213 (2.6%)
72 (0.9%)799 (9.9%)102 (0.6%)539 (3.3%)
14904 (92.4%)423 (2.6%)
166 (1.0%)
1586 (9.8%)

3871 (47.9%)2834 (35.0%)1221 (15.1%)
162 (2.0%)3786 (47.1%)
2891 (35.9%)1198 (14.9%)
171 (2.1%)

7657 (47.5%)5725 (35.5%)2419 (15.0%)333 (2.1%)

803 (9.9%)2960 (36.6%)
3187 (39.4%)
1138 (14.1%)

788 (9.8%)2952 (36.7%)
3186 (39.6%)1120 (13.9%)

1591 (9.9%)5912 (36.6%)6373 (39.5%)2258 (14.0%)2264 (28.0%)2734 (33.8%)
2371 (29.3%)
719 (8.9%)2155 (26.8%)2934 (36.5%)
2290 (28.5%)
667 (8.3%)

4419 (27.4%)5668 (35.1%)
4661 (28.9%)1386 (8.6%)6603 (81.6%)
1151 (14.2%)
298 (3.7%)
36 (0.4%)6564 (81.6%)
1140 (14.2%)
288 (3.6%)
54 (0.7%)

13167 (81.6%)
2291 (14.2%)
586 (3.6%)
90 (0.6%)

6599 (81.6%)
1073 (13.3%)
331 (4.1%)
85 (1.1%)

6593 (81.9%)1094 (13.6%)
296 (3.7%)
63 (0.8%)

13192 (81.8%)2167 (13.4%)
627 (3.9%)
148 (0.9%)5660 (70.0%)
1589 (19.6%)
541 (6.7%)

5802 (72.1%)
1473 (18.3%)
512 (6.4%)

11462 (71.0%)3062 (19.0%)1053 (6.5%)

図 2-3-2-6 PANORAMIC試験から抽出した症例の背景因子(感度分析) 続き

ATAG. Rep. 2024;2(2)41Molnupiravir
plus usual care
(N=8088)298 (3.7%)

Usual Care

Overall(N=8046)259 (3.2%)(N=16134)
557 (3.5%)

No problem
Minor problem
Moderate problem
Major problem

1753 (21.7%)
3293 (40.7%)2316 (28.6%)
726 (9.0%)

1837 (22.8%)3205 (39.8%)2337 (29.0%)
667 (8.3%)

3590 (22.3%)
6498 (40.3%)4653 (28.8%)1393 (8.6%)

No problem
Minor problem
Moderate problem
Major problem

5306 (65.6%)
1946 (24.1%)
701 (8.7%)
135 (1.7%)5174 (64.3%)2034 (25.3%)
699 (8.7%)
139 (1.7%)10480 (65.0%)3980 (24.7%)
1400 (8.7%)
274 (1.7%)

No problem
Minor problem
Moderate problem
Major problem

6541 (80.9%)1143 (14.1%)
359 (4.4%)
45 (0.6%)

6466 (80.4%)
1191 (14.8%)351 (4.4%)
38 (0.5%)

13007 (80.6%)2334 (14.5%)710 (4.4%)
83 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

347 (4.3%)
3162 (39.1%)
3637 (45.0%)
942 (11.6%)345 (4.3%)
3212 (39.9%)3591 (44.6%)
898 (11.2%)

692 (4.3%)
6374 (39.5%)
7228 (44.8%)
1840 (11.4%)

No problem
Minor problem
Moderate problem
Major problem

3563 (44.1%)
3019 (37.3%)
1375 (17.0%)
131 (1.6%)3583 (44.5%)3021 (37.5%)1315 (16.3%)
127 (1.6%)7146 (44.3%)
6040 (37.4%)
2690 (16.7%)
258 (1.6%)

837 (10.3%)
3811 (47.1%)
2910 (36.0%)
530 (6.6%)
5.2 (1.7) [0.0 to
10.0]802 (10.0%)3805 (47.3%)
2968 (36.9%)
471 (5.9%)
5.2 (1.7) [0.0 to
10.0]1639 (10.2%)7616 (47.2%)
5878 (36.4%)
1001 (6.2%)
5.2 (1.7) [0.0 to
10.0]1106 (13.7%)
4167 (51.5%)
1211 (15.0%)
938 (11.6%)
446 (5.5%)
220 (2.7%)
1607 (19.9%)93 (1.1%)

1127 (14.0%)4104 (51.0%)1197 (14.9%)
998 (12.4%)
412 (5.1%)
208 (2.6%)
1696 (21.1%)
84 (1.0%)2233 (13.8%)8271 (51.3%)2408 (14.9%)
1936 (12.0%)858 (5.3%)
428 (2.7%)3303 (20.5%)
177 (1.1%)

Major problem
Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean (SD) [min,max]People in household, n(%)
0
1
2
3
4
5
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)

図 2-3-2-6 PANORAMIC試験から抽出した症例の背景因子(感度分析) 続き

42
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Primary Care
Clinical Trials Unit

Molnupiravir

Usual Care

Overall(N=8046)
0 (0.0%)(N=16134)
0 (0.0%)PANORAMIC-MOLNUPIRAVIR Statistical Analysisplus
Part
1 Report
usual
care Version 1.0
Monoclonal antibodies for COVID, n(%)
Comorbidities
4.3
NUMBER ANALYSED(N=8088)
0 (0.0%)Lung disease 1620 (20.0%)1718 (21.4%)3338 (20.7%)
Heart disease 993 (12.3%)
952 (11.8%)
1945 (12.1%)
Of the 16134 participants included in the subgroup analysis 15703 (97.3%) had data collected
Kidney disease 222 (2.7%)
253 (3.1%)
475 (2.9%)
on hospitalisation/death and so couldbeincludedintheprimary
analysis.
15324 (95.0%)
Liver disease 131 (1.6%)
119 (1.5%)250 (1.5%)
completed any diaries or calls
and so could
be included
Neurologicaldisease295 (3.6%)in the secondary
281 (3.5%) analysis.
576 (3.6%)
Learning disability 32 (0.4%)
26 (0.3%)
58 (0.4%)
Down's syndrome' 24 (0.3%)
26 (0.3%)
50 (0.3%)
Diabetes 1473 (18.2%)
1507 (18.7%)2980 (18.5%)
4.4 PRIMARY ANALYSES
Weakened immune system 1110 (13.7%)1055 (13.1%)
2165 (13.4%)
Transplant recipient 55 (0.7%)
69 (0.9%)124 (0.8%)
4.4.1 PRIMARY OUTCOME
Obesity 1957 (24.2%)
1932 (24.0%)
3889 (24.1%)
Mental illness 143 (1.8%)
159 (2.0%)302 (1.9%)
The primary outcome is definedas all cause unplanned hospitalisationordeath from
Hypertension 2854 (35.3%)
2895 (36.0%)5749 (35.6%)
randomisation to 28 days follow-up.
Data is derived from participant
daily diaries,
phone calls,
Other vulnerability 1683 (20.8%)
1615 (20.1%)
3298 (20.4%)

routinedata.
If a presented
primary endpointis reporteddistributed
from any data
source then this*andMedianand electronicinterquartilerange
for non-normallyvariables.

outcome is counted as “yes”. If the participant has completed 28 days follow-up and is not
図 2-3-2-6 PANORAMIC試験から抽出した症例の背景因子(感度分析) 続き
hospitalised or is lost to follow-up but has been checked against routine electronic data andno hospitalisation or death is found then this outcome is coded “no”. An odds ratio<1 suggests
fewer hospitalisations/deaths in the Molnupiravir arm. The results show probability of
本解析対象者において、モルヌピラビルの標準治療に対する主要評価項目(入院又は死亡)のオッズ
superiority just below 0.5, indicating equivalence of Molnupiravir with Usual Care.

比は1.022 (95% CI：0.738 to 1.382)であった(図2-3-2-7)。
TABLE 8 PRIMARY OUTCOME

Molnupiravir
plus usual care
(N=8088)
81/7933 (1.0%)

Hospitalization ordeath
Deaths3/7933
Hospitalizations
79/7933 (1.0%)*OR < 1 favours Molnupiravir

Usual care
(N=8046)

Estimated treatment
effect (95% BCI)

78/7770 (1.0%)

1.022 (0.738 to 1.382)

Probabilityofsuperiority
0.47785/777076/7770 (1.0%)

Not estimable
1.023 (0.737 to 1.385)

0.4762

図 2-3-2-7 主要評価項目の結果(感度分析)

結果の解釈
PANORAMIC試験から、本邦における重症化リスク因子の定義や標準治療の内容に合致した症例のみを抽出した上で分析を実施した。その結果、標準治療に対するモルヌピラビルの入院又は死亡におけるオッズ比は1.053 (95% CI：0.775 to 1.396)であり、点推定値ではオッズ比が1以上であった。また、その構成要素である入院のオッズ比も1.055 (95% CI：0.773 to 1.413)であり、点推定値では1をStatistical Analysis Report
Page 34 of 44

Effective: 22nd September 2022

ATAG. Rep. 2024;2(2)43超過していた。
諸外国の医療技術評価機関や公的機関においても、PANORAMIC試験は、モルヌピラビルの治療効果の評価として参照されており、それぞれ対応が行われている。具体的には、NICEでは、新たにSTAを実施し、その結論が出るまで最終ガイダンスは公表しないこととなっているが、評価の過程においてモルヌピラビルが標準治療に対する優越性を示していないことが指摘された。PBACにおいては、PANORAMIC試験を考慮して、ニルマトレルビル/リトナビルが禁忌または適切ではない場合のみ、
モルヌピラビルによる治療を検討すべきであることが提言されている。また、EMAではMOVe-OUT
試験の外的妥当性に対する課題やPANORAMIC試験の結果を受けて、モルヌピラビルの臨床的有用性が証明されていないとして、モルヌピラビルの販売承認の取下げを勧告した。
その一方で、PANORAMIC試験事後解析の解析対象者における平均年齢は56.8歳であり、本邦の実臨床における投与対象と比較して、若年で相対的に重症化リスクの低い症例が多く含まれていたことが考えられる。実際に、製造販売業者の特定使用成績調査によると、モルヌピラビルが投与された日本人患者(3,384例)における年齢の中央値は69歳であったことが示されている。そして、高齢者を多く解析対象としている、いくつかのリアルワールドデータを用いた観察研究では、モルヌピラビルは標準治療と比較して、入院又は死亡の発生を抑制しうる効果が報告されている。
例 え ば、 米 国 退 役 軍 人 の デ ー タ ベ ー ス を 用 い た 観 察 研 究 で は、 重 症 化 リ ス ク 因 子 を 有 す る
COVID-19患者85,998例(平均年齢：67.3歳)が解析対象となったが、モルヌピラビル投与群において、30日目までの入院又は死亡の発生率が低値であったことが報告されている(RR 0.72 [95% CI：0.64 to
0.79]) (13)。また、PANORAMIC試験事後解析においても、統計学的に有意な異質性は検出されなかったが、80歳以上でのサブグループでは、入院又は死亡におけるオッズ比は0.52 (95% CI：0.17 to1.48)であり、点推定値では全体集団よりも治療効果が改善する方向にあった。このように、臨床専門家からの示唆によれば、高齢者集団に対しては、モルヌピラビルが一定の有用性を有する可能性もあるが、多くの高齢者を解析対象として含んだ、モルヌピラビルが入院又は死亡の発生を抑制することを示唆した研究の多くは海外における大規模データベースを用いた後ろ向き観察研究であり、また
PANORAMIC試験における80歳以上集団もその数が各群で数百人程度とわずかであることから、高齢者における有用性については今後のさらなるデータの蓄積や検討が必要であろう。
よって、PANORAMIC試験の事後解析結果を参照すれば、現時点では全体集団に対してモルヌピラ
ビルが比較対照技術に対して追加的有用性を有すると判断できる明確な根拠が欠けており、追加的有用性を有すると判断することは困難であると評価した。

44
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

2.4

追加的有用性の有無に関する評価
表 2-4 モルヌピラビルの追加的有用性に関する評価

対象集団

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*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＋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

比較対照

標準治療

アウトカム

入院又は死亡追加的有用性の有無□ 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」□ その他()□ RCTのメタアナリシス □ 単一のRCT□ 前向きの比較観察研究 □ RCTの間接比較判断の根拠となったデータ□ 単群試験の比較■ その他(単一のRCTの事後解析)
PANORAMIC試験から、本邦における重症化リスク因子の定義や標準治療の内容に合致した症例のみを抽出した上で分析を実施した。その結果、標準治療に対するモルヌピラビルの入院又は死亡におけるオッズ比は 1.053 (95% CI： 0.775 to 1.396)であり、点推定値ではオッズ比が 1 以上であった。また、その構成要素である入院のオッズ比も 1.055 (95% CI： 0.773 to 1.413)であり、点推定値では 1 以上であった。
ただし、多くの高齢者を解析対象として含んだ、いくつかの大規模データベースを用いた後ろ向き観追加的有用性の有無を判断
察研究では、モルヌピラビルは標準治療と比較して、入院又は死亡の発生を抑制しうる効果も報告されした理由ている。また、PANORAMIC試験事後解析においても、 80 歳以上でのサブグループでは、入院又は死亡におけるオッズ比は 0.52 (95% CI： 0.17 to 1.48)と全体集団よりも治療効果が改善する傾向が見られた。臨床専門家からの示唆によれば、このように高齢者に対しては、モルヌピラビルが一定の有用性を有する可能性があるが、実際のエビデンスとしては限定的であることから、今後のさらなるデータの蓄積や検討が必要である。

【製造販売業者の提出資料 ( 追加的有用性 ) に対するレビュー結果】得られたデータに基づくと、評価対象技術は比較対照技術に対し□追加的有用性を有すると考えられたため、費用効果分析が妥当である。

■

追加的有用性を有すると判断できないため、費用最小化分析が妥当である。

□

その他(

)

ATAG. Rep. 2024;2(2)453. 費用対効果の評価
3.1.1

標準治療と比較した費用効果分析の概要

製造販売業者は、COVID-19外来患者における臨床経過をモデル化し、モルヌピラビルの費用対効果を評価した (図3-1-1-1)。COVID-19の発症から急性期治療終了までの分析期間(30日）には決定樹モデルを、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年としたマルコフモ
デルを用いた。患者の健康状態は、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、死亡の8状態とし、治療(モルヌピラビル又は標準治療)による入院または死亡リスクの差異を考慮した。決定樹モデルは、軽症・中等症の健康状態から開始し、COVID-19重症化に伴い、外来から入院(一般病棟、ICU、ICU+MV/ECMO)への移行を仮定した。マルコフモデルでは、入院後の患者の転帰として、長期の後遺症、長期の後遺症なしの回復、再入院、死亡への移行を仮定した。

図 3-1-1-1 費用効果分析のモデル構造(製造販売業者の報告書より)モルヌピラビルの有効性(入院、入院患者の重症化及び死亡のRR)には、MOVe-OUTのデータを用いた。ベースラインの患者背景(年齢、性別)、入院患者の遷移確率、後遺症発生率、外来または入院費用等、COVID-19疾患特性に関わるパラメータには、メディカル・データ・ビジョン(MDV)社のEBM Providerの集計結果を用いた。分析対象集団におけるベースラインの入院割合には、厚生労働省「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」(15)における2022年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用いた。

46
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

製造販売業者のモデルにおける主な仮定は以下の通りであった。
⃝モルヌピラビル群は、モルヌピラビルの投与によって、標準治療群に比べて入院率、入院時の死亡率が低下する。
⃝入院患者の健康状態は、一般病棟、ICU、ICU+MV/ECMOの3状態のいずれかに移行する。
⃝有害事象(AE)または治療上緊急を要する有害事象は発生しない。
⃝外来、入院患者は一定の確率で後遺症を発症する。後遺症の継続期間は初期治療終了日〜30日までとし、後遺症の継続期間中はQOLの低下、診療費用が発生する。
⃝再入院の健康状態におけるQOL値は、一般病棟の健康状態と同等である。
製造販売業者による基本分析の結果は以下の表3-1-1の通りであった。
表 3-1-1 製造販売業者による費用効果分析の基本分析の結果
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

25.5960.044

175,291

84,391

1,930,637

標準治療25.552

3.1.2

90,900

標準治療群と比較した費用効果分析に対する見解

公的分析によるレビューの結果、製造販売業者が用いたモデルの構造や費用パラメータの設定方法
はおおむね妥当と考えられた。一方で、以下の論点が挙げられた。
費用最小化分析の実施
上記「2.4 追加的有用性の有無に関する評価」に記載の通りモルヌピラビルは比較対照技術に対して追加的有用性を有すると判断できないと評価した。このことから、費用最小化分析の実施が適当である。
3.2

レビュー結果による再分析の必要な箇所の有無

□

特になし

→

本節で終了

■

あり

→

以下に続く

□

その他(

)

ATAG. Rep. 2024;2(2)

47

3.3

実施が必要な再分析の概要

3.3.1

再検討が必要な分析手法やパラメータなど(主要な[結果への影響が大きい]もの)a)費用最小化分析の実施
3.3.2

再検討が必要な分析手法やパラメータなど(3.3.1 以外のもの)

該当なし
3.4

主要な点 ( 結果に与える影響が大きい点 ) についての再分析の内容

3.4.1

費用最小化分析の実施
表 3-4-1 製造販売業者による報告書の該当部分

製造販売業者の提出した報告書等における
セクション

ページ数

開始行番号(あるいは図表番号)

5.1.1

p.65

表 21

【報告書等の記述】
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

25.5960.044

175,291

84,391

1,930,637

標準治療25.55290,900【具体的な再分析の内容】
追加的有用性の検討結果から、入院や死亡に関連する治療効果に群間差を設定せず、治療費用を比較する費用最小化分析を実施した。製造販売業者におけるモルヌピラビルの治療費用推計方法について、公的分析では妥当であると判断し、その結果を治療費用として用いた。
表 3-4-2 製造販売業者によるモルヌピラビル治療費用の推計方法
項目
モルヌピラビル治療費用

3.5

費用

推計方法

モルヌピラビル(ラゲブリオカプセル 200mg)の添付文書における用法及び用量として「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。」
94,312 円とされている。このことから、分析時点の薬価(200mgカプセル： 2,357.8 円)に基づいて、 4カプセル[1 回当たり]× 2 回[1 日当たり]× 5 日の計算から算出した。

3.4 以外に検討が必要な点における再分析の内容

該当なし

48
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

4. 分析結果
4.1

再分析における基本分析の結果□ 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)□ その他(
4.1.1)

再分析における基本分析の増分費用
表 4-1-1-1 製造販売業者による基本分析の結果
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

25.5960.044

175,291

84,391

1,930,637

標準治療25.55290,900

表 4-1-1-2 再分析における基本分析の結果
増分費用(円)モルヌピラビル+標準治療

4.1.2

94,312

費用効果分析を実施する場合に、増分費用効果比に影響を与えうる要因a) ベースラインの患者背景に関するモデル設定について製造販売業者は、分析モデルに組み込むベースラインの患者背景(年齢や性別等)の分析パラメータを算出するために、重症化リスク因子の有無に関わらず、COVID-19と診断された患者をレセプトデー
タベースから抽出して、分析を行った。しかし、費用対効果評価専門組織において決定された分析枠組みにおける分析対象集団は、「重症化リスク因子を有するCOVID-19患者」である。重症化リスク
因子の有無によって、適用すべき年齢や男女の比率は異なることが想定される。
b) 長期の後遺症について
製造販売業者は、分析モデルに組み入れられた患者がCOVID-19罹患後に一定の確率で長期の後遺症を発症することを仮定しており、後遺症の発症確率は重症度の高い状態(軽症・中等症から、一般
病棟、ICU、ICU+MV/ECMO)ほど高くなる設定となっていた。つまり、分析モデルにおいて、モルヌピラビルは重症度の高い状態へ移行することを抑制する効果を有するために、間接的に長期の後遺症発症までも抑制することが仮定されていた。しかし、データソースとしたRCTにおいて、モルヌピ
ラビルの長期の後遺症発症に対する有効性は検討されておらず、その効果を分析に組み込むにはエビ
デンスとして不十分である。
c) QOL値について

ATAG. Rep. 2024;2(2)49

製造販売業者はCOVID-19関連の健康状態におけるQOL値を取得するために、ビネット(記述された
健康状態について一般人にその状態を想起させることにより評価を行う手法)に基づくQOL調査デー
タを用いた。当該データは英国の一般人を対象に、ビネットで記述された健康状態について、EQ5D-5Lのどの選択肢に該当するかを調査したものである。得られたデータを日本の換算表を用いてQOL値に変換することにより、分析モデルに組み込んだ。しかし、費用対効果評価の分析ガイドラ
イン第3版では、対象者本人からQOL値を得ることが困難な場合には一般の人々を対象に健康状態を想起させることにより基準的賭け法や時間得失法といった直接法の手法を用いてQOL値を測定してもよいとされているが、EQ-5D-5Lのような選好基づく尺度に回答することは学術的にも一般的ではなく、また適切な手法とも言えない。
4.2

再分析における感度分析の結果

本品目では費用最小化分析を実施したため、本項は該当しない。
4.3

再分析におけるシナリオ分析の結果

該当なし
4.4

分析結果の解釈
表 4-4 分析結果の解釈

分析対象集団

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*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。

比較対照技術標準治療*(評価対象技術：モルヌピラビル＋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

ICERの基準値

■

□
□
□
□
ICERの所属する確率が最も□高いと考える区間□□■□
そのように判断した理由

4.5

通常の品目

□

配慮が必要な品目

ドミナント(比較対照技術に対し効果が増加し、かつ費用が削減)
比較対照技術に対し効果が同等であり、かつ費用が削減
200 万円/QALY未満
200 万円/QALY以上(200 万円/QALY以上)かつ 500 万円/QALY未満(750 万円/QALY未満)
500 万円/QALY以上(750 万円/QALY以上)かつ 750 万円/QALY未満(1125 万円/QALY未満)
750 万円/QALY以上(1125 万円/QALY以上)かつ 1000 万円/QALY以下(1500 万円/QALY未満)
1000 万円/QALY以上(1500 万円/QALY以上)効果が同等(あるいは劣り)、かつ費用が高い
その他()

費用最小化分析の結果、評価対象技術は比較対照技術と比較して 94,312 円の費用増加であった。

価格調整率の重み該当なし

50
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

謝辞
公的分析に際して、データをご提供いただきましたオックスフォード大学のLy-Mee YU先生、Christopher Butler先生、Victoria Harris先生、Milensu Shanyinde先生、ならびにPANORAMIC Trial Collaborative Groupの全ての先生方に厚く御礼申し上げます。

5. 参考文献[1] National Institute for Health and Care Excellence. Molnupiravir, remdesivir and tixagevimab plus
cilgavimab for treating COVID-19 [ID6261] In development [GID-TA11297] 2023 [Available from:https://www.nice.org.uk/guidance/indevelopment/GID-TA11297.
[2] Pharmaceutical Benefits Advisory Committee. Lagevrio® (molnupiravir) Pharmaceutical Benefits
Scheme Factsheet – Updated July 2023 2023 [Available from: https://www.pbs.gov.au/publication/
factsheets/covid-19-treatments/Factsheet-lagevrio-molnupiravir-July-2023.pdf.
[3] Department of Health and Social Care. Defining the highest-risk clinical subgroups upon community infection with SARS-CoV-2 when considering the use of neutralising monoclonal antibodies(nMABs) and antiviral drugs: independent advisory group report 2022 [Available from: https://www.
gov.uk/government/publications/higher-risk-patients-eligible-for-covid-19-treatments-independent-advisory-group-report/defining-the-highest-risk-clinical-subgroups-upon-community-infection-with-sars-cov-2-when-considering-the-use-of-neutralising-monoclonal-antibodies.
[4] The European Medicines Agency. Lagevrio: Withdrawal of the marketing authorisation application
2023 [Available from: https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/lagevrio.
[5] Khoo SH, FitzGerald R, Saunders G, Middleton C, Ahmad S, Edwards CJ, et al. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK(AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis.
2023;23(2):183-95.
[6] Fischer WA, 2nd, Eron JJ, Jr., Holman W, Cohen MS, Fang L, Szewczyk LJ, et al. A phase 2a clinical
trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance andelimination of infectious virus. Science translational medicine. 2022;14(628):eabl7430.
[7] Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V,
et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med.
2022;386(6):509-20.
[8] Johnson MG, Puenpatom A, Moncada PA, Burgess L, Duke ER, Ohmagari N, et al. Effect of Mol-

ATAG. Rep. 2024;2(2)51nupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial. Ann Intern Med. 2022;175(8):1126-34.
[9] Johnson MG, Strizki JM, Brown ML, Wan H, Shamsuddin HH, Ramgopal M, et al. Molnupiravir forthe treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial. Infection. 2023:1-12.
[10] Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus
usual care versus usual care alone as early treatment for adults with COVID-19 at increased riskof adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.
Lancet. 2023;401(10373):281-93.
[11] Sinha S, N K, Suram VK, Chary SS, Naik S, Singh VB, et al. Efficacy and Safety of Molnupiravir in
Mild COVID-19 Patients in India. Cureus. 2022;14(11):e31508.
[12] Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G, et al. Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial. Front Pharmacol.
2022;13:939573.
[13] Xie Y, Bowe B, Al-Aly Z. Molnupiravir and risk of hospital admission or death in adults with covid-19:
emulation of a randomized target trial using electronic health records. Bmj. 2023;380:e072705.
[14] 首相官邸. 新型コロナワクチンについて 2023 [Available from: https://www.kantei.go.jp/jp/headline/
kansensho/vaccine.html.
[15] 厚生労働省. 療養状況等及び入院患者受入病床数等に関する調査 2022 [Available from: https://www.
mhlw.go.jp/stf/seisakunitsuite/newpage_00023.html.

52
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

STATISTICAL ANALYSIS PART 1 REPORT
Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In theCommunity
Reference Number / Short title: PANORAMICMONUPIRAVIR

Ethics Ref: 21/SC/0393
IRAS Project ID: 1004274
EudraCT Number: 2021-005748-31
Based on protocol version 5.0 9th May 2022
Version 2.0

Date: 9th October 2023

Report prepared and analysis carried out by

Dr Victoria Harris, Department of Primary
Care Health Sciences, University of Oxford

Report reviewed by

Dr Milensu Shanyinde, Department ofPrimary Care Health Sciences, University of
OxfordStatistical Analysis Part 2 Report

Effective: 9th October 2022

Page 1 of 46

ATAG. Rep. 2024;2(2)53Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

2 CONTENTS
3

LIST OF TABLES........................................................................................................... 44

LIST OF FIGURES ......................................................................................................... 51

BACKGROUND............................................................................................................ 6

2

INTRODUCTION.......................................................................................................... 6
2.1

3

SOFTWARE EMPLOYED ........................................................................................................8

METHODS .................................................................................................................. 9
3.1 TRIAL OVERVIEW ...............................................................................................................9
3.2 STUDY DESIGN ...................................................................................................................9
3.3 ADAPTIVE DESIGN ............................................................................................................10
3.4 OBJECTIVES ....................................................................................................................10
3.5 TARGET POPULATION ........................................................................................................123.5.1 Inclusion Criteria ..................................................................................................13
3.5.2 Exclusion criteria ..................................................................................................143.5.3 A Risk factors........................................................................................................14
3.5.4 Concomitant use of other COVID-19 medications ...............................................19
3.6 INTERVENTIONS ...............................................................................................................20
3.7 OUTCOMES ....................................................................................................................20
3.7.1 Primary outcome..................................................................................................20
3.7.2 Secondary outcomes ............................................................................................20
3.7.2.1
3.7.2.2
3.7.2.3
3.7.2.4
3.7.2.5
3.7.2.6
3.7.2.7
3.7.2.8

TIME TO RECOVERY...................................................................................................................................20
PATIENT REPORTED ILLNESS SEVERITY .....................................................................................................20
DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE .......................................................... 21
CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF FOLLOW-UP (FU). ....21
NEW INFECTIONS IN THE HOUSEHOLD .....................................................................................................21
SAFETY OF ANTIVIRAL AGENTS .................................................................................................................21
LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS........................................21
HEALTHCARE MEASURES (EQ-5D-5L) ........................................................................................................22

3.8 SAMPLE SIZE ...................................................................................................................22
3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE .........................................................22
3.10
DEFINITION OF POPULATION FOR ANALYSIS ........................................................................23
3.10.1.1
3.10.1.2

4

Primary analysis population..................................................................................................................23
Secondary analysis population .............................................................................................................24

RESULTS ................................................................................................................... 25

Statistical Analysis Report
Page 2 of 46

54
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0
4.1

REPRESENTATIVENESS OF STUDY SAMPLE AND PATIENT THROUGHPUTERROR!

BOOKMARKNOTDEFINED.

4.2 RECRUITMENT .................................................................................................................25
4.3 BASELINE CHARACTERISTICS OF PARTICIPANTS ........................................................................27
4.4 NUMBER ANALYSED ..........................................................................................................36
4.5 PRIMARY ANALYSES..........................................................................................................36
4.5.1 Primary outcome..................................................................................................36
4.5.2 Secondary outcomes ............................................................................................37
4.6 SUBGROUP ANALYSES .......................................................................................................42
4.7 VIROLOGY SUB-STUDY ANALYSIS ..........................................................................................44

Statistical Analysis Report

Effective: 22nd September 2022

Page 3 of 46

ATAG. Rep. 2024;2(2)55Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

LIST OF TABLES
Table 1 The MHLW defined risk factors for severe COVID-19................................................ 14
Table 2 The modified definition of risk factors for severe COVID-19..................................... 16
Table 3 The diagnostic criteria for each risk factor in the PANORAMIC study....................... 18
Table 4 The definition of other COVID-19 medications.......................................................... 19
Table 5 Baseline characteristic by randomised group............................................................ 27
Table 6 Baseline characteristic of the subgroup population by randomised group .............. 31
Table 7 Prevalence of risk factors for severe COVID-19 (modified definition) among eligible
participants ............................................................................................................................. 35
Table 8 PRIMARY OUTCOME .................................................................................................. 36
Table 9 Secondary outcomes.................................................................................................. 39
Table 10 Summary of Virology sub-study............................................................................... 44
Table 11 Virology substudy..................................................................................................... 45

Statistical Analysis Report
Page 4 of 46

56
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

LIST OF FIGURES
Figure 1 Flow diagram of trial participants for the subgroup population ............................. 26
Figure 2 Kaplan-Meier curve and model estimates for time to recovery .............................. 41
Figure 3 Forest plot of Subgroup analysis of primary outcome ............................................. 42
Figure 4 Forest plot of Subgroup analysis of Time to recovery .............................................. 43

Statistical Analysis Report

Effective: 22nd September 2022

Page 5 of 46

ATAG. Rep. 2024;2(2)571 BACKGROUNDThe Center for Outcomes Research and Economic Evaluation for Health (C2H) is currently
conducting a cost-effectiveness evaluation of molnupiravir as a part of the Japanese healthtechnology assessment (HTA) process. The data from the PANORAMIC study(Butler CC, et al. Lancet.
2023:28;401:281-293) could potentially be the source to assess the additional benefit of molnupiravir
in the Japanese setting. However, there are several differences between the study design of
the PANORAMIC and the indication for molnupiravir in Japan. For example, molnupiravir isapproved in Japan for the treatment of COVID-19 in adults with risk factors for severe COVID19 whereas the PANORAMIC study included adults without these risk factors. Additionally,
differences in the definition of standard of care also exist. In Japan, concomitant use ofmolnupiravir with other COVID-19 medications (e.g., remdesivir) is not recommended. Given
these differences, the purpose of this report is to present the results of sub-group analysis of
the PANORAMIC study in line with the indication and clinical practice of molnupiravir in Japan.
The results are presented excluding both A) participants without risk factors and B)
participants using other COVID-19 medications at the prescription of molnupiravir.
DISCLAIMER: Publication of the results presented in this report requires approval inwriting to the Chief Investigators.

2 INTRODUCTION
This document details the analysis for the subgroup reporting results for the comparison of
Molnupiravir with usual care from the PANORAMIC trial. The results reported in these papers
follow the strategy set out in the statistical analysis plan. Subsequent analyses of a more
exploratory nature will not be bound by this strategy, though they are expected to follow thebroad principles laid down here.
The analysis strategy will be available on request when the principal papers are submitted for
publication in a journal. Suggestions for subsequent analyses by journal editors or referees,
will be considered carefully, and carried out as far as possible in line with the principles of thisanalysis strategy; if reported, the source of the suggestion will be acknowledged.
This report is based on the statistical analysis plan { Subgroup analysis of PANORAMIC study
in Japan_Plan2.docx}. Any deviations from the statistical analysis plan will be described andjustified in this report of the trial.

Statistical Analysis Part 2 Report
Page 6 of 46

58
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 9th October 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

Trial/Study statistician(s):Dr Victoria Harris
Lead Trial Statisticians Professor Ly-Mee Yu and Dr Ben SavilleCo-chief Investigator:
Professor Chris Butler, Professor Paul Little, and Professor Richard Hobbs
Senior Trial Manager: Lucy Cureton
Senior Data Manager: Meena Patil

Statistical Analysis Report

Effective: 22nd September 2022

Page 7 of 46

ATAG. Rep. 2024;2(2)592.1 SOFTWARE EMPLOYED
Analysis was carried out using STATA v18

Statistical Analysis Part 2 Report
Page 8 of 46

60
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 9th October 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3

METHODS

3.1 TRIAL OVERVIEW
Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK
and in many countries around the world, with many patients continuing to require hospital
admission. COVID-19 causes considerable suffering, including loss of ability to perform
activities of daily living, loss of educational and work opportunities, and inability to perform
caring duties, with far reaching personal and societal consequences. Many go on toexperience persisting and/or relapsing symptoms. People with underlying health conditions,unvaccinated people, and those in whom the vaccine is not effective are at increased risk ofmore severe disease. 1 1 New ‘vaccine escaping’ variants may yet emerge, and the impact ofearly antiviral treatment on long COVID syndromes is as yet unknown. Early treatment withantiviral agents may prevent progression to the later phase of COVID-19. Therefore, there isan urgent need to identify treatments for COVID-19 for use in the community early on in theillness that speeds recovery and prevents the need for hospital admission.
Antiviral agents may reduce viral shedding, and use of antiviral agents may lead to theemergence of resistance to novel antiviral agents, but the impact of novel antiviral agents on
shedding and resistance is not yet known.

3.2 STUDY DESIGNPANORAMIC is an open label, prospective, individually randomised, platform, adaptive,
controlled clinical trial in community care. Trial arms will include:
Intervention arms: Novel antiviral agents (or combinations) targeting SARS-CoV-2, initially
specified by The UK Antivirals National Taskforce (ATF) and with capacity for sequential
introduction of each treatment regimen into the trial plus Usual Care. This report presents
the primary and secondary analysis for the Molnupiravir arm.
Comparator arm: Usual Care, defined as the currently recommended treatment delivered byresponsible clinicians. Usual Care was not mandated by the trial, as recommended treatments
may change and be tailored to individual characteristics, and self-care will vary. Use of overthe counter medication as well as key medications such as inhaled steroids and monoclonal
antibodies was captured. In this report only usual care participants randomised concurrently
and eligible to Molnupiravir were included.
Statistical Analysis Report

Effective: 22nd September 2022

Page 9 of 46

ATAG. Rep. 2024;2(2)61Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.3 ADAPTIVE DESIGN
The trial design allows for interim analysis and early stopping due to futility or efficacy andthe addition or removal of interventions. The number and timing of interim analyses depends
on the rate of recruitment. Full details of the design and decision criteria are given in the
Adaptive Design Report. Due to rapid recruitment no interim analyses were carried out on
the Molnupiravir arm. Paxlovid was added as an additional arm on 21st April 2022.

3.4 OBJECTIVES
Main Trial: The primary aim is to determine the effectiveness of selected antiviral agents inpreventing hospitalisation and/or death in higher-risk patients with a confirmed positive PCRor LFT SARS-CoV-2 test result (see Inclusion/Exclusion Criteria, below).

Main Study

Objectives

Endpoint Measures

Timepoint (s)Primary

To determine whether
antiviral treatment in thecommunity safely reduces
non-elective
hospitalisations/ deaths inhigher risk,

All cause, non-elective Within 28 days of
hospitalisation and/or randomisation
death, within 28 days
Patient report, Studyof randomisation
Partner report,
HES/ONS/medical
record data linkage

symptomatic patientswith confirmed COVID-19
Secondary

To explore whether
antiviral treatment affects
1) Time to recovery(defined as the first
instance that a
participant report offeeling recoveredfrom the illness)

Statistical Analysis Report
Page 10 of 46

62
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

1-3) Participant
reports symptoms
daily for 28 days
and at 3 and 6
months.

1-3) Daily online
symptom scores.
Telephone call ortext on days 7, 14
and 28 if data is not
obtained throughthe online diary.

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

2) Participant reported
illness severity,
reported by daily
rating of how wellparticipant feels,
enabling identificationof sustained recovery.

Also, at 3 and 6
months.

3) Duration of severe
symptoms andsymptom recurrence,
including time toalleviation ofsymptoms, time toinitial reduction ofseverity of symptoms,
time to sustained
recovery, time tosustained alleviationof symptoms, numberof days of severe
symptoms andworsening ofsymptoms

4) Contacts with thehealth services

Statistical Analysis Report

4) Contacts withhealth services
reported bypatients and/or
captured by reportsof patients’ medical
records

4) GP notes review if
available throughOxford RCGP RSC
network; otherwise,other sources ofroutinely collected
data after 28 days.
Medical notes review
for up to 10 years.
Effective: 22nd September 2022

Page 11 of 46

ATAG. Rep. 2024;2(2)63Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.05) New infections inhousehold5) Reports of new
infections in thehousehold fromdaily diary6) To investigate thesafety of antiviral
agents6) Evaluation of
overall safety ofdrugs by themonitoring ofadverse events (Aesas defined in the
ISAs)7) Longer term effects,
including proportion
with long covid, longcovid symptoms,
health care use andwellness8) Cost effectiveness7) Well-being,
symptoms andheath careutilisation

8) Resource use andcost data and EQ5D-5L5) Daily online
symptom scores ortelephone call or text
on days 7, 14 and 28

6) For the duration of
the antiviral course
and a defined period
after the antiviralfinishes (see ISAs)

7) Patient contact atthree and six
months, electronic
medical record
search for up to one
year8) Baseline and Day 28

3.5 TARGET POPULATION

Statistical Analysis Report
Page 12 of 46

64
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

The trial includes participants who test positive for SARS-CoV-2 infection and with ongoing
symptoms consistent with COVID-19, not hospitalised, and who are aged 50 years and over,or 18-49 years and considered clinically vulnerable (see Inclusion Criteria below).
3.5.1 INCLUSION C RITERIAParticipant is able and willing to provide informed consent, or their legal
representative is willing to provide informed consent
Symptoms attributable to COVID-19 started within the past 5 days and ongoing
A positive PCR or LFT SARS-CoV-2 test* Aged ≥50 years OR aged 18-49 years with oneof the following known underlying chronic health condition considered to make themclinically vulnerable:o chronic respiratory disease (including chronic obstructive pulmonary disease(COPD), cystic fibrosis and asthma requiring at least daily use of preventative
and/or reliever medication)o chronic heart or vascular diseaseo chronic kidney diseaseo chronic liver diseaseo chronic neurological disease (including dementia, stroke, epilepsy)
o severe and profound learning disabilityo Down’s syndromeo Diabetes mellitus (Type I or Type II)o immunosuppression: primary (e.g., inherited immune disorders resulting fromgenetic mutations, usually present at birth and diagnosed in childhood) or
secondary due to disease or treatment (e.g., sickle cell, HIV, cancer,
chemotherapy)
o solid organ, bone marrow and stem cell transplant recipientso morbid obesity (BMI >35)
o severe mental illness
o care home resident
o judged by recruiting clinician or research nurse (registered medical
practitioner or trained study nurse) to be clinically vulnerable* Any positive PCR test taken between two days before symptom onset and randomisation
qualifies. A positive lateral flow test in a symptomatic person qualifies for randomisation andwill be subject to pre-specified secondary analysis by type of diagnostic test.
Statistical Analysis Report

Effective: 22nd September 2022

Page 13 of 46

ATAG. Rep. 2024;2(2)65Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.5.2 EXCLUSION CRITERIAPatient currently admitted to hospital (inpatient)Previous randomisation in the PANORAMIC trial
Currently participating in a clinical trial of a therapeutic agent for acute COVID-19
Additional exclusions specific to each intervention arm, if any, as listed in theIntervention Specific Appendices (ISA’s) of currently open trial arms

3.5.3 A RISK FACTORS
Risk factors for severe COVID-19 by the Ministry of Health, Labour and Welfare (MHLW) in
Japan may not be available in the PANORAMIC study. Therefore, we propose the following 2
options to extract the data according to risk or modified risk factors that could be applicableto the Japanese setting.
1. Risk factors for severe COVID-19 defined by the Ministry of Health, Labour and Welfare(MHLW) is shown in Table 1.
TABLE 1 THE MHLW DEFINED RISK FACTORS FOR SEVERE COVID-19

Older adults aged ≥ 65 Hypertension
years

History of smoking

Malignant tumor

Dyslipidemia

Immunodeficiency after
solid organ transplantation

Chronic respiratory
disease(i.e., COPD)

Cardiovascular disease

Use of immunomodulatoryagent
orimmunosuppressant

Chronic renal disease

Cerebrovascular disease

HIV infection(particularly CD4 < 200/μL)

Diabetes

Obesity (BMI ≥ 30 kg/m )2

Clinical Management of Patients with COVID-19 in Japan version 9.0 (In Japanese)(https://www.mhlw.go.jp/content/000936655.pdf)
The diagnostic criteria for each risk factor have not been clearly indicated.

Statistical Analysis Report
Page 14 of 46

66
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

Statistical Analysis Report

Effective: 22nd September 2022

Page 15 of 46

ATAG. Rep. 2024;2(2)67Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

2. The modified definition of risk factors for severe COVID-19 is shown in Table 2. By

reviewing the article of the PANORAMIC study, we believe that we could define themodified risk factors as follows:
TABLE 2 THE MODIFIED DEFINITION OF RISK FACTORS FOR SEVERE COVID-19

Risk factor

DetailsAge

Older adults aged ≥ 65 years



Hematologic malignancies

Chronic kidney diseasePeople receiving dialysis

Chronic lung diseases limited to:











Bronchiectasis
COPD (Chronic obstructive pulmonary disease)
Interstitial lung disease
Pulmonary embolism
Pulmonary hypertension
Cirrhosis
Non-alcoholic fatty liver disease
Alcoholic liver disease
Autoimmune hepatitis

Mood disorders, including depression
Schizophrenia spectrum disorders

BMI ≥ 30 kg/m

AsthmaCancerCerebrovascular disease

Chronic liver diseases limited to:

Cystic fibrosis
Diabetes mellitus, type 1
Diabetes mellitus, type 2
Down syndrome
Heart conditions (such as heart failure, coronary
artery disease, or cardiomyopathies)
HIV (Human immunodeficiency virus)
Mental health conditions limited to:
Neurologic conditions limited to dementia
Obesity2

Physical inactivity

Statistical Analysis Report
Page 16 of 46

68
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

Primary immunodeficiencies
Smoking, current and former
Solid organ or blood stem cell transplantation
Tuberculosis
Useof
corticosteroids
immunosuppressive medications

or

other

Risk factors have been defined by CDC criteria(https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinicalcare/underlyingconditions.html). We only extracted factors categorized into "Higher Risk (conclusive)"from the CDC criteria.
Clinical Management of Patients with COVID-19 in Japan version 10.0 (001136687.pdf (mhlw.go.jp))(In
Japanese).
Disabilities were excluded from a risk factor.
2

a: Obesity was originally defined as BMI ≥ 35 kg/m in the PANORAMIC study.

Statistical Analysis Report

Effective: 22nd September 2022

Page 17 of 46

ATAG. Rep. 2024;2(2)69TABLE 3 THE DIAGNOSTIC CRITERIA FOR EACH RISK FACTOR IN THE PANORAMIC STUDY

Risk factor
Older adults aged ≥ 65 years
AsthmaCancer (Hematologic malignancies)
Cerebrovascular disease
Chronic kidney disease (People receiving
dialysis)
Bronchiectasis
COPD (Chronic obstructive pulmonary
disease)Interstitial lung disease
Pulmonary embolism
Pulmonary hypertension
Cirrhosis
Non-alcoholic fatty liver disease
Alcoholic liver disease
Autoimmune hepatitis
Cystic fibrosis
Diabetes mellitus, type 1
Diabetes mellitus, type 2
Down syndrome
Heart conditions (such as heart failure,coronary
arterydisease,or
cardiomyopathies)
HIV (Human immunodeficiency virus)
Mood disorders, including depression
Schizophrenia spectrum disorders
Neurologic
dementia

conditions

limitedto2

Obesity (BMI ≥ 30 kg/m )Physical inactivity
Primary immunodeficiencies
Smoking, current and former
Solid organ or blood stem celltransplantation
Tuberculosis
Use of corticosteroids or otherimmunosuppressive medications

Statistical Analysis Part 2 Report
Page 18 of 46

70
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Diagnostic criteria or definition
Aged ≥ 65 years
From free text and collected under lung disease.
From free text only. Mentions “blood cancer”.
From free text, mentions “stroke” or “cerebral aneurysm”
Collected as “long term kidney disease”, not clear if receiving
dialysis. Have counted anyone who has this checked.
Collect “long term lung disease (including chronic obstructive
pulmonary disease (COPD), cystic fibrosis or asthma requiring atleast daily use of inhalers)”.
Collected as lung disease
Collected as lung disease
Collected as lung disease
Collected as lung disease
Collected as liver disease
Collected as liver disease
Collected as liver disease
Collected as liver disease
Collected as lung disease
Collected as diabetes, not separated by type.
Collected as diabetes, not separated by type.
Down syndrome
Defined as long term heart or vascular disease
Comes under weakened immune system or free text mentions HIV
Collected under severe mental health disorderFree text mentions “Schizoaffective disorder” or collected under
severe mental health disorderCollected as long term neurological disease (including dementia,
stroke, epilepsy).
2

Defined as BMI≥ 35 kg/m
Not collected
Collected as weakened immune system due to a condition you
were born with or due to disease or treatment (e.g. sickle cell, HIV,cancer, chemotherapy)
Current only
Collected as transplant
Not collected, no free text.
Free text mentions “steroids” or “immunosuppressant”

Effective: 9th October 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.5.4 CONCOMITANT USE OF OTHER COVID-19 MEDICATIONSIn Japan, concomitant use of molnupiravir with other COVID-19 medications (e.g., remdesivir)
is not recommended. We would like to exclude adults taking the following medications at theprescription of molnupiravir (Table 4) from the dataset. On the other hand, we consider that
adults using the following medications after the completion of treatment with molnupiravir
should not be excluded from the analysis because they are most likely to have progressed tosevere COVID-19 (e.g., adults prescribed the following medications 10 days after aprescription for molnupiravir, adults who stopped treatment with molnupiravir within 5 days
and subsequently received the following medications).
TABLE 4 THE DEFINITION OF OTHER COVID-19 MEDICATIONS

Remdesivir

Tixagevimab/cilgavimab

Any other neutralizing
antibody for COVID-19

Nirmatrelvir/ritonavir

Tocilizumab

Any
other
immunosuppressive
medications for COVID-19

Ensitrelvir

Baricitinib

Favipiravir

Casirivimab/imdevimab

Dexamethasone

Ivermectin

Sotrovimab

Any
other
antiviral
medications for COVID-19

Statistical Analysis Report

Effective: 22nd September 2022

Page 19 of 46

ATAG. Rep. 2024;2(2)71Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.6 INTERVENTIONS
Based on version 5.0 of the Protocol, the main randomisation was between the following
treatment arms (although not all treatments were available at all times and not all
participants were eligible for all treatments). However, the trial design accommodates
interventions being added and dropped as appropriate.
Usual care
Molnupiravir (recruitment between 8th December 2021 and 27th April 2022)
PAXLOVID (recruitment started 21st April 2022)

3.7 OUTCOMES
3.7.1 PRIMARY OUTCOME
The primary outcome is all-cause, non-elective hospitalisation and/or death within 28 days of
randomisation.
3.7.2 SECONDARY OUTCOMES
Secondary outcomes include time to self-reported recovery defined as the first instance thata participant reports feeling fully recovered from the illness; duration of symptoms; symptom
recurrence; daily rating of feeling well reported by participants; healthcare service use;
participant reported household infection rate; safety outcomes and cost-effectivenessoutcomes; symptoms and well-being at three and six months (with determination of
proportion with Long Covid) from randomisation.
3.7.2.1 TIME TO RECOVERYTime to recovery from COVID-19 infection within 28 days from randomisation, where
recovery is defined as the first instance that a participant reported feeling recovered.
3.7.2.2 PATIENT REPORTED ILLNESS SEVERITY

Participants are asked to rate how well they are feeling overall each day on a scale of 1-10 (1being the worst and 10 being the best). This is captured on the patients’ daily diaries andthe Call CRF.

Statistical Analysis Report
Page 20 of 46

72
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.7.2.3 DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE

Participants are asked to rate their symptoms of fever, cough, shortness of breath, fatigue(tiredness), muscle ache, nausea / vomiting, diarrhoea, loss of smell and/or taste, headache,dizziness, abdominal pain and generally feeling unwell on a four point scale from 0=no
problem, 1=mild problem, 2=moderate problem and 3=major problem.
This is captured on patients’ daily diaries and Call CRF.
The outcomes to be analysed include time to alleviation of symptoms, time to initial
reduction in severe symptoms, time to sustained recovery, time to sustained alleviation ofsymptoms, number of days of severe symptoms, number reporting severe symptoms atdays 7, 14 and 28, symptom recurrence and worsening of symptoms.
3.7.2.4 CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF
FOLLOW-UP (FU).

This is captured on patients’ daily diaries and telephone call CRFs.
3.7.2.5 NEW INFECTIONS IN THE HOUSEHOLD

Number of new infections within the household are captured within the participant daily
diaries and call CRF.
3.7.2.6 SAFETY OF ANTIVIRAL AGENTS

Common side effects, according to the SmPC, include dizziness, headache, diarrhoea, andnausea. These symptoms, potential medication side-effects and Serious Adverse Events(SAE) were collected from participant daily diaries, calls to participants/Study Partners, faceto-face visits with Hub clinicians, medical records, notes reviews, NHS Digital data extracts
and RCGP data downloads.
Pregnancy was recorded as an AE of Special Interest and was monitored from the start oftreatment for the 28-day trial duration.
3.7.2.7 LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS

The primary analysis is based on data collected through 28 days from randomisation;
however additional outcomes will be collected at 3 and 6 months follow-up to capture theStatistical Analysis Report

Effective: 22nd September 2022

Page 21 of 46

ATAG. Rep. 2024;2(2)73Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

long term outcomes of participants. This report covers outcomes for the first 28 days followup. The long term follow-up analysis will be covered in a future report.
3.7.2.8 HEALTHCARE MEASURES (EQ-5D-5L)

The EQ-5D-5L is a questionnaire consisting of 5 items (crosswalk) and a scale from 0 to 100(VAS) defining overall health. These were captured in participant’s daily diaries and call CRF.
Cost effectiveness outcomes will be reported in a separate health economic analysis report
and the analysis of this outcome will be described in a separate health economic analysis plan.

3.8 SAMPLE SIZE
The sample size calculation as stated in the protocol:
An estimated maximum of approximately 5300 participants per arm will be required toprovide approximately 90% power for detecting a 33% relative reduction in thehospitalisation/death in an experimental arm relative to Usual Care, based on the assumptionof an underlying 3% combined hospitalisation/death rate in the Usual Care arm, and anintervention lowering the hospitalisation/death rate to 2%. We expect fewer participants will
be needed to detect the same relative reduction if the event rate is larger than 3% in the
Usual Care arm, or if there is a greater reduction in the relative risk of hospitalisation/death
for a given intervention. However, should the event rate be lower than expected, then thetarget sample size will be increased to reflect this.
We recruited 25783 for the comparison of Molnupiravir with Usual Care.

3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE
Participants were randomised using a secure, fully validated and compliant web-based
randomisation system. Once deemed eligible, the medically qualified clinician or researchnurse from the central clinical team or Hub (as documented on the delegation log)
randomised the participant. Participants were randomised to one study arm using equal
allocation ratios corresponding to the number of arms they were eligible for that wererecruiting in the trial at that time. This started as 1:1 Molnupiravir:Usual Care, and once
Paxlovid was introduced on 21st April 2022 changed to 1:1:1 Molnupiravir:Usual
Care:Paxlovid. Patients had to be eligible for at least two arms (Usual Care and at least one
novel antiviral intervention). Stratification was by age ( < 50/ ≥ 50 years) and vaccination
status (see 2.2.3).
Statistical Analysis Report
Page 22 of 46

74
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

The randomisation database automatically alerted the relevant IMP distributor and theparticipant, trial team and legal representative if applicable were notified electronically of thetreatment allocation. If the participant did not have an email address, they were notified by
telephone.

3.10 DEFINITION OF POPULATION FOR ANALYSISThe analysis population will include participants as defined by the protocol eligibility criteria
and having at least one of the vulnerabilities as listed in Table 3.
As per ICH E9 guidance the following participants will be excluded from the analysis
population;(a) Participants randomised but subsequently found to be not eligible for randomization(b) Participants previously randomised to an arm in the PANORAMIC trial (subsequent
randomisations will be excluded)
In addition, the following participants will be excluded;(c) Participants who withdraw consent for data linkage and notes review and for whom no
outcome data has been collected.
(d) Participants taking medications listed in Table 4
3.10.1.1 P RIMARY ANALYSIS POPULATION

The primary analysis population is defined as participants who were randomised to
Molnupiravir or usual care and were eligible for randomisation to Molnupiravir, during thesame time frame when Molnupiravir was actively randomising (i.e. Concurrent Randomisedand Eligible Analysis Population). That is, participants who were eligible for Molnupiravir
and randomised to either Molnupiravir or usual care between 8th December 2021 and 27th
April 2022.
This includes participants for whom data are available with participants analysed according
to the groups they were randomly allocated to, regardless of deviation from protocol.

Statistical Analysis Report

Effective: 22nd September 2022

Page 23 of 46

ATAG. Rep. 2024;2(2)75Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

3.10.1.2 S ECONDARY ANALYSIS POPULATION

Analysis of the secondary outcomes for a given intervention will be based on the same
population as the primary analysis.

Statistical Analysis Report
Page 24 of 46

76
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

4 RESULTS
4.1 RECRUITMENT
Randomisation to the Molnupiravir arm was stopped on 27th April 2022. Participants
randomised to the Molnupiravir arm and Usual Care between 8th December 2021 and 27th
April 2022 (inclusive) are included in this report (see SAP for more details). During this time
111,383 participants were screened, 44,073 of whom were not eligible on screening and afurther 41,517 were excluded after GP eligibility check (see CONSORT in appendix forreasons). 25,793 in total were randomised, of which 25,783 were randomised between
Molnupiravir and Usual Care and were eligible for randomisation to Molnupiravir. 504
participants were randomised to other arms or randomised to Usual Care and not eligible for
Molnupiravir. 75 participants were excluded from the analysis population as they were foundto be ineligible after randomisation, leaving 25,708 participants in the analysis population.
Figure 2 shows the flow of participants for the subgroup analysis as presented in this report.
7380 participants were excluded as they did not have any risk factors for severe COVID-19
and a further 54 were excluded due to taking other medications. This leaves 18,274 in thesubgroup analysis population.

Statistical Analysis Report

Effective: 22nd September 2022

Page 25 of 46

ATAG. Rep. 2024;2(2)77Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

FIGURE 1 FLOW DIAGRAM OF TRIAL PARTICIPANTS FOR THE SUBGROUP POPULATIONPANORAMIC study participants (n=25,708)(12,774 molnupiravir plus usual care group + 12,934 usual care group)↓↓→

Excluded
Adults without any risk factors for severe COVID-19(n=7380)→

Excluded
Adults using other COVID-19 medications (n=54)
Remdesivir (n=0)
Nirmatrelvir/ritonavir (n=5)
Ensitrelvir (n=0)
Casirivimab/imdevimab (n=0)
Sotrovimab (n=0)
Tixagevimab/cilgavimab (n=0)
Tocilizumab (n=0)
Baricitinib (n=0)
Dexamethasone (n=1)
Any other antiviral medications for COVID-19(n=2)
Any other neutralizing antibody for COVID-19(n=46)
Any other immunosuppressive medications for
COVID-19 (n=0)
Favipiravir (n=0)
Ivermectin (n=0)

Adults with risk factors for severe
COVID-19(n=18328)↓↓
Eligible participants(n=18,274)

Statistical Analysis Report
Page 26 of 46

78
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

4.2 BASELINE CHARACTERISTICS OF PARTICIPANTS
Baseline characteristics by randomised group and overall are given in Table 5 for the
concurrent and eligible population.
TABLE 5 BASELINE CHARACTERISTIC BY RANDOMISED GROUP

Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=12821)
56.7 (12.5)[18.0 to 99.0]

Usual Care

Overall(N=12962)
56.5 (12.7)[18.0 to 98.0](N=25783)
56.6 (12.6)[18.0 to 99.0]

7451 (58.1%)
5367 (41.9%)
3 (0.0%)2.0 (2.0 to 2.0)7650 (59.0%)5308 (41.0%)
4 (0.0%)N/A

15101 (58.6%)
10675 (41.4%)
7 (0.0%)2.0 (2.0 to 2.0)

5.0 (4.0 to 6.0)

N/A

5.0 (4.0 to 6.0)

12088 (94.3%)
366 (2.9%)203 (1.6%)
78 (0.6%)
86 (0.7%)

12182 (94.0%)
434 (3.3%)
189 (1.5%)77 (0.6%)80 (0.6%)24270 (94.1%)
800 (3.1%)
392 (1.5%)
155 (0.6%)
166 (0.6%)

259 (2.0%)539 (4.2%)
1117 (8.7%)

272 (2.1%)
577 (4.5%)1114 (8.6%)

531 (2.1%)1116 (4.3%)
2231 (8.7%)

1496 (11.7%)

1464 (11.3%)

2960 (11.5%)6541 (51.0%)746 (5.8%)6591 (50.8%)768 (5.9%)

13132 (50.9%)1514 (5.9%)997 (7.8%)1063 (8.2%)

2060 (8.0%)1126 (8.8%)1113 (8.6%)

2239 (8.7%)

2491 (19.4%)
2679 (20.9%)2524 (19.7%)
2784 (21.7%)

2558 (19.7%)
2636 (20.3%)
2660 (20.5%)2767 (21.3%)

5049 (19.6%)5315 (20.6%)5184 (20.1%)
5551 (21.5%)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receiptof medication*, median(IQR)
Days from start of symptoms to taking
medication*, median(IQR)
Missing, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
2
3
4
Statistical Analysis Part 2 Report288 (1.1%)

Effective: 9th October 2022

Page 27 of 46

ATAG. Rep. 2024;2(2)79Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
4(Least deprived) 5
Missing, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Statistical Analysis Report
Page 28 of 46

80
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir
plus usual care
(N=12821)
2343 (18.3%)
5965 (46.5%)

Usual Care

Overall(N=12962)
2341 (18.1%)
5902 (45.5%)(N=25783)
4684 (18.2%)
11867 (46.0%)1234 (9.6%)
1913 (14.9%)2569 (20.0%)3216 (25.1%)
3839 (29.9%)50 (0.4%)
11892 (92.8%)
12678 (98.9%)1182 (9.1%)
1956 (15.1%)
2592 (20.0%)3213 (24.8%)
3960 (30.6%)
59 (0.5%)
N/A
12830 (99.0%)2416 (9.4%)
3869 (15.0%)5161 (20.0%)6429 (24.9%)
7799 (30.2%)
109 (0.4%)
11892 (46.1%)
25508 (98.9%)87 (0.7%)519 (4.0%)11836 (92.3%)
236 (1.8%)
143 (1.1%)
795 (6.2%)

88 (0.7%)458 (3.5%)
12044 (92.9%)240 (1.9%)
132 (1.0%)805 (6.2%)

175 (0.7%)977 (3.8%)23880 (92.6%)476 (1.8%)275 (1.1%)
1600 (6.2%)

6111 (47.7%)4514 (35.2%)
1936 (15.1%)
260 (2.0%)6125 (47.3%)
4684 (36.1%)
1896 (14.6%)
257 (2.0%)12236 (47.5%)
9198 (35.7%)
3832 (14.9%)517 (2.0%)1251 (9.8%)
4721 (36.8%)5083 (39.6%)
1766 (13.8%)

1216 (9.4%)
4853 (37.4%)5127 (39.6%)
1766 (13.6%)

2467 (9.6%)
9574 (37.1%)
10210 (39.6%)3532 (13.7%)

3479 (27.1%)
4504 (35.1%)
3763 (29.4%)
1075 (8.4%)3425 (26.4%)
4791 (37.0%)3684 (28.4%)
1062 (8.2%)

6904 (26.8%)
9295 (36.1%)
7447 (28.9%)2137 (8.3%)

10440 (81.4%)
1847 (14.4%)478 (3.7%)
56 (0.4%)

10503 (81.0%)
1913 (14.8%)477 (3.7%)
69 (0.5%)

20943 (81.2%)
3760 (14.6%)955 (3.7%)
125 (0.5%)10600 (82.7%)
1649 (12.9%)

10732 (82.8%)
1681 (13.0%)

21332 (82.7%)3330 (12.9%)

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0
Usual Care

Overall

Moderate problem
Major problem

Molnupiravir
plus usual care
(N=12821)
471 (3.7%)
101 (0.8%)(N=12962)
457 (3.5%)
92 (0.7%)(N=25783)
928 (3.6%)
193 (0.7%)

No problem
Minor problem
Moderate problem
Major problem

9066 (70.7%)2484 (19.4%)
825 (6.4%)
446 (3.5%)9402 (72.5%)
2368 (18.3%)
800 (6.2%)
392 (3.0%)

18468 (71.6%)4852 (18.8%)
1625 (6.3%)
838 (3.3%)

No problem
Minor problem
Moderate problem
Major problem

2702 (21.1%)
5194 (40.5%)3783 (29.5%)
1142 (8.9%)2820 (21.8%)5215 (40.2%)3838 (29.6%)
1089 (8.4%)5522 (21.4%)
10409 (40.4%)7621 (29.6%)2231 (8.7%)

No problem
Minor problem
Moderate problem
Major problem

8446 (65.9%)3087 (24.1%)
1096 (8.5%)
192 (1.5%)

8382 (64.7%)
3295 (25.4%)
1087 (8.4%)
198 (1.5%)

16828 (65.3%)
6382 (24.8%)
2183 (8.5%)
390 (1.5%)

No problem
Minor problem
Moderate problem
Major problem

10391 (81.0%)
1834 (14.3%)
524 (4.1%)
72 (0.6%)

10440 (80.5%)
1920 (14.8%)
542 (4.2%)
60 (0.5%)

20831 (80.8%)3754 (14.6%)
1066 (4.1%)
132 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

525 (4.1%)
5028 (39.2%)
5789 (45.2%)
1479 (11.5%)535 (4.1%)
5145 (39.7%)
5838 (45.0%)1444 (11.1%)

1060 (4.1%)
10173 (39.5%)
11627 (45.1%)
2923 (11.3%)

No problem
Minor problem
Moderate problem
Major problem

5670 (44.2%)
4813 (37.5%)2107 (16.4%)
231 (1.8%)5765 (44.5%)4955 (38.2%)
2042 (15.8%)200 (1.5%)

11435 (44.4%)9768 (37.9%)4149 (16.1%)
431 (1.7%)1410 (11.0%)6153 (48.0%)4502 (35.1%)
756 (5.9%)
5.1 (1.7) [0.0 to
10.0]1343 (10.4%)6384 (49.3%)
4509 (34.8%)
726 (5.6%)
5.2 (1.7) [0.0 to
10.0]2753 (10.7%)12537 (48.6%)
9011 (34.9%)1482 (5.7%)
5.1 (1.7) [0.0 to
10.0]1660 (12.9%)
6113 (47.7%)

1660 (12.8%)6019 (46.4%)

3320 (12.9%)
12132 (47.1%)

Loss of smell or taste, n(%)

Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean(SD) [min,max]People in household, n(%)
01
Statistical Analysis Report

Effective: 22nd September 2022

Page 29 of 46

ATAG. Rep. 2024;2(2)81Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

2
3
4
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)
Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir
plus usual care
(N=12821)
2129 (16.6%)
1765 (13.8%)808 (6.3%)
2990 (23.3%)
183 (1.4%)
26 (0.2%)

Usual Care

Overall(N=12962)
2176 (16.8%)
1979 (15.3%)
772 (6.0%)3152 (24.3%)
158 (1.2%)
19 (0.1%)(N=25783)
4305 (16.7%)
3744 (14.5%)
1580 (6.1%)
6142 (23.8%)341 (1.3%)
45 (0.2%)

3014 (23.5%)1000 (7.8%)
227 (1.8%)
159 (1.2%)
430 (3.4%)
36 (0.3%)
24 (0.2%)
1483 (11.6%)1125 (8.8%)
57 (0.4%)
1968 (15.3%)
198 (1.5%)2880 (22.5%)2295 (17.9%)

3171 (24.5%)
957 (7.4%)
253 (2.0%)
144 (1.1%)
438 (3.4%)
27 (0.2%)30 (0.2%)
1512 (11.7%)
1070 (8.3%)
71 (0.5%)
1944 (15.0%)
220 (1.7%)2902 (22.4%)
2341 (18.1%)

6185 (24.0%)
1957 (7.6%)
480 (1.9%)
303 (1.2%)
868 (3.4%)
63 (0.2%)
54 (0.2%)2995 (11.6%)
2195 (8.5%)
128 (0.5%)3912 (15.2%)
418 (1.6%)
5782 (22.4%)4636 (18.0%)*Median and interquartile range presented for non-normally distributed variables.

Statistical Analysis Report
Page 30 of 46

82
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 6 BASELINE CHARACTERISTIC OF THE SUBGROUP POPULATION BY RANDOMISED GROUP

Age, mean(SD) [min,max]

Molnupiravir plus
usual care
(N=9120)56.9 (14.4)[18.0 to 99.0]

Usual Care
(N=9154)

Overall(N=18274)

56.7 (14.7)[18.0 to 98.0]

56.8 (14.5)[18.0 to 99.0]5267 (57.8%)
3851 (42.2%)
2 (0.0%)2.0 (2.0 to 2.0) [0.0
to 7.0]4.0 (3.0 to 5.0) [1.0to 29.0]7163 (78.5%)

5319 (58.1%)
3832 (41.9%)
3 (0.0%)N/A

0 (0.0%)10586 (57.9%)7683 (42.0%)
5 (0.0%)2.0 (2.0 to 2.0) [0.0
to 7.0]4.0 (3.0 to 5.0) [1.0to 29.0]7163 (39.2%)

8589 (94.2%)
257 (2.8%)
150 (1.6%)
54 (0.6%)70 (0.8%)8596 (93.9%)318 (3.5%)
138 (1.5%)52 (0.6%)50 (0.5%)

17185 (94.0%)575 (3.1%)
288 (1.6%)
106 (0.6%)
120 (0.7%)

256 (2.8%)537 (5.9%)1115 (12.2%)

271 (3.0%)573 (6.3%)
1108 (12.1%)

527 (2.9%)1110 (6.1%)
2223 (12.2%)

1488 (16.3%)

1463 (16.0%)

2951 (16.1%)

5577 (61.2%)
37 (0.4%)

5582 (61.0%)
35 (0.4%)11159 (61.1%)
72 (0.4%)

43 (0.5%)56 (0.6%)

99 (0.5%)67 (0.7%)

66 (0.7%)

133 (0.7%)623 (6.8%)
1810 (19.8%)2108 (23.1%)
2442 (26.8%)
2137 (23.4%)
4267 (46.8%)

633 (6.9%)
1780 (19.4%)2157 (23.6%)
2439 (26.6%)2145 (23.4%)
4161 (45.5%)1256 (6.9%)3590 (19.6%)4265 (23.3%)
4881 (26.7%)
4282 (23.4%)
8428 (46.1%)

985 (10.8%)1427 (15.6%)
1838 (20.2%)

930 (10.2%)1466 (16.0%)
1833 (20.0%)

1915 (10.5%)2893 (15.8%)3671 (20.1%)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting
receipt of medication*, median(IQR)
Days from start of symptoms to taking
medication*, median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70
and clinically extremely vulnerable
Aged ≥65 and <70 and not clinicallyextremely vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinicallyextremely vulnerable or in an at risk group
Aged ≥55 and <60 and not clinicallyextremely vulnerable or in an at risk group
Aged ≥50 and <55 and not clinicallyextremely vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
23
4
5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
Statistical Analysis Part 2 Report

N/A

Effective: 9th October 2022

Page 31 of 46

ATAG. Rep. 2024;2(2)83Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Moderate problem
Major problem
Loss of smell or taste, n(%)
No problem
Minor problem
Moderate problem
Statistical Analysis Report
Page 32 of 46

84
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir plus
usual care
(N=9120)2248 (24.6%)
2590 (28.4%)
32 (0.4%)
8412 (92.2%)9015 (98.8%)

Usual Care
(N=9154)

Overall(N=18274)

2238 (24.4%)2640 (28.8%)47 (0.5%)9064 (99.0%)

4486 (24.5%)5230 (28.6%)
79 (0.4%)
8412 (46.0%)
18079 (98.9%)

67 (0.7%)
369 (4.0%)
8361 (91.7%)
218 (2.4%)
105 (1.2%)
787 (8.6%)

72 (0.8%)329 (3.6%)
8440 (92.2%)
223 (2.4%)
90 (1.0%)799 (8.7%)

139 (0.8%)698 (3.8%)
16801 (91.9%)
441 (2.4%)
195 (1.1%)
1586 (8.7%)4011 (44.0%)
3289 (36.1%)
1585 (17.4%)
235 (2.6%)

3948 (43.1%)
3393 (37.1%)
1577 (17.2%)
236 (2.6%)

7959 (43.6%)
6682 (36.6%)
3162 (17.3%)
471 (2.6%)853 (9.4%)
3251 (35.6%)
3672 (40.3%)1344 (14.7%)

836 (9.1%)
3254 (35.5%)3694 (40.4%)1370 (15.0%)

1689 (9.2%)6505 (35.6%)
7366 (40.3%)2714 (14.9%)2501 (27.4%)
3051 (33.5%)2724 (29.9%)844 (9.3%)

2384 (26.0%)
3295 (36.0%)2649 (28.9%)
826 (9.0%)4885 (26.7%)
6346 (34.7%)
5373 (29.4%)
1670 (9.1%)

7361 (80.7%)1339 (14.7%)
380 (4.2%)
40 (0.4%)

7340 (80.2%)1381 (15.1%)
371 (4.1%)
62 (0.7%)

14701 (80.4%)2720 (14.9%)751 (4.1%)
102 (0.6%)7414 (81.3%)
1237 (13.6%)
380 (4.2%)
89 (1.0%)7476 (81.7%)
1249 (13.6%)
358 (3.9%)
71 (0.8%)14890 (81.5%)
2486 (13.6%)
738 (4.0%)
160 (0.9%)6379 (69.9%)1791 (19.6%)
614 (6.7%)

6567 (71.7%)
1686 (18.4%)
600 (6.6%)

12946 (70.8%)3477 (19.0%)1214 (6.6%)
Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0
Molnupiravir plus
usual care
(N=9120)336 (3.7%)

Usual Care
(N=9154)

Overall(N=18274)301 (3.3%)

637 (3.5%)

No problem
Minor problem
Moderate problem
Major problem

1912 (21.0%)3630 (39.8%)2718 (29.8%)860 (9.4%)

2015 (22.0%)3570 (39.0%)2734 (29.9%)835 (9.1%)

3927 (21.5%)7200 (39.4%)
5452 (29.8%)
1695 (9.3%)

No problem
Minor problem
Moderate problem
Major problem

5820 (63.8%)2286 (25.1%)
855 (9.4%)
159 (1.7%)

5748 (62.8%)
2373 (25.9%)864 (9.4%)
169 (1.8%)

11568 (63.3%)4659 (25.5%)
1719 (9.4%)
328 (1.8%)

No problem
Minor problem
Moderate problem
Major problem

7311 (80.2%)1329 (14.6%)
417 (4.6%)
63 (0.7%)7280 (79.5%)1410 (15.4%)
417 (4.6%)
47 (0.5%)

14591 (79.8%)2739 (15.0%)
834 (4.6%)
110 (0.6%)

No problem
Minor problem
Moderate problem
Major problem

383 (4.2%)
3449 (37.8%)4160 (45.6%)1128 (12.4%)

381 (4.2%)
3521 (38.5%)
4138 (45.2%)1114 (12.2%)

764 (4.2%)
6970 (38.1%)
8298 (45.4%)2242 (12.3%)

No problem
Minor problem
Moderate problem
Major problem

3990 (43.8%)3428 (37.6%)
1541 (16.9%)
161 (1.8%)4052 (44.3%)
3481 (38.0%)1464 (16.0%)
157 (1.7%)8042 (44.0%)6909 (37.8%)3005 (16.4%)
318 (1.7%)1004 (11.0%)4242 (46.5%)
3277 (35.9%)
597 (6.5%)
5.1 (1.7) [0.0 to
10.0]937 (10.2%)4352 (47.5%)3291 (36.0%)
574 (6.3%)
5.1 (1.7) [0.0 to
10.0]1941 (10.6%)8594 (47.0%)6568 (35.9%)
1171 (6.4%)
5.1 (1.7) [0.0 to
10.0]1245 (13.7%)4489 (49.2%)
1376 (15.1%)
1156 (12.7%)
580 (6.4%)
274 (3.0%)2848 (31.2%)

1236 (13.5%)4368 (47.7%)1409 (15.4%)1309 (14.3%)
547 (6.0%)285 (3.1%)
3010 (32.9%)2481 (13.6%)
8857 (48.5%)2785 (15.2%)
2465 (13.5%)1127 (6.2%)
559 (3.1%)
5858 (32.1%)

Major problem
Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean(SD) [min,max]People in household, n(%)
0
1
2
3
4
5
Taking inhaled corticosteroids, n(%)

Statistical Analysis Report

Effective: 22nd September 2022

Page 33 of 46

ATAG. Rep. 2024;2(2)85Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

Taking inhaled corticosteroids for COVID,n(%)
Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir plus
usual care
(N=9120)159 (1.7%)

Usual Care
(N=9154)

Overall(N=18274)

143 (1.6%)302 (1.7%)

0 (0.0%)0 (0.0%)0 (0.0%)2989 (32.8%)993 (10.9%)222 (2.4%)
158 (1.7%)423 (4.6%)
33 (0.4%)
24 (0.3%)
1473 (16.2%)
1110 (12.2%)
50 (0.5%)
1957 (21.5%)
196 (2.1%)
2285 (25.1%)
1886 (20.7%)3161 (34.5%)952 (10.4%)253 (2.8%)
143 (1.6%)
432 (4.7%)
27 (0.3%)
29 (0.3%)
1507 (16.5%)
1055 (11.5%)60 (0.7%)
1932 (21.1%)
220 (2.4%)2303 (25.2%)
1883 (20.6%)6150 (33.7%)
1945 (10.6%)475 (2.6%)301 (1.6%)855 (4.7%)
60 (0.3%)
53 (0.3%)2980 (16.3%)
2165 (11.8%)
110 (0.6%)3889 (21.3%)
416 (2.3%)
4588 (25.1%)
3769 (20.6%)*Median and interquartile range presented for non-normally distributed variables.

Statistical Analysis Report
Page 34 of 46

86
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 7 PREVALENCE OF RISK FACTORS FOR SEVERE COVID-19 (MODIFIED DEFINITION) AMONG ELIGIBLE PARTICIPANTS

Molnupiravir plus usual
care (n=9120)

Usual care(n=9154)3396 (37.2%)
233 (2.6%)
1 (0.0%)16 (0.2%)
1 (0.0%)222 (2.4%)
2989 (32.8%)
158 (1.7%)
1473 (16.2%)
24 (0.3%)
993 (10.9%)1110 (12.2%)
196 (2.1%)
423 (4.6%)
1957 (21.5%)3415 (37.3%)
290 (3.2%)
1 (0.0%)24 (0.3%)
0 (0.0%)253 (2.8%)3161 (34.5%)
143 (1.6%)
1507 (16.5%)
29 (0.3%)
952 (10.4%)1055 (11.5%)
220 (2.4%)
432 (4.7%)
1932 (21.1%)

787 (8.6%)
50 (0.5%)28 (0.3%)

799 (8.7%)
60 (0.7%)37 (0.4%)

Risk factors
Older adults aged ≥ 65 years
AsthmaCancer (Hematologic malignancies)
StrokeAneurysm
Kidney disease
Lung disease
Liver disease
Diabetes
Down syndrome
Heart disease
Immune disease
Mental illness
Neurologic conditions
2

Obesity (BMI ≥ 35 kg/m )Current smoker
Transplant
Use of corticosteroids or otherimmunosuppressive medications

Statistical Analysis Part 2 Report

Effective: 9th October 2022

Page 35 of 46

ATAG. Rep. 2024;2(2)87Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

4.3 NUMBER ANALYSED
Of the 18274 participants included in the subgroup analysis 17754 (97.2%) had data collectedon hospitalisation/death and so could be included in the primary analysis. 17334 (94.9%)
completed any diaries or calls and so could be included in the secondary analysis.

4.4 PRIMARY ANALYSES
4.4.1 PRIMARY OUTCOME
The primary outcome is defined as all cause unplanned hospitalisation or death fromrandomisation to 28 days follow-up. Data is derived from participant daily diaries, phone calls,
and routine electronic data. If a primary endpoint is reported from any data source then thisoutcome is counted as “yes”. If the participant has completed 28 days follow-up and is not
hospitalised or is lost to follow-up but has been checked against routine electronic data andno hospitalisation or death is found then this outcome is coded “no”. An odds ratio<1 suggests
fewer hospitalisations/deaths in the Molnupiravir arm. The results show probability ofsuperiority below 0.5, indicating no benefit of Molnupiravir compared to Usual Care.
TABLE 8 PRIMARY OUTCOME

Hospitalization or death
DeathsHospitalizations*OR < 1 favours molnupiravir

Molnupiravir plus
usual care
(N=9120)92/8932 (1.0%)
3/893290/8932 (1.0%)

Statistical Analysis Report
Page 36 of 46

88
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Usual care
(N=9154)

Estimated treatment
effect (95% BCI)

87/8822 (1.0%)
5/8822
85/8822 (1.0%)

1.053 (0.775 to 1.396)
Not estimable
1.055 (0.773 to 1.413)

Probabilityofsuperiority
0.39190.3963

Effective: 22nd September 2022

4.4.2 SECONDARY OUTCOMES
Definition of outcomes:
1. Time to recovery: time to first reporting of feeling recovered in diary or call. A hazard ratio>1 suggests faster recovery in the Molnupiravirarm.
2. Time to sustained recovery: time to reporting recovery in diary or call followed by no subsequent relapse. A hazard ratio>1 favours
Monupiravir.
3. Early sustained recovery: reported recovered within the first 14 days with no subsequent relapse. An odds ratio >1 favours Molnupiravir.
4. Alleviation of symptoms: Time to first rating of symptoms as mild/none. If all symptoms are rated mild/none at baseline then theparticipant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
5. Sustained alleviation of symptoms: Time to rating of symptoms as mild/none followed by no subsequent relapse. If all symptoms are
rated mild/none at baseline then the participant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
6. Reduction of symptoms: Time to reduction of all symptoms by at least one grade. A hazard ratio>1 favours Molnupiravir.
7. Rating of how well participant feels (1 worst, 10 best): Participant rating of wellness at each day. Estimates represent the meandifferences and a values >0 favours Molnupiravir.
8. Household infections: Participant reported another member of their household becoming unwell with COVID-19. Participants who live
alone at baseline are excluded. An odds ratio <1 favours Molnupiravir (fewer household infections). For number of infections a rate ratio<1 favours Molnupiravir.
The following assumptions have been made in the following analysis:
1. For time to event outcomes participants are censored at the last point of contact or 28 days, whichever is sooner. For time to sustained
recovery if a participant reported feeling recovered and is subsequently lost to follow-up it is assumed they remained recovered (lastStatistical Analysis Part 2 Report

Effective: 9th October 2022

Page 37 of 46

ATAG. Rep. 2024;2(2)89Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR

2.
3.
4.
5.

Statistical Analysis Part 2 Report Version 2.0

observation carried forward). A similar principle is used for time to sustained alleviation of symptoms. Therefore the only missing data
for time to event outcomes is participants who completed no diary data
For early sustained recovery if a participant is lost to follow-up, such that it is not possible to establish if they remained recovered, thenthis outcome is treated as missing.
For time to alleviation and time to reduction of symptoms if a symptom is missing but the participant reported feeling recovered, thatsymptom is assumed to be rated “none”.
For household infections if a participant has incomplete diaries but has not stated that they have an infection within the household thisoutcome is assumed to be zero. Participants who live alone at baseline are excluded from the analysis.
Analysis of daily symptom scores uses a frequentist mixed model, due to the computational difficultly running the Bayesian model with
the number of parameters.

Results in Table 9 have showed estimated median (95% BCI) time to first reported recovery from the Bayesian model were 10.381 (10.137 to
10.640) days and 14.853 (14.383 to 15.345) days, respectively, which suggested that Molnupiravir has a 4.5 days benefit in TTR compared with
Usual Care.
There was a significant benefit in early sustained recovery by 9.7%, i.e. recovered within the first 14 days and remained well until day 28 fromrandomisation, in Molnupiravir group (31.4%) compared to Usual Care (21.7%) (OR = 1.7; 95% BCI (1.56 to 1.81)).

Statistical Analysis Report
Page 38 of 46

90
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 9 SECONDARY OUTCOMES
Usual careFirst reported recovery
Days to first reported recovery

Molnupiravir plus usualcare
6860/8837 (77.6%)
10.381 (10.137 to 10.640)

Estimated treatment effect(95% BCI)

Estimated benefit (95%
BCI)

Probability ofsuperiority

Early sustained recovery

2530/8062 (31.4%)

5722/8497 (67.3%)
14.853 (14.383 to 15.345)

1.374 (1.326 to 1.423) *1.679 (1.558 to 1.807) **-4.472 (-5.001 to -3.953) †>0.99

1625/7495 (21.7%)

Sustained recovery
Days to sustained recovery

5995/8837 (67.8%)
20.215 (19.771 to 20.686)

4950/8497 (58.3%)
23.746 (23.430 to 24.066)

1.262 (1.213 to 1.310) *6447/6997 (92.1%)
3.794 (3.691 to 3.896)

5839/6720 (86.9%)
4.625 (4.493 to 4.770)-3.533 (-4.055 to -2.978) †>0.99

Alleviation of all symptoms
Days to alleviations of all symptoms

1.220 (1.177 to 1.263) *5799/6997 (82.9%)
9.912 (9.533 to 10.304)

5187/6720 (77.2%)
11.956 (11.489 to 12.442)-0.833 (-0.993 to -0.676) †>0.99

Sustained alleviation of all symptoms
Days to sustained alleviation of all
symptoms
Initial reduction of symptom severity
Days to initial reduction of symptom
severity
Participant rating of wellness
Day 7

1.158 (1.117 to 1.202) *-2.040 (-2.592 to -1.505) †>0.99

7634/8820 (86.6%)
7.500 (7.333 to 7.673)

6732/8487 (79.3%)
9.435 (9.202 to 9.672)

1.292 (1.248 to 1.336) *-1.934 (-2.204 to -1.666) †>0.99

7.3 (1.8) [8396]

6.7 (1.8) [7800]

0.5 (0.5 to 0.6) ¶P<0.001 ll

7.8 (1.7) [8142]

7.5 (1.8) [7422]

0.3 (0.2 to 0.3) ¶P<0.001 ll¶

P<0.001 ll

Day 14>0.99

Day 218.1 (1.7) [7535]

7.9 (1.7) [6602]

0.2 (0.1 to 0.2)

Day 288.3 (1.6) [7515]

8.2 (1.6) [6731]

0.2 (0.1 to 0.2) ¶P<0.001 ll

New infections in household

2852/7630 (37.4%)

2803/7307 (38.4%)

0.960 (0.898 to 1.025) **0.8879Contact with health and social careservices
NHS 111487/8835 (5.5%)

614/8492 (7.2%)

0.746 (0.660 to 0.843) **>0.99

General practitioner

2009/8835 (22.7%)2332/8493 (27.5%)

0.774 (0.721 to 0.830) **>0.99

Ambulance service (nothospitalised)

256/8831 (2.9%)

233/8479 (2.7%)

1.060 (0.881 to 1.267) **0.2847

Statistical Analysis Part 2 Report

Effective: 9th October 2022

Page 39 of 46

ATAG. Rep. 2024;2(2)91Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR

Statistical Analysis Part 2 Report Version 2.0

Community nurse

226/8835 (2.6%)

243/8489 (2.9%)

0.894 (0.736 to 1.073) **0.8927

Physiotherapist

115/8835 (1.3%)

66/8489 (0.8%)

1.696 (1.239 to 2.277) **0.0006Counsellor

72/8835 (0.8%)

89/8489 (1.0%)

0.784 (0.565 to 1.063) **0.9464Social worker

21/8835 (0.2%)

27/8489 (0.3%)

0.774 (0.420 to 1.296) **0.8498Home carer

82/8834 (0.9%)77/8487 (0.9%)

1.027 (0.747 to 1.397) **0.4688

Occupational therapist

191/8834 (2.2%)

169/8489 (2.0%)

1.095 (0.884 to 1.338) **0.2049Hospital emergency department

512/8835 (5.8%)

489/8490 (5.8%)

1.009 (0.886 to 1.144) **Outpatient respiratory clinic

208/8835 (2.4%)

218/8489 (2.6%)

0.914 (0.751 to 1.101) **0.8319Hospital at home for COVID-19

298/8835 (3.4%)

356/8489 (4.2%)

0.798 (0.679 to 0.930) **0.9980

Other services

485/8835 (5.5%)

539/8488 (6.4%)

0.856 (0.751 to 0.970) **0.99260.4584*Estimated HR derived from a piecewise exponential model adjusted for age, comorbidity and vaccination status. HR > 1 favours Molnupiravir.

†Model based estimated benefit median time to event <0 favours Molnupiravir.
ll Frequentist model estimates display p-value rather than a probability¶Linear mixed effect model adjusted for age, comorbidity and vaccination status. Participant fitted as a random effect. Estimated mean difference > 0 favours Molnupiravir.
**Bayesian logistic regression, adjusted for, age, comorbidity and vaccination status

Statistical Analysis Report
Page 40 of 46

92
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

The following plot shows the actual data for time to recovery (solid lines) and the model based
estimates (dashed lines). The model based estimates are derived from the piecewise
exponential where all the standardised covariates are set to zero (corresponding to thesample average).
FIGURE 2 KAPLAN-MEIER CURVE AND MODEL ESTIMATES FOR TIME TO RECOVERY

Statistical Analysis Part 2 Report

Effective: 9th October 2022

Page 41 of 46

ATAG. Rep. 2024;2(2)93

4.5 SUBGROUP ANALYSES
Frequentist model estimates are presented for the moderation analysis of the primary
outcome. An odds ratio<1 favours Molnupiravir. P-values indicate the test for the interaction
and statistically significant p-value suggests a differential effect size between subgroups.
FIGURE 3 FOREST PLOT OF SUBGROUP ANALYSIS OF PRIMARY OUTCOME

Statistical Analysis Part 2 Report
Page 42 of 46

94
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 9th October 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0
Frequentist model estimates are presented for the moderation analysis of time to recovery.
A hazard ratio>1 favours Molnupiravir. P-values indicate the test for the interaction and astatistically significant p-value suggests a differential effect size between subgroups.
FIGURE 4 FOREST PLOT OF SUBGROUP ANALYSIS OF TIME TO RECOVERY

Statistical Analysis Report

Effective: 22nd September 2022

Page 43 of 46

ATAG. Rep. 2024;2(2)95Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 2 Report Version 2.0

4.6 VIROLOGY SUB-STUDY ANALYSISTABLE 10 SUMMARY OF VIROLOGY SUB-STUDY
Number of participants, nIntensive samples cohortLess intensive samples cohort
At least 7 samples received from
intensive samples cohort, n/N (%)
At least 2 samples received from lessintensive sample cohort, n/N (%)
Female, n/N (%)
Intensive samples cohortLess intensive samples cohort
OverallAge, mean (SD)Intensive samples cohortLess intensive samples cohort
OverallStatistical Analysis Report
Page 44 of 46

96
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir

Usual Care

Total

22
142
22/22 (100.0%)28
16327/28 (96.4%)50
305
49/50 (98.0%)

142/142 (100.0%)

163/163 (100.0%)

305/305 (100.0%)

12/22 (54.5%)
80/142 (56.3%)
92/164 (56.1%)

14/28 (50.0%)
102/163 (62.6%)
116/191 (60.7%)

26/50 (52.0%)
182/305 (59.7%)
208/355 (58.6%)

58.1 (12.0) [27.0 to 79.0]
59.2 (11.9) [29.0 to 82.0]
59.1 (11.9) [27.0 to 82.0]

64.1 (9.6) [34.0 to 74.0]
59.5 (13.0) [22.0 to 86.0]
60.2 (12.7) [22.0 to 86.0]

61.4 (11.0) [27.0 to 79.0]
59.4 (12.5) [22.0 to 86.0]
59.7 (12.3) [22.0 to 86.0]

Effective: 22nd September 2022

TABLE 11 VIROLOGY SUBSTUDY
Molnupiravir plus usual care

Usual care

Estimated treatment effect(95% CI)P value

Intensive samples
Undetectable viral load
Day 2
0/22
0/27
Day 3
0/22
0/27
Day 4
1/22 (4.5%)
0/28
Day 5
3/22 (13.6%)
0/27
Day 6
4/22 (18.2%)
1/28 (3.6%)
4.605 (0.579 to 36.623) †0.14895/22 (22.7%)
1/28 (3.6%)
5.769 (0.797 to 41.752) †0.0827
Day 7*
Viral load, mean(SD)Day 1
7.268 (1.252)
7.303 (1.309)
Day 2
6.764 (1.422)
7.083 (1.187)-0.352 (-0.952 to 0.247) ‡0.2498Day 3
6.258 (1.353)
6.474 (1.149)-0.250 (-0.849 to 0.350) ‡0.4145Day 4
5.350 (1.437)
5.919 (1.299)-0.586 (-1.182 to 0.009) ‡0.0537Day 5
4.435 (1.518)
5.786 (1.113)-1.385 (-1.984 to -0.785) ‡ <0.0001
Day 6
4.020 (1.552)
5.457 (1.380)-1.454 (-2.049 to -0.858) ‡ <0.0001
Day 7
3.633 (1.392)
5.048 (1.379)-1.432 (-2.027 to -0.836) ‡ <0.0001
All samples
Undetectable viral load
Day 5
14/160 (8.8%)
4/185 (2.2%)
6.038 (1.513 to 24.094) **0.0109Day 1464/138 (46.4%)
75/154 (48.7%)
0.867 (0.436 to 1.721) **0.6826
Viral load, mean(SD)Day 5
4.409 (1.527)
5.607 (1.323)-1.201 (-1.609 to -0.794) ‡ <0.0001
Day 142.828 (1.335)
2.530 (1.113)
0.277 (-0.035 to 0.589) ‡0.0821* Primary outcome† Firth logistic regression adjusting for sex, age, and baseline log10(viral load). Adjusted OR > 1 favours molnupiravir‡Mixed effect model adjusting for sex, age, and baseline log10(viral load); adjusted difference < 0 favours molnupiravir** Mixed effects logistic regression adjusting for sex, age, and baseline log 10(viral load).
molnupiravir

Adjusted OR > 1 favours

Statistical Analysis Part 2 Report

Effective: 9th October 2022

Page 45 of 46

ATAG. Rep. 2024;2(2)97

~~~ END OF REPORT ~~~Statistical Analysis Part 2 Report
Page 46 of 46

98
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 9th October 2022

STATISTICAL ANALYSIS PART 1 REPORT
Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In theCommunity
Reference Number / Short title: PANORAMICMOLNUPIRAVIR

Ethics Ref: 21/SC/0393
IRAS Project ID: 1004274
EudraCT Number: 2021-005748-31
Based on protocol version 5.0 9th May 2022
Version 1.0

Date: 22nd September 2023

Report prepared and analysis carried out by

Dr Victoria Harris, Department of Primary
Care Health Sciences, University of Oxford

Report reviewed by

Dr Milensu Shanyinde, Department ofPrimary Care Health Sciences, University of
OxfordStatistical Analysis Part 1 Report

Effective: 22nd September 2022

Page 1 of 44

ATAG. Rep. 2024;2(2)99Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

2 CONTENTS
LIST OF TABLES ................................................................................................................. 4
LIST OF FIGURES ............................................................................................................... 51

BACKGROUND............................................................................................................ 6

2

INTRODUCTION.......................................................................................................... 6
2.1

3

SOFTWARE EMPLOYED ........................................................................................................8

METHODS .................................................................................................................. 9
3.1 TRIAL OVERVIEW ...............................................................................................................9
3.2 STUDY DESIGN ...................................................................................................................9
3.3 ADAPTIVE DESIGN ............................................................................................................10
3.4 OBJECTIVES ....................................................................................................................10
3.5 TARGET POPULATION ........................................................................................................123.5.1 Inclusion Criteria ..................................................................................................13
3.5.2 Exclusion criteria ..................................................................................................143.5.3 A Risk factors........................................................................................................14
3.5.4 Concomitant use of other COVID-19 medications ...............................................17
3.6 INTERVENTIONS ...............................................................................................................18
3.7 OUTCOMES ....................................................................................................................18
3.7.1 Primary outcome..................................................................................................18
3.7.2 Secondary outcomes ............................................................................................18
3.7.2.1
3.7.2.2
3.7.2.3
3.7.2.4
3.7.2.5
3.7.2.6
3.7.2.7
3.7.2.8

TIME TO RECOVERY...................................................................................................................................18
PATIENT REPORTED ILLNESS SEVERITY .....................................................................................................18
DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE .......................................................... 19
CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF FOLLOW-UP (FU). ....19
NEW INFECTIONS IN THE HOUSEHOLD .....................................................................................................19
SAFETY OF ANTIVIRAL AGENTS .................................................................................................................19
LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS........................................19
HEALTHCARE MEASURES (EQ-5D-5L) ........................................................................................................20

3.8 SAMPLE SIZE ...................................................................................................................20
3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE .........................................................20
3.10
DEFINITION OF POPULATION FOR ANALYSIS ........................................................................21
3.10.1.1
3.10.1.2

4

Primary analysis population..................................................................................................................21
Secondary analysis population .............................................................................................................22

RESULTS ................................................................................................................... 23

Statistical Analysis Report
Page 2 of 44

100
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0
4.1 RECRUITMENT .................................................................................................................23
4.2 BASELINE CHARACTERISTICS OF PARTICIPANTS ........................................................................25
4.3 NUMBER ANALYSED ..........................................................................................................34
4.4 PRIMARY ANALYSES..........................................................................................................34
4.4.1 Primary outcome..................................................................................................34
4.4.2 Secondary outcomes ............................................................................................35
4.5 SUBGROUP ANALYSES .......................................................................................................40
4.6 VIROLOGY SUB-STUDY ANALYSIS ..........................................................................................42

Statistical Analysis Report

Effective: 22nd September 2022

Page 3 of 44

ATAG. Rep. 2024;2(2)101Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

LIST OF TABLES
Table 1 The ministry of health, labour and welfare defined risk factors for severe COVID-19................................................................................................................................................. 14
Table 2 The modified definition of risk factors for severe COVID-19..................................... 15
Table 3 The diagnostic criteria for each risk factor in the PANORAMIC study....................... 16
Table 4 The definition of other COVID-19 medications.......................................................... 17
Table 5 Baseline characteristic by randomised group for the concurrent and eligible
population............................................................................................................................... 25
Table 6 Baseline characteristic of the subgroup population by randomised group .............. 29
Table 7 Prevalence of risk factors for severe COVID-19 (modified definition) among eligible
participants ............................................................................................................................. 33
Table 8 Primary outcome........................................................................................................ 34
Table 9 Secondary outcomes.................................................................................................. 37
Table 10 Summary of Virology sub-study............................................................................... 42
Table 11 Virology substudy..................................................................................................... 43

Statistical Analysis Report
Page 4 of 44

102
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

LIST OF FIGURES
Figure 1 Flow diagram of trial participants for the subgroup population ............................. 24
Figure 2 Kaplan-Meier curve and model estimates for time to recovery .............................. 39
Figure 3 Forest plot of Subgroup analysis of primary outcome ............................................. 40
Figure 4 Forest plot of Subgroup analysis of Time to recovery .............................................. 41

Statistical Analysis Report

Effective: 22nd September 2022

Page 5 of 44

ATAG. Rep. 2024;2(2)1031 BACKGROUNDThe Center for Outcomes Research and Economic Evaluation for Health (C2H) is currently
conducting a cost-effectiveness evaluation of Molnupiravir as a part of the Japanese healthtechnology assessment (HTA) process. The data from the PANORAMIC study(Butler CC, et al. Lancet.
2023:28;401:281-293) could potentially be the source to assess the additional benefit of Molnupiravir
in the Japanese setting. However, there are several differences between the study design of
the PANORAMIC and the indication for Molnupiravir in Japan. For example, Molnupiravir isapproved in Japan for the treatment of COVID-19 in adults with risk factors for severe COVID19 whereas the PANORAMIC study included adults without these risk factors. Additionally,
differences in the definition of standard of care also exist. In Japan, concomitant use of
Molnupiravir with other COVID-19 medications (e.g., remdesivir) is not recommended. Given
these differences, the purpose of this report is to present the results of sub-group analysis of
the PANORAMIC study in line with the indication and clinical practice of Molnupiravir in Japan.
The results are presented excluding both A) participants without risk factors; and B)
participants using other COVID-19 medications at the prescription of Molnupiravir .
DISCLAIMER: Publication of the results presented in this report requires approval inwriting to the Chief Investigators.

2 INTRODUCTION
This document details the analysis for the subgroup reporting results for the comparison of
Molnupiravir with usual care from the PANORAMIC trial. The results reported in these papers
follow the strategy set out in the statistical analysis plan. Subsequent analyses of a more
exploratory nature will not be bound by this strategy, though they are expected to follow thebroad principles laid down here.
The analysis strategy will be available on request when the principal papers are submitted for
publication in a journal. Suggestions for subsequent analyses by journal editors or referees,
will be considered carefully, and carried out as far as possible in line with the principles of thisanalysis strategy; if reported, the source of the suggestion will be acknowledged.
This report is based on the statistical analysis plan { Subgroup analysis of PANORAMIC study
in Japan_Plan1.docx}. Any deviations from the statistical analysis plan will be described andjustified in this report of the trial.

Statistical Analysis Part 1 Report
Page 6 of 44

104
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

Trial/Study statistician(s):Dr Victoria Harris
Lead Trial Statisticians Professor Ly-Mee Yu and Dr Ben SavilleCo-chief Investigator:
Professor Chris Butler, Professor Paul Little, and Professor Richard Hobbs
Senior Trial Manager: Lucy Cureton
Senior Data Manager: Meena Patil

Statistical Analysis Report

Effective: 22nd September 2022

Page 7 of 44

ATAG. Rep. 2024;2(2)1052.1 SOFTWARE EMPLOYED
Analysis was carried out using STATA v18

Statistical Analysis Part 1 Report
Page 8 of 44

106
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3

METHODS

3.1 TRIAL OVERVIEW
Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK
and in many countries around the world, with many patients continuing to require hospital
admission. COVID-19 causes considerable suffering, including loss of ability to perform
activities of daily living, loss of educational and work opportunities, and inability to perform
caring duties, with far reaching personal and societal consequences. Many go on toexperience persisting and/or relapsing symptoms. People with underlying health conditions,unvaccinated people, and those in whom the vaccine is not effective are at increased risk ofmore severe disease. 1 1 New ‘vaccine escaping’ variants may yet emerge, and the impact ofearly antiviral treatment on long COVID syndromes is as yet unknown. Early treatment withantiviral agents may prevent progression to the later phase of COVID-19. Therefore, there isan urgent need to identify treatments for COVID-19 for use in the community early on in theillness that speeds recovery and prevents the need for hospital admission.
Antiviral agents may reduce viral shedding, and use of antiviral agents may lead to theemergence of resistance to novel antiviral agents, but the impact of novel antiviral agents on
shedding and resistance is not yet known.

3.2 STUDY DESIGNPANORAMIC is an open label, prospective, individually randomised, platform, adaptive,
controlled clinical trial in community care. Trial arms will include:
Intervention arms: Novel antiviral agents (or combinations) targeting SARS-CoV-2, initially
specified by The UK Antivirals National Taskforce (ATF) and with capacity for sequential
introduction of each treatment regimen into the trial plus Usual Care. This report presents
the primary and secondary analysis for the Molnupiravir arm.
Comparator arm: Usual Care, defined as the currently recommended treatment delivered byresponsible clinicians. Usual Care was not mandated by the trial, as recommended treatments
may change and be tailored to individual characteristics, and self-care will vary. Use of overthe counter medication as well as key medications such as inhaled steroids and monoclonal
antibodies was captured. In this report only usual care participants randomised concurrently
and eligible to Molnupiravir were included.
Statistical Analysis Report

Effective: 22nd September 2022

Page 9 of 44

ATAG. Rep. 2024;2(2)107Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.3 ADAPTIVE DESIGN
The trial design allows for interim analysis and early stopping due to futility or efficacy andthe addition or removal of interventions. The number and timing of interim analyses depends
on the rate of recruitment. Full details of the design and decision criteria are given in the
Adaptive Design Report. Due to rapid recruitment no interim analyses were carried out on
the Molnupiravir arm. Paxlovid was added as an additional arm on 21st April 2022.

3.4 OBJECTIVES
Main Trial: The primary aim is to determine the effectiveness of selected antiviral agents inpreventing hospitalisation and/or death in higher-risk patients with a confirmed positive PCRor LFT SARS-CoV-2 test result (see Inclusion/Exclusion Criteria, below).

Main Study

Objectives

Endpoint Measures

Timepoint (s)Primary

To determine whether
antiviral treatment in thecommunity safely reduces
non-elective
hospitalisations/ deaths inhigher risk,

All cause, non-elective Within 28 days of
hospitalisation and/or randomisation
death, within 28 days
Patient report, Studyof randomisation
Partner report,
HES/ONS/medical
record data linkage

symptomatic patients withconfirmed COVID-19
SecondaryTo
explorewhether
antiviral treatment affects
1) Time to recovery 1-3) Participant(defined as the firstreports symptoms
instancethatadaily for 28 days
participant report ofand at 3 and 6
feeling recovered frommonths.
the illness)

Statistical Analysis Report
Page 10 of 44

108
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

1-3) Daily online
symptom scores.
Telephone call ortext on days 7, 14
and 28 if data is not
obtained throughthe online diary.

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

2) Participant reported
illness
severity,
reported by daily
rating of how wellparticipant
feels,
enabling identificationof sustained recovery.

Also, at 3 and 6
months.

3) Duration of severe
symptoms
andsymptom recurrence,
including time toalleviationofsymptoms, time toinitial reduction ofseverity of symptoms,
time to sustained
recovery, time tosustained alleviationof symptoms, numberof days of severe
symptoms
andworseningof
symptoms

4) Contacts withhealth services

Statistical Analysis Reportthe4) Contacts withhealth services
reported bypatients and/or
captured by reportsof patients’ medical
records

4) GP notes review if
available throughOxford RCGP RSC
network; otherwise,other sources ofroutinely collected
data after 28 days.
Medical notes

Effective: 22nd September 2022

Page 11 of 44

ATAG. Rep. 2024;2(2)109Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

review for up to 10
years.
5) New infections
householdin 5) Reports of new
infections in thehousehold fromdaily diary6) To investigate the 6) Evaluation ofsafety of antiviraloverall safety ofagentsdrugs by themonitoring ofadverse events (AEsas defined in the
ISAs)7) Longer term effects, 7) Well-being,
including proportion
symptoms andwith long covid, longheath care
covid
symptoms,
utilisation
health care use andwellness8) Cost effectiveness8) Resource use andcost data and EQ5D-5L5) Daily online
symptom scores ortelephone call or text
on days 7, 14 and 28

6) For the duration of
the antiviral course
and a defined period
after the antiviralfinishes (see ISAs)

7) Patient contact atthree and six
months, electronic
medical record
search for up to one
year8) Baseline and Day 28

3.5 TARGET POPULATION
Statistical Analysis Report
Page 12 of 44

110
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

The trial includes participants who test positive for SARS-CoV-2 infection and with ongoing
symptoms consistent with COVID-19, not hospitalised, and who are aged 50 years and over,or 18-49 years and considered clinically vulnerable (see Inclusion Criteria below).
3.5.1 INCLUSION C RITERIAParticipant is able and willing to provide informed consent, or their legal
representative is willing to provide informed consent
Symptoms attributable to COVID-19 started within the past 5 days and ongoing
A positive PCR or LFT SARS-CoV-2 test* Aged ≥50 years OR aged 18-49 years with oneof the following known underlying chronic health condition considered to make themclinically vulnerable:o chronic respiratory disease (including chronic obstructive pulmonary disease(COPD), cystic fibrosis and asthma requiring at least daily use of preventative
and/or reliever medication)o chronic heart or vascular diseaseo chronic kidney diseaseo chronic liver diseaseo chronic neurological disease (including dementia, stroke, epilepsy)
o severe and profound learning disabilityo Down’s syndromeo Diabetes mellitus (Type I or Type II)o immunosuppression: primary (e.g., inherited immune disorders resulting fromgenetic mutations, usually present at birth and diagnosed in childhood) or
secondary due to disease or treatment (e.g., sickle cell, HIV, cancer,
chemotherapy)
o solid organ, bone marrow and stem cell transplant recipientso morbid obesity (BMI >35)
o severe mental illness
o care home resident
o judged by recruiting clinician or research nurse (registered medical
practitioner or trained study nurse) to be clinically vulnerable* Any positive PCR test taken between two days before symptom onset and randomisation
qualifies. A positive lateral flow test in a symptomatic person qualifies for randomisation andwill be subject to pre-specified secondary analysis by type of diagnostic test.
Statistical Analysis Report

Effective: 22nd September 2022

Page 13 of 44

ATAG. Rep. 2024;2(2)111Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.5.2 EXCLUSION CRITERIAPatient currently admitted to hospital (inpatient)Previous randomisation in the PANORAMIC trial
Currently participating in a clinical trial of a therapeutic agent for acute COVID-19
Additional exclusions specific to each intervention arm, if any, as listed in theIntervention Specific Appendices (ISA’s) of currently open trial arms

3.5.3 A RISK FACTORS
Risk factors for severe COVID-19 by the Ministry of Health, Labour and Welfare (MHLW) in
Japan may not be available in the PANORAMIC study. Therefore, we propose the following 2
options to extract the data according to risk or modified risk factors that could be applicableto the Japanese setting.
1. Risk factors for severe COVID-19 defined by the Ministry of Health, Labour and Welfare(MHLW) is shown in Table 1.
TABLE 1 THE MINISTRY OF HEALTH, LABOUR AND WELFARE DEFINED RISK FACTORS FOR SEVERE COVID-19

Older adults aged ≥ 65 years

Hypertension

History of smoking

Malignant tumor

Dyslipidemia

Immunodeficiency after solidorgan transplantation

Chronic respiratory disease(i.e., COPD)

Cardiovascular disease

Use of immunomodulatory
agent orimmunosuppressant

Chronic renal disease

Cerebrovascular disease

HIV infection(particularly CD4 < 200/μL)

Diabetes

Obesity (BMI ≥ 30 kg/m )2

Clinical Management of Patients with COVID-19 in Japan version 9.0 (In Japanese)(https://www.mhlw.go.jp/content/000936655.pdf)
The diagnostic criteria for each risk factor have not been clearly indicated.

Statistical Analysis Report
Page 14 of 44

112
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

2. The modified definition of risk factors for severe COVID-19 is shown in Table 2. By

reviewing the article of the PANORAMIC study, we believe that we could define themodified risk factors as follows:
TABLE 2 THE MODIFIED DEFINITION OF RISK FACTORS FOR SEVERE COVID-19

Older adults aged ≥ 65 years

Hypertension

Current smoker(high blood pressure)
Cancer or chemotherapy

Chronic heart or vasculardiseaseSolid organ, bone marrowand stem cell transplant
recipients

Chronic respiratory disease

StrokeImmunosuppression

Chronic kidney disease

Obesity (BMI ≥ 30 kg/m )a2

HIV infection

Diabetes2

a: Obesity was originally defined as BMI ≥ 35 kg/m in the PANORAMIC study.

Statistical Analysis Report

Effective: 22nd September 2022

Page 15 of 44

ATAG. Rep. 2024;2(2)113

TABLE 3 THE DIAGNOSTIC CRITERIA FOR EACH RISK FACTOR IN THE PANORAMIC STUDY

Risk factor

Diagnostic criteria or definition

Older adults aged ≥ 65 years

Aged ≥ 65 years

Cancer or chemotherapy

Free text field mentions “cancer”. Only current cancers
included.

Chronic respiratory disease

Self-reported long term lung disease (including chronic
obstructive pulmonary disease (COPD), cystic fibrosis or
asthma requiring at least daily use of inhalers)

Chronic kidney disease

Self-reported long term kidney disease

Diabetes

Self-reported diabetes

Hypertension (high blood pressure)Self-reported high blood pressure

Chronic heart or vascular disease

Self-reported long term heart or vascular disease

StrokeSelf-reported long term neurological disease (including
dementia, stroke, epilepsy) or free text mentions stroke22

Obesity (BMI ≥ 30 kg/m )BMI ≥ 35 kg/m

Current smoker

Current smoker

Solid organ, bone marrow and stem Self-report have had a transplant (e.g. kidney, liver, heart,cell transplant recipientslung, bone marrow or stem cells)

Immunosuppression

Self-reported weakened immune system due to a condition
you were born with or due to disease or treatment (e.g. sickle
cell, HIV, cancer, chemotherapy)

HIV infection

Collected under immunosuppression.

Statistical Analysis Part 1 Report
Page 16 of 44

114
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.5.4 CONCOMITANT USE OF OTHER COVID-19 MEDICATIONSIn Japan, concomitant use of Molnupiravir with other COVID-19 medications (e.g., remdesivir)
is not recommended. We would like to exclude adults taking the following medications at theprescription of Molnupiravir (Table 4) from the dataset. On the other hand, we consider that
adults using the following medications after the completion of treatment with Molnupiravir
should not be excluded from the analysis because they are most likely to have progressed tosevere COVID-19 (e.g., adults prescribed the following medications 10 days after aprescription for Molnupiravir , adults who stopped treatment with Molnupiravir within 5 days
and subsequently received the following medications).

TABLE 4 THE DEFINITION OF OTHER COVID-19 MEDICATIONS

Remdesivir

Tixagevimab/cilgavimab

Any other neutralizing
antibody for COVID-19

Nirmatrelvir/ritonavir

Tocilizumab

Any otherimmunosuppressive
medications for COVID-19

Ensitrelvir

Baricitinib

Favipiravir

Casirivimab/imdevimab

Dexamethasone

Ivermectin

Sotrovimab

Any other antiviral
medications for COVID-19

Statistical Analysis Report

Effective: 22nd September 2022

Page 17 of 44

ATAG. Rep. 2024;2(2)115Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.6 INTERVENTIONS
Based on version 5.0 of the Protocol, the main randomisation was between the following
treatment arms (although not all treatments were available at all times and not all
participants were eligible for all treatments). However, the trial design accommodates
interventions being added and dropped as appropriate.
Usual care
Molnupiravir (recruitment between 8th December 2021 and 27th April 2022)
PAXLOVID (recruitment started 21st April 2022)

3.7 OUTCOMES
3.7.1 PRIMARY OUTCOME
The primary outcome is all-cause, non-elective hospitalisation and/or death within 28 days of
randomisation.
3.7.2 SECONDARY OUTCOMES
Secondary outcomes include time to self-reported recovery defined as the first instance thata participant reports feeling fully recovered from the illness; duration of symptoms; symptom
recurrence; daily rating of feeling well reported by participants; healthcare service use;
participant reported household infection rate; safety outcomes and cost-effectivenessoutcomes; symptoms and well-being at three and six months (with determination of
proportion with Long Covid) from randomisation.
3.7.2.1 TIME TO RECOVERYTime to recovery from COVID-19 infection within 28 days from randomisation, where
recovery is defined as the first instance that a participant reports feeling recovered.
3.7.2.2 PATIENT REPORTED ILLNESS SEVERITY

Participants are asked to rate how well they are feeling overall each day on a scale of 1-10 (1being the worst and 10 being the best). This is captured on the patients’ daily diaries andthe Call CRF.

Statistical Analysis Report
Page 18 of 44

116
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.7.2.3 DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE

Participants are asked to rate their symptoms of fever, cough, shortness of breath, fatigue(tiredness), muscle ache, nausea / vomiting, diarrhoea, loss of smell and/or taste, headache,dizziness, abdominal pain and generally feeling unwell on a four point scale from 0=no
problem, 1=mild problem, 2=moderate problem and 3=major problem.
This is captured on patients’ daily diaries and Call CRF.
The outcomes to be analysed include time to alleviation of symptoms, time to initial
reduction in severe symptoms, time to sustained recovery, time to sustained alleviation ofsymptoms, number of days of severe symptoms, number reporting severe symptoms atdays 7, 14 and 28, symptom recurrence and worsening of symptoms.
3.7.2.4 CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF
FOLLOW-UP (FU).

This is captured on patients’ daily diaries and telephone call CRFs.
3.7.2.5 NEW INFECTIONS IN THE HOUSEHOLD

Number of new infections within the household are captured within the participant daily
diaries and call CRF.
3.7.2.6 SAFETY OF ANTIVIRAL AGENTS

Common side effects, according to the SmPC, include dizziness, headache, diarrhoea, andnausea. These symptoms, potential medication side-effects and Serious Adverse Events(SAE) were collected from participant daily diaries, calls to participants/Study Partners, faceto-face visits with Hub clinicians, medical records, notes reviews, NHS Digital data extracts
and RCGP data downloads.
Pregnancy was recorded as an AE of Special Interest and was monitored from the start oftreatment for the 28-day trial duration.
3.7.2.7 LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS

The primary analysis is based on data collected through 28 days from randomisation;
however additional outcomes will be collected at 3 and 6 months follow-up to capture theStatistical Analysis Report

Effective: 22nd September 2022

Page 19 of 44

ATAG. Rep. 2024;2(2)117Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

long term outcomes of participants. This report covers outcomes for the first 28 days followup. The long term follow-up analysis will be covered in a future report.
3.7.2.8 HEALTHCARE MEASURES (EQ-5D-5L)

The EQ-5D-5L is a questionnaire consisting of 5 items (crosswalk) and a scale from 0 to 100(VAS) defining overall health. These were captured in participant’s daily diaries and call CRF.
Cost effectiveness outcomes will be reported in a separate health economic analysis report
and the analysis of this outcome will be described in a separate health economic analysis plan.

3.8 SAMPLE SIZE
The sample size calculation as stated in the protocol:
An estimated maximum of approximately 5300 participants per arm will be required toprovide approximately 90% power for detecting a 33% relative reduction in thehospitalisation/death in an experimental arm relative to Usual Care, based on the assumptionof an underlying 3% combined hospitalisation/death rate in the Usual Care arm, and anintervention lowering the hospitalisation/death rate to 2%. We expect fewer participants will
be needed to detect the same relative reduction if the event rate is larger than 3% in the
Usual Care arm, or if there is a greater reduction in the relative risk of hospitalisation/death
for a given intervention. However, should the event rate be lower than expected, then thetarget sample size will be increased to reflect this.
We recruited 25783 for the comparison of Molnupiravir with Usual Care.

3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE
Participants were randomised using a secure, fully validated and compliant web-based
randomisation system. Once deemed eligible, the medically qualified clinician or researchnurse from the central clinical team or Hub (as documented on the delegation log)
randomised the participant. Participants were randomised to one study arm using equal
allocation ratios corresponding to the number of arms they were eligible for that wererecruiting in the trial at that time. This started as 1:1 Molnupiravir :Usual Care, and once
Paxlovid was introduced on 21st April 2022 changed to 1:1:1 Molnupiravir :Usual
Care:Paxlovid. Patients had to be eligible for at least two arms (Usual Care and at least one
novel antiviral intervention). Stratification was by age ( < 50/ ≥ 50 years) and vaccination
status (see 2.2.3).
Statistical Analysis Report
Page 20 of 44

118
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

The randomisation database automatically alerted the relevant IMP distributor and theparticipant, trial team and legal representative if applicable were notified electronically of thetreatment allocation. If the participant did not have an email address, they were notified by
telephone.

3.10 DEFINITION OF POPULATION FOR ANALYSISThe analysis population will include participants as defined by the protocol eligibility criteria
and having at least one of the vulnerabilities as listed in Table 3.
As per ICH E9 guidance the following participants will be excluded from the analysis
population;(a) Participants randomised but subsequently found to be not eligible for randomization(b) Participants previously randomised to an arm in the PANORAMIC trial (subsequent
randomisations will be excluded)
In addition, the following participants will be excluded;(c) Participants who withdraw consent for data linkage and notes review and for whom no
outcome data has been collected.
(d) Participants taking medications listed in Table 4

3.10.1.1 P RIMARY ANALYSIS POPULATION

The primary analysis population is defined as participants who were randomised to
Molnupiravir or usual care and were eligible for randomisation to Molnupiravir , during thesame time frame when Molnupiravir was actively randomising (i.e. Concurrent Randomisedand Eligible Analysis Population). That is, participants who were eligible for Molnupiravir
and randomised to either Molnupiravir or usual care between 8th December 2021 and 27th
April 2022.
This includes participants for whom data are available with participants analysed according
to the groups they were randomly allocated to, regardless of deviation from protocol.

Statistical Analysis Report

Effective: 22nd September 2022

Page 21 of 44

ATAG. Rep. 2024;2(2)119Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

3.10.1.2 S ECONDARY ANALYSIS POPULATION

Analysis of the secondary outcomes for a given intervention will be based on the same
population as the primary analysis.

Statistical Analysis Report
Page 22 of 44

120
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

4 RESULTS
4.1 RECRUITMENT
Randomisation to the Molnupiravir arm was stopped on 27th April 2022. Participants
randomised to the Molnupiravir arm and Usual Care between 8th December 2021 and 27th
April 2022 (inclusive) are included in this report (see SAP for more details). During this time
111,383 participants were screened, 44,073 of whom were not eligible on screening and afurther 41,517 were excluded after GP eligibility check (see CONSORT in appendix forreasons). 25,793 in total were randomised, of which 25,783 were randomised between
Molnupiravir and Usual Care and were eligible for randomisation to Molnupiravir. 504
participants were randomised to other arms or randomised to Usual Care and not eligible for
Molnupiravir. 75 participants were excluded from the analysis population as they were foundto be ineligible after randomisation, leaving 25,708 participants in the analysis population.
Figure 2 shows the flow of participants for the subgroup analysis as presented in this report.
9520 participants were excluded as they did not have any risk factors for severe COVID-19
and a further 54 were excluded due to taking other medications. This leaves 16,134 in thesubgroup analysis population.

Statistical Analysis Report

Effective: 22nd September 2022

Page 23 of 44

ATAG. Rep. 2024;2(2)121Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

FIGURE 1 FLOW DIAGRAM OF TRIAL PARTICIPANTS FOR THE SUBGROUP POPULATIONPANORAMIC study participants (n=25,708)(12,774 Molnupiravir plus usual care group + 12,934 usual care group)↓↓→

Adults with risk factors for severe
COVID-19(n=16188 )↓→Excluded
Adults without any risk factors for severe COVID-19(n= 9520)a

Excluded
Adults using other COVID-19 medications (n=54)b
Remdesivir (n=0)
Nirmatrelvir/ritonavir (n=5)
Ensitrelvir (n=0)
Casirivimab/imdevimab (n=0)
Sotrovimab (n=0)
Tixagevimab/cilgavimab (n=0)
Tocilizumab (n=0)
Baricitinib (n=0)
Dexamethasone (n=1)
Any other antiviral medications for COVID-19 (n=2)
Any other neutralizing antibody for COVID-19 (n=46)
Any other immunosuppressive medications for COVID19 (n=0)
Favipiravir (n=0)
Ivermectin (n=0)↓

Eligible participants(n=16134)

Statistical Analysis Report
Page 24 of 44

122
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

4.2 BASELINE CHARACTERISTICS OF PARTICIPANTS
Baseline characteristics by randomised group and overall are given in Table 5 for the
concurrent and eligible population.
TABLE 5 BASELINE CHARACTERISTIC BY RANDOMISED GROUP FOR THE CONCURRENT AND ELIGIBLE POPULATION

Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=12821)
56.7 (12.5)[18.0 to 99.0]

Usual Care

Overall(N=12962)
56.5 (12.7)[18.0 to 98.0](N=25783)
56.6 (12.6)[18.0 to 99.0]

7451 (58.1%)
5367 (41.9%)
3 (0.0%)2.0 (2.0 to 2.0)7650 (59.0%)5308 (41.0%)
4 (0.0%)N/A

15101 (58.6%)
10675 (41.4%)
7 (0.0%)2.0 (2.0 to 2.0)

5.0 (4.0 to 6.0)

N/A

5.0 (4.0 to 6.0)

12088 (94.3%)
366 (2.9%)203 (1.6%)
78 (0.6%)
86 (0.7%)

12182 (94.0%)
434 (3.3%)
189 (1.5%)77 (0.6%)80 (0.6%)24270 (94.1%)
800 (3.1%)
392 (1.5%)
155 (0.6%)
166 (0.6%)

259 (2.0%)539 (4.2%)
1117 (8.7%)

272 (2.1%)
577 (4.5%)1114 (8.6%)

531 (2.1%)1116 (4.3%)
2231 (8.7%)

1496 (11.7%)

1464 (11.3%)

2960 (11.5%)6541 (51.0%)746 (5.8%)6591 (50.8%)768 (5.9%)

13132 (50.9%)1514 (5.9%)997 (7.8%)1063 (8.2%)

2060 (8.0%)1126 (8.8%)1113 (8.6%)

2239 (8.7%)

2491 (19.4%)
2679 (20.9%)2524 (19.7%)
2784 (21.7%)

2558 (19.7%)
2636 (20.3%)
2660 (20.5%)2767 (21.3%)

5049 (19.6%)5315 (20.6%)5184 (20.1%)
5551 (21.5%)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receipt of
medication*, median(IQR)
Days from start of symptoms to taking
medication*, median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
2
3
4
Statistical Analysis Part 1 Report288 (1.1%)

Effective: 22nd September 2022

Page 25 of 44

ATAG. Rep. 2024;2(2)123Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Current smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Statistical Analysis Report
Page 26 of 44

124
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir
plus usual care
(N=12821)
2343 (18.3%)
5965 (46.5%)

Usual Care

Overall(N=12962)
2341 (18.1%)
5902 (45.5%)(N=25783)
4684 (18.2%)
11867 (46.0%)1234 (9.6%)
1913 (14.9%)2569 (20.0%)3216 (25.1%)
3839 (29.9%)50 (0.4%)
11892 (92.8%)
12678 (98.9%)1182 (9.1%)
1956 (15.1%)
2592 (20.0%)3213 (24.8%)
3960 (30.6%)
59 (0.5%)
N/A
12830 (99.0%)2416 (9.4%)
3869 (15.0%)5161 (20.0%)6429 (24.9%)
7799 (30.2%)
109 (0.4%)
11892 (46.1%)
25508 (98.9%)87 (0.7%)519 (4.0%)11836 (92.3%)
236 (1.8%)
143 (1.1%)
795 (6.2%)

88 (0.7%)458 (3.5%)
12044 (92.9%)240 (1.9%)
132 (1.0%)805 (6.2%)

175 (0.7%)977 (3.8%)23880 (92.6%)476 (1.8%)275 (1.1%)
1600 (6.2%)

6111 (47.7%)4514 (35.2%)
1936 (15.1%)
260 (2.0%)6125 (47.3%)
4684 (36.1%)
1896 (14.6%)
257 (2.0%)12236 (47.5%)
9198 (35.7%)
3832 (14.9%)517 (2.0%)1251 (9.8%)
4721 (36.8%)5083 (39.6%)
1766 (13.8%)

1216 (9.4%)
4853 (37.4%)5127 (39.6%)
1766 (13.6%)

2467 (9.6%)
9574 (37.1%)
10210 (39.6%)3532 (13.7%)

3479 (27.1%)
4504 (35.1%)
3763 (29.4%)
1075 (8.4%)3425 (26.4%)
4791 (37.0%)3684 (28.4%)
1062 (8.2%)

6904 (26.8%)
9295 (36.1%)
7447 (28.9%)2137 (8.3%)

10440 (81.4%)
1847 (14.4%)478 (3.7%)
56 (0.4%)

10503 (81.0%)
1913 (14.8%)477 (3.7%)
69 (0.5%)

20943 (81.2%)
3760 (14.6%)955 (3.7%)
125 (0.5%)10600 (82.7%)
1649 (12.9%)

10732 (82.8%)
1681 (13.0%)

21332 (82.7%)3330 (12.9%)

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

Usual Care

Overall

Moderate problem
Major problem

Molnupiravir
plus usual care
(N=12821)
471 (3.7%)
101 (0.8%)(N=12962)
457 (3.5%)
92 (0.7%)(N=25783)
928 (3.6%)
193 (0.7%)

No problem
Minor problem
Moderate problem
Major problem

9066 (70.7%)2484 (19.4%)
825 (6.4%)
446 (3.5%)9402 (72.5%)
2368 (18.3%)
800 (6.2%)
392 (3.0%)

18468 (71.6%)4852 (18.8%)
1625 (6.3%)
838 (3.3%)

No problem
Minor problem
Moderate problem
Major problem

2702 (21.1%)
5194 (40.5%)3783 (29.5%)
1142 (8.9%)2820 (21.8%)5215 (40.2%)3838 (29.6%)
1089 (8.4%)5522 (21.4%)
10409 (40.4%)7621 (29.6%)2231 (8.7%)

No problem
Minor problem
Moderate problem
Major problem

8446 (65.9%)3087 (24.1%)
1096 (8.5%)
192 (1.5%)

8382 (64.7%)
3295 (25.4%)
1087 (8.4%)
198 (1.5%)

16828 (65.3%)
6382 (24.8%)
2183 (8.5%)
390 (1.5%)

No problem
Minor problem
Moderate problem
Major problem

10391 (81.0%)
1834 (14.3%)
524 (4.1%)
72 (0.6%)

10440 (80.5%)
1920 (14.8%)
542 (4.2%)
60 (0.5%)

20831 (80.8%)3754 (14.6%)
1066 (4.1%)
132 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

525 (4.1%)
5028 (39.2%)
5789 (45.2%)
1479 (11.5%)535 (4.1%)
5145 (39.7%)
5838 (45.0%)1444 (11.1%)

1060 (4.1%)
10173 (39.5%)
11627 (45.1%)
2923 (11.3%)

No problem
Minor problem
Moderate problem
Major problem

5670 (44.2%)
4813 (37.5%)2107 (16.4%)
231 (1.8%)5765 (44.5%)4955 (38.2%)
2042 (15.8%)200 (1.5%)

11435 (44.4%)9768 (37.9%)4149 (16.1%)
431 (1.7%)1410 (11.0%)6153 (48.0%)4502 (35.1%)
756 (5.9%)
5.1 (1.7) [0.0 to
10.0]1343 (10.4%)6384 (49.3%)
4509 (34.8%)
726 (5.6%)
5.2 (1.7) [0.0 to
10.0]2753 (10.7%)12537 (48.6%)
9011 (34.9%)1482 (5.7%)
5.1 (1.7) [0.0 to
10.0]1660 (12.9%)
6113 (47.7%)

1660 (12.8%)6019 (46.4%)

3320 (12.9%)
12132 (47.1%)

Loss of smell or taste, n(%)

Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean(SD) [min,max]People in household, n(%)
01
Statistical Analysis Report

Effective: 22nd September 2022

Page 27 of 44

ATAG. Rep. 2024;2(2)125Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

2
3
4
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)
Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir
plus usual care
(N=12821)
2129 (16.6%)
1765 (13.8%)808 (6.3%)
2990 (23.3%)
183 (1.4%)
26 (0.2%)

Usual Care

Overall(N=12962)
2176 (16.8%)
1979 (15.3%)
772 (6.0%)3152 (24.3%)
158 (1.2%)
19 (0.1%)(N=25783)
4305 (16.7%)
3744 (14.5%)
1580 (6.1%)
6142 (23.8%)341 (1.3%)
45 (0.2%)

3014 (23.5%)1000 (7.8%)
227 (1.8%)
159 (1.2%)
430 (3.4%)
36 (0.3%)
24 (0.2%)
1483 (11.6%)1125 (8.8%)
57 (0.4%)
1968 (15.3%)
198 (1.5%)2880 (22.5%)2295 (17.9%)

3171 (24.5%)
957 (7.4%)
253 (2.0%)
144 (1.1%)
438 (3.4%)
27 (0.2%)30 (0.2%)
1512 (11.7%)
1070 (8.3%)
71 (0.5%)
1944 (15.0%)
220 (1.7%)2902 (22.4%)
2341 (18.1%)

6185 (24.0%)
1957 (7.6%)
480 (1.9%)
303 (1.2%)
868 (3.4%)
63 (0.2%)
54 (0.2%)2995 (11.6%)
2195 (8.5%)
128 (0.5%)3912 (15.2%)
418 (1.6%)
5782 (22.4%)4636 (18.0%)*Median and interquartile range presented for non-normally distributed variables.

Statistical Analysis Report
Page 28 of 44

126
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 6 BASELINE CHARACTERISTIC OF THE SUBGROUP POPULATION BY RANDOMISED GROUP

Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=8088)
59.2 (13.4)[18.0 to 99.0]

Usual Care

Overall(N=8046)59.2 (13.6)[18.0 to 98.0](N=16134)59.2 (13.5)[18.0 to 99.0]4452 (55.0%)3634 (44.9%)
2 (0.0%)2.0 (2.0 to 2.0)4450 (55.3%)
3595 (44.7%)
1 (0.0%)N/A

8902 (55.2%)
7229 (44.8%)
3 (0.0%)2.0 (2.0 to 2.0)

4.0 (3.0 to 5.0)

N/A

4.0 (3.0 to 5.0)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receipt of
medication*, median(IQR)
Days from start of symptoms to taking medication*,
median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
23
4
5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
Statistical Analysis Part 1 Report6434 (79.5%)6434 (39.9%)7628 (94.3%)
233 (2.9%)
117 (1.4%)
53 (0.7%)
57 (0.7%)7573 (94.1%)
269 (3.3%)
105 (1.3%)
53 (0.7%)
46 (0.6%)

15201 (94.2%)
502 (3.1%)
222 (1.4%)
106 (0.7%)103 (0.6%)

256 (3.2%)
537 (6.6%)1115 (13.8%)271 (3.4%)
573 (7.1%)
1108 (13.8%)

527 (3.3%)1110 (6.9%)
2223 (13.8%)1488 (18.4%)

1463 (18.2%)

2951 (18.3%)4545 (56.2%)
37 (0.5%)4474 (55.6%)
35 (0.4%)

9019 (55.9%)
72 (0.4%)

43 (0.5%)56 (0.7%)

99 (0.6%)

67 (0.8%)66 (0.8%)

133 (0.8%)623 (7.7%)
1698 (21.0%)
1861 (23.0%)2084 (25.8%)
1822 (22.5%)3680 (45.5%)633 (7.9%)
1660 (20.6%)
1898 (23.6%)2063 (25.6%)
1792 (22.3%)
3585 (44.6%)

1256 (7.8%)3358 (20.8%)3759 (23.3%)
4147 (25.7%)3614 (22.4%)
7265 (45.0%)835 (10.3%)1250 (15.5%)
1659 (20.5%)808 (10.0%)1265 (15.7%)
1629 (20.2%)1643 (10.2%)2515 (15.6%)
3288 (20.4%)

Effective: 22nd September 2022

Page 29 of 44

ATAG. Rep. 2024;2(2)127Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Current smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Moderate problem
Major problem
Loss of smell or taste, n(%)
No problem
Minor problem
Moderate problem
Statistical Analysis Report
Page 30 of 44

128
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir
plus usual care
(N=8088)
2011 (24.9%)2305 (28.5%)
28 (0.3%)
7495 (92.7%)
7994 (98.8%)

Usual Care

Overall(N=8046)
1967 (24.4%)
2340 (29.1%)
37 (0.5%)
7974 (99.1%)(N=16134)
3978 (24.7%)4645 (28.8%)65 (0.4%)
7495 (46.5%)
15968 (99.0%)

54 (0.7%)
290 (3.6%)7440 (92.0%)
210 (2.6%)
94 (1.2%)
787 (9.7%)

48 (0.6%)
249 (3.1%)
7464 (92.8%)
213 (2.6%)
72 (0.9%)799 (9.9%)102 (0.6%)539 (3.3%)
14904 (92.4%)423 (2.6%)
166 (1.0%)
1586 (9.8%)

3871 (47.9%)2834 (35.0%)1221 (15.1%)
162 (2.0%)3786 (47.1%)
2891 (35.9%)1198 (14.9%)
171 (2.1%)

7657 (47.5%)5725 (35.5%)2419 (15.0%)333 (2.1%)

803 (9.9%)2960 (36.6%)
3187 (39.4%)
1138 (14.1%)

788 (9.8%)2952 (36.7%)
3186 (39.6%)1120 (13.9%)

1591 (9.9%)5912 (36.6%)6373 (39.5%)2258 (14.0%)2264 (28.0%)2734 (33.8%)
2371 (29.3%)
719 (8.9%)2155 (26.8%)2934 (36.5%)
2290 (28.5%)
667 (8.3%)

4419 (27.4%)5668 (35.1%)
4661 (28.9%)1386 (8.6%)6603 (81.6%)
1151 (14.2%)
298 (3.7%)
36 (0.4%)6564 (81.6%)
1140 (14.2%)
288 (3.6%)
54 (0.7%)

13167 (81.6%)
2291 (14.2%)
586 (3.6%)
90 (0.6%)

6599 (81.6%)
1073 (13.3%)
331 (4.1%)
85 (1.1%)

6593 (81.9%)1094 (13.6%)
296 (3.7%)
63 (0.8%)

13192 (81.8%)2167 (13.4%)
627 (3.9%)
148 (0.9%)5660 (70.0%)
1589 (19.6%)
541 (6.7%)

5802 (72.1%)
1473 (18.3%)
512 (6.4%)

11462 (71.0%)3062 (19.0%)1053 (6.5%)

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

Molnupiravir
plus usual care
(N=8088)298 (3.7%)

Usual Care

Overall(N=8046)259 (3.2%)(N=16134)
557 (3.5%)

No problem
Minor problem
Moderate problem
Major problem

1753 (21.7%)
3293 (40.7%)2316 (28.6%)
726 (9.0%)

1837 (22.8%)3205 (39.8%)2337 (29.0%)
667 (8.3%)

3590 (22.3%)
6498 (40.3%)4653 (28.8%)1393 (8.6%)

No problem
Minor problem
Moderate problem
Major problem

5306 (65.6%)
1946 (24.1%)
701 (8.7%)
135 (1.7%)5174 (64.3%)2034 (25.3%)
699 (8.7%)
139 (1.7%)10480 (65.0%)3980 (24.7%)
1400 (8.7%)
274 (1.7%)

No problem
Minor problem
Moderate problem
Major problem

6541 (80.9%)1143 (14.1%)
359 (4.4%)
45 (0.6%)

6466 (80.4%)
1191 (14.8%)351 (4.4%)
38 (0.5%)

13007 (80.6%)2334 (14.5%)710 (4.4%)
83 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

347 (4.3%)
3162 (39.1%)
3637 (45.0%)
942 (11.6%)345 (4.3%)
3212 (39.9%)3591 (44.6%)
898 (11.2%)

692 (4.3%)
6374 (39.5%)
7228 (44.8%)
1840 (11.4%)

No problem
Minor problem
Moderate problem
Major problem

3563 (44.1%)
3019 (37.3%)
1375 (17.0%)
131 (1.6%)3583 (44.5%)3021 (37.5%)1315 (16.3%)
127 (1.6%)7146 (44.3%)
6040 (37.4%)
2690 (16.7%)
258 (1.6%)

837 (10.3%)
3811 (47.1%)
2910 (36.0%)
530 (6.6%)
5.2 (1.7) [0.0 to
10.0]802 (10.0%)3805 (47.3%)
2968 (36.9%)
471 (5.9%)
5.2 (1.7) [0.0 to
10.0]1639 (10.2%)7616 (47.2%)
5878 (36.4%)
1001 (6.2%)
5.2 (1.7) [0.0 to
10.0]1106 (13.7%)
4167 (51.5%)
1211 (15.0%)
938 (11.6%)
446 (5.5%)
220 (2.7%)
1607 (19.9%)93 (1.1%)

1127 (14.0%)4104 (51.0%)1197 (14.9%)
998 (12.4%)
412 (5.1%)
208 (2.6%)
1696 (21.1%)
84 (1.0%)2233 (13.8%)8271 (51.3%)2408 (14.9%)
1936 (12.0%)858 (5.3%)
428 (2.7%)3303 (20.5%)
177 (1.1%)

Major problem
Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean (SD) [min,max]People in household, n(%)
0
1
2
3
4
5
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)
Statistical Analysis Report

Effective: 22nd September 2022

Page 31 of 44

ATAG. Rep. 2024;2(2)129Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir
plus usual care
(N=8088)
0 (0.0%)Usual Care

Overall(N=8046)
0 (0.0%)(N=16134)
0 (0.0%)1620 (20.0%)993 (12.3%)
222 (2.7%)
131 (1.6%)295 (3.6%)
32 (0.4%)
24 (0.3%)
1473 (18.2%)1110 (13.7%)
55 (0.7%)
1957 (24.2%)
143 (1.8%)2854 (35.3%)
1683 (20.8%)1718 (21.4%)
952 (11.8%)
253 (3.1%)
119 (1.5%)281 (3.5%)
26 (0.3%)
26 (0.3%)
1507 (18.7%)1055 (13.1%)
69 (0.9%)
1932 (24.0%)
159 (2.0%)2895 (36.0%)
1615 (20.1%)3338 (20.7%)
1945 (12.1%)
475 (2.9%)250 (1.5%)
576 (3.6%)
58 (0.4%)
50 (0.3%)2980 (18.5%)2165 (13.4%)
124 (0.8%)3889 (24.1%)
302 (1.9%)5749 (35.6%)
3298 (20.4%)*Median and interquartile range presented for non-normally distributed variables.

Statistical Analysis Report
Page 32 of 44

130
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 7 PREVALENCE OF RISK FACTORS FOR SEVERE COVID-19 (MODIFIED DEFINITION) AMONG ELIGIBLE PARTICIPANTS

Risk factors
Older adults aged ≥ 65 years
Cancer or chemotherapy
Chronic respiratory disease
Chronic kidney disease
Diabetes
Hypertension (high blood pressure)
Chronic heart or vascular disease
StrokeObesity (BMI ≥ 35 kg/m2)
Current smoker
Solid organ, bone marrow and stem celltransplant recipients
Immunosuppression and HIV infection

Statistical Analysis Part 1 Report

Molnupiravir
plus usual care(n=8088)

Usual care

3396 (42.0%)
10 (0.1%)
1620 (20.0%)222 (2.7%)
1473 (18.2%)
2854 (35.3%)
993 (12.3%)
16 (0.2%)
1957 (24.2%)
787 (9.7%)
55 (0.7%)3415 (42.4%)
14 (0.2%)
1718 (21.4%)
253 (3.1%)
1507 (18.7%)2895 (36.0%)
952 (11.8%)
24 (0.3%)
1932 (24.0%)
799 (9.9%)69 (0.9%)1110 (13.7%)1055 (13.1%)(n=8046)

Effective: 22nd September 2022

Page 33 of 44

ATAG. Rep. 2024;2(2)131Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

4.3 NUMBER ANALYSED
Of the 16134 participants included in the subgroup analysis 15703 (97.3%) had data collectedon hospitalisation/death and so could be included in the primary analysis. 15324 (95.0%)
completed any diaries or calls and so could be included in the secondary analysis.

4.4 PRIMARY ANALYSES
4.4.1 PRIMARY OUTCOME
The primary outcome is defined as all cause unplanned hospitalisation or death fromrandomisation to 28 days follow-up. Data is derived from participant daily diaries, phone calls,
and routine electronic data. If a primary endpoint is reported from any data source then thisoutcome is counted as “yes”. If the participant has completed 28 days follow-up and is not
hospitalised or is lost to follow-up but has been checked against routine electronic data andno hospitalisation or death is found then this outcome is coded “no”. An odds ratio<1 suggests
fewer hospitalisations/deaths in the Molnupiravir arm. The results show probability ofsuperiority just below 0.5, indicating equivalence of Molnupiravir with Usual Care.
TABLE 8 PRIMARY OUTCOME

Molnupiravir
plus usual care
(N=8088)
81/7933 (1.0%)

Hospitalization ordeath
Deaths3/7933
Hospitalizations
79/7933 (1.0%)*OR < 1 favours Molnupiravir

Statistical Analysis Report
Page 34 of 44

132
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Usual care
(N=8046)

Estimated treatment
effect (95% BCI)

78/7770 (1.0%)

1.022 (0.738 to 1.382)

Probabilityofsuperiority
0.47785/777076/7770 (1.0%)

Not estimable
1.023 (0.737 to 1.385)

0.4762

Effective: 22nd September 2022

4.4.2 SECONDARY OUTCOMES
Definition of outcomes:
1. Time to recovery: time to first reporting of feeling recovered in diary or call. A hazard ratio>1 suggests faster recovery in the Molnupiravirarm
2. Time to sustained recovery: time to reporting recovery in diary or call followed by no subsequent relapse. A hazard ratio>1 favours
Molnupiravir.
3. Early sustained recovery: reported recovered within the first 14 days with no subsequent relapse. An odds ratio >1 favours Molnupiravir.
4. Alleviation of symptoms: Time to first rating of symptoms as mild/none. If all symptoms are rated mild/none at baseline then theparticipant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
5. Sustained alleviation of symptoms: Time to rating of symptoms as mild/none followed by no subsequent relapse. If all symptoms are
rated mild/none at baseline then the participant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
6. Reduction of symptoms: Time to reduction of all symptoms by at least one grade. A hazard ratio>1 favours Molnupiravir.
7. Rating of how well participant feels (1 worst, 10 best): Participant rating of wellness at each day. Estimates represent the meandifferences and a values >0 favours Molnupiravir.
8. Household infections: Participant reported another member of their household becoming unwell with COVID-19. Participants who live
alone at baseline are excluded. An odds ratio <1 favours Molnupiravir (fewer household infections). For number of infections a rate ratio<1 favours Molnupiravir.
The following assumptions have been made in the following analysis:
1. For time to event outcomes participants are censored at the last point of contact or 28 days, whichever is sooner. For time to sustained
recovery if a participant reported feeling recovered and is subsequently lost to follow-up it is assumed they remained recovered (lastStatistical Analysis Part 1 Report

Effective: 22nd September 2022

Page 35 of 44

ATAG. Rep. 2024;2(2)133Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR

2.
3.
4.
5.

Statistical Analysis Part 1 Report Version 1.0

observation carried forward). A similar principle is used for time to sustained alleviation of symptoms. Therefore the only missing data
for time to event outcomes is participants who completed no diary data
For early sustained recovery if a participant is lost to follow-up, such that it is not possible to establish if they remained recovered, thenthis outcome is treated as missing.
For time to alleviation and time to reduction of symptoms if a symptom is missing but the participant reported feeling recovered, thatsymptom is assumed to be rated “none”.
For household infections if a participant has incomplete diaries but has not stated that they have an infection within the household thisoutcome is assumed to be zero. Participants who live alone at baseline are excluded from the analysis.
Analysis of daily symptom scores uses a frequentist mixed model, due to the computational difficultly running the Bayesian model with
the number of parameters.

Results in Table 9 have showed that the estimated median (95% BCI) TTR from the Bayesian model were 10.022 (9.775 to 10.274) days and13.940 (13.447 to 14.445) days, respectively, which suggested that Molnupiravir has a nearly 4 days benefit in TTR compared with Usual Care.
There was a significant benefit in early sustained recovery by 9.5%, i.e. recovered within the first 14 days and remained well until day 28 fromrandomisation, in Molnupiravir group (32.8%) compared to Usual Care (23.3%) (OR = 1.6; 95% BCI (1.52 to 1.77)).

Statistical Analysis Report
Page 36 of 44

134
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

TABLE 9 SECONDARY OUTCOMES

Molnupiravir plus
usual care (N=8088)

Usual care

Estimated treatment
effect (95% BCI)

Estimated benefit (95%
BCI)

Probability ofsuperiority

First reported recovery

6177/7850 (78.7%)

5195/7474 (69.5%)

Days to first reported recovery

10.022 (9.775 to 10.274)

Early sustained recovery

2360/7188 (32.8%)

13.940 (13.447 to 14.445)

1.353 (1.301 to 1.403) *-3.920 (-4.453 to -3.384) †>0.99

1547/6649 (23.3%)

1.638 (1.517 to 1.768) **Sustained recovery

5401/7850 (68.8%)4512/7474 (60.4%)

Days to sustained recovery

19.746 (19.275 to 20.232)

23.272 (22.882 to 23.611)

Alleviation of all symptoms

5674/6132 (92.5%)5136/5816 (88.3%)

Days to alleviations of all symptoms

3.694 (3.589 to 3.802)

4.388 (4.252 to 4.535)

Sustained alleviation of all symptoms

5125/6132 (83.6%)

4609/5816 (79.2%)

Days to sustained alleviation of all
symptoms

9.374 (8.974 to 9.799)

11.038 (10.585 to 11.525)

Initial reduction of symptom severity

6821/7835 (87.1%)

6010/7464 (80.5%)

Days to initial reduction of symptom
severity

7.349 (7.167 to 7.534)

Day 7
Day 14(N=8046)>0.99

1.237 (1.189 to 1.288) *-3.524 (-4.093 to -2.926) †>0.99

1.188 (1.143 to 1.234) *-0.695 (-0.856 to -0.535) †>0.99

1.134 (1.090 to 1.178) *-1.669 (-2.221 to -1.111) †>0.99

9.162 (8.929 to 9.404)

1.278 (1.234 to 1.322) *-1.812 (-2.086 to -1.537) †>0.99

7.3 (1.8) [7471]

6.8 (1.8) [6927]

0.5 (0.5 to 0.6) ¶P<0.001 ll

7.8 (1.7) [7276]

7.6 (1.7) [6605]

0.3 (0.2 to 0.3) ¶P<0.001 ll

Day 218.1 (1.7) [6782]

7.9 (1.7) [5927]

0.1 (0.1 to 0.2) ¶P<0.001 ll

Day 288.4 (1.6) [6746]

8.2 (1.6) [6062]

0.1 (0.1 to 0.2) ¶P<0.001 ll

2542/ (31.4%)

2469/ (30.7%)

0.961 (0.896 to 1.025) **0.8873404/7849 (5.1%)

510/7470 (6.8%)

0.738 (0.645 to 0.841) **>0.99

Participant rating of wellness

New infections in household
Contact with health and social careservices
NHS 111
Statistical Analysis Part 1 Report

Effective: 22nd September 2022

Page 37 of 44

ATAG. Rep. 2024;2(2)135Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR

Statistical Analysis Part 1 Report Version 1.0

Molnupiravir plus
usual care (N=8088)

Usual care
(N=8046)

Estimated treatment
effect (95% BCI)

Estimated benefit (95%
BCI)

General practitioner

1673/7848 (21.3%)

1885/7470 (25.2%)

0.797 (0.738 to 0.860) **>0.99

Ambulance service (nothospitalised)

225/7845 (2.9%)

203/7460 (2.7%)

1.060 (0.868 to 1.281) **0.2966

Community nurse

193/7849 (2.5%)

216/7468 (2.9%)0.854 (0.696 to 1.035) **0.9466

Physiotherapist

98/7849 (1.2%)

57/7468 (0.8%)

1.659 (1.184 to 2.270) **0.0020Counsellor

53/7849 (0.7%)66/7468 (0.9%)

0.762 (0.520 to 1.071) **0.9419Social worker

18/7849 (0.2%)

24/7468 (0.3%)

0.736 (0.384 to 1.281) **0.8785Home carer

74/7848 (0.9%)73/7466 (1.0%)

0.973 (0.695 to 1.328) **0.5979

Occupational therapist

167/7848 (2.1%)

146/7468 (2.0%)

1.100 (0.870 to 1.366) **0.2201

Hospital emergency department

445/7849 (5.7%)

401/7468 (5.4%)

1.056 (0.916 to 1.213) **0.2334Outpatient respiratory clinic

152/7849 (1.9%)

173/7467 (2.3%)

0.835 (0.665 to 1.038) **0.9492

Hospital at home for COVID-19

253/7849 (3.2%)

298/7468 (4.0%)

0.803 (0.673 to 0.947) **0.9960

Other services

429/7849 (5.5%)

469/7467 (6.3%)

0.862 (0.751 to 0.985) **0.9849*Estimated HR derived from a piecewise exponential model adjusted for age, comorbidity and vaccination status. HR > 1 favours Molnupiravir.

Probability ofsuperiority†Model based estimated benefit median time to event > 0 favours Molnupiravir.
ll Frequentist model estimates display p-value rather than a probability.
¶Linear mixed effect model adjusted for age, comorbidity and vaccination status. Participant fitted as a random effect. Estimated mean difference > 0 favours Molnupiravir.
**Bayesian logistic regression, adjusted for, age, comorbidity and vaccination status

Statistical Analysis Report
Page 38 of 44

136
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

The following plot shows the actual data for time to recovery (solid lines) and the modelbased estimates (dashed lines). The model-based estimates are derived from the piecewise
exponential where all the standardised covariates are set to zero (corresponding to thesample average).
FIGURE 2 KAPLAN-MEIER CURVE AND MODEL ESTIMATES FOR TIME TO RECOVERY

Statistical Analysis Part 1 Report

Effective: 22nd September 2022

Page 39 of 44

ATAG. Rep. 2024;2(2)1374.5 SUBGROUP ANALYSES
Frequentist model estimates are presented for the moderation analysis of the primary
outcome. An odds ratio<1 favours Molnupiravir. P-values indicate the test for the interaction
and statistically significant p-value suggests a differential effect size between subgroups.
FIGURE 3 FOREST PLOT OF SUBGROUP ANALYSIS OF PRIMARY OUTCOME

Statistical Analysis Part 1 Report
Page 40 of 44

138
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022

Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0
Frequentist model estimates are presented for the moderation analysis of time to recovery.
A hazard ratio>1 favours Molnupiravir. P-values indicate the test for the interaction and astatistically significant p-value suggests a differential effect size between subgroups.
FIGURE 4 FOREST PLOT OF SUBGROUP ANALYSIS OF TIME TO RECOVERY

Statistical Analysis Report

Effective: 22nd September 2022

Page 41 of 44

ATAG. Rep. 2024;2(2)139Primary Care
Clinical Trials Unit

PANORAMIC-MOLNUPIRAVIR Statistical Analysis Part 1 Report Version 1.0

4.6 VIROLOGY SUB-STUDY ANALYSISTABLE 10 SUMMARY OF VIROLOGY SUB-STUDY

Number of participants, nIntensive samples cohortLess intensive samples cohort
At least 7 samples received from
intensive samples cohort, n/N (%)
At least 2 samples received fromless intensive sample cohort, n/N(%)
Female, n/N (%)
Intensive samples cohortLess intensive samples cohort
OverallAge, mean (SD)Intensive samples cohortLess intensive samples cohort
OverallStatistical Analysis Report
Page 42 of 44

140
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Molnupiravir
plus usual care

Usual Care

Total

23
126
23/23 (100%)30
149
29/30 (96.7%)53
275
52/53 (98.1%)

126/126 (100%)

149/149 (100%)275/275(100%)

11/23 (47.8%)
67/126 (53.2%)

16/30 (53.3%)
87/129 (58.4%)

78/149 (52.3%)

103/159(57.5%)

27/53 (50.9%)
154/255(56.0%)
181/308(55.2%)

61.0 (8.7)
61.3 (11.0)
61.2 (10.7)

63.6 (9.5)
62.0 (11.4)
62.3 (11.1)

62.5 (9.1)
61.7 (11.2)
61.8 (10.9)

Effective: 22nd September 2022

TABLE 11 VIROLOGY SUBSTUDY

Intensive samples
Undetectable viral load, n/N(%)
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7*
Viral load, mean(sd)
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
All samples
Undetectable viral load, n/N(%)
Day 5
Day 14
Viral load, mean(sd)Day 5
Day 14

Molnupiravir
plus usual care

Usual care

Estimated treatment
effect (95% CI)

P value

0/23
0/23
1/22 (0.5%)
3/20 (15%)
3/20 (15 %)3/20 (15 %)

0/29
0/29
0/30
0/29
1/29 (0.3%)
1/29 (0.3%)

5.508 (0.501 to 60.549) †6.041 (0.306 to 119.352) †0.16300.23747.318 (1.173)
6.794 (1.457)
6.196 (1.408)
5.409 (1.541)
4.590 (1.574)
4.276 (1.477)
3.959 (1.245)

7.346 (1.266)
7.077 (1.144)
6.435 (1.148)
6.000 (1.182)
5.781 (1.133)
5.412 (1.340)
4.930 (1.413)-0.342 (-0.908 to 0.225) ‡-0.270 (-0.831 to 0.292) ‡-0.606 (-1.164 to -0.048) ‡-1.221 (-1.782 to -0.660) ‡-1.151 (-1.709 to -0.593) ‡-0.986 (-1.543 to -0.428) ‡0.23680.34640.0333<0.0001
0.00010.0005

11/144 (7.6%)
55/123 (44.7%)

5/167 (3.0%)
78/152 (51.3%)

3.684 (0.920 to 14.763)**0.664 (0.307 to 1.435)**

0.06550.29724.473 (1.567)
2.940 (1.357)

5.576 (1.300)
2.526 (1.145)-1.133 (-1.548 to -0.718) ‡0.318 (-0.008 to 0.644) ‡<0.0001
0.0556* Primary outcome† Firth logistic regression adjusting for sex, age, and baseline log10(viral load). Adjusted OR > 1 favours Molnupiravir‡Mixed effect model adjusting for sex, age, and baseline log10(viral load); adjusted difference < 0 favours Molnupiravir** Mixed effects logistic regression adjusting for sex, age, and baseline log 10(viral load). Adjusted OR > 1 favours
Molnupiravir

Statistical Analysis Part 1 Report

Effective: 22nd September 2022

Page 43 of 44

ATAG. Rep. 2024;2(2)141

~~~ END OF REPORT ~~~Statistical Analysis Part 1 Report
Page 44 of 44

142
ATAG. Rep.保健医療経済評価研究センター（C2H）
2024;2(2)
国立保健医療科学院

Effective: 22nd September 2022