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Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic

Suzuki et al., Clinical and Experimental Medicine, doi:10.1007/s10238-022-00949-3 (date from preprint)

Oct 2022

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Retrospective 1,921 patients in Japan, showing lower progression with molnupiravir use.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

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risk of death, 100% higher, RR 2.00, p = 0.60, treatment 2 of 230 (0.9%), control 3 of 690 (0.4%), propensity score matching.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 1.00, treatment 0 of 230 (0.0%), control 1 of 690 (0.1%), NNT 690, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), propensity score matching.

risk of progression, 53.0% lower, RR 0.47, p = 0.04, treatment 9 of 230 (3.9%), control 58 of 690 (8.4%), NNT 22, adjusted per study, odds ratio converted to relative risk, propensity score matching, multivariable.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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Suzuki et al., 5 Oct 2022, retrospective, Japan, peer-reviewed, 53 authors. Contact: shibatay@fmu.ac.jp.

This Paper Molnupiravir All

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic

Yasuhito Suzuki, Yoko Shibata, Hiroyuki Minemura, Takefumi Nikaido, Yoshinori Tanino, Atsuro Fukuhara, Ryuzo Kanno, Hiroyuki Saito, Shuzo Suzuki, Yayoi Inokoshi, Eiichiro Sando, Hirofumi Sakuma, Tatsuho Kobayashi, Hiroaki Kume, Masahiro Kamimoto, Hideko Aoki, Akira Takama, Taku Iizuka, Takamichi Kamiyama, Masaru Nakayama, Kiyoshi Saito, Koichi Tanigawa, Masahiko Sato, Yuichi Waragai, Toshiyuki Kambe, Norio Kanzaki, Teruhisa Azuma, Hiromasa Okamoto, Keiji Sakamoto, Yuichi Nakamura, Hiroshi Ohtani, Mitsuru Waragai, Shinsaku Maeda, Tokiya Ishida, Keishi Sugino, Wataru Abe, Yasuhiko Tsukada, Tomoyoshi Lee, Ryuki Yamada, Riko Sato, Takumi Onuma, Hikaru Tomita, Mikako Saito, Natsumi Watanabe, Mami Rikimaru, Takaya Kawamata, Julia Morimoto, Ryuichi Togawa, Yuki Sato, Junpei Saito, Kenya Kanazawa, Sugihiro Hamaguchi, Ken Iseki

Clinical and Experimental Medicine, doi:10.1007/s10238-022-00949-3

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase. Keywords Molnupiravir • COVID-19 • Omicron variant • Real-world • Effectiveness Abbreviations CI Confidence interval CKD Chronic kidney disease COVID-19 Coronavirus disease 2019 CRP C-reactive protein CT Computed tomography ECMO Extracorporeal membrane oxygenation IPTW Inverse probability of treatment weighting LDH Lactate dehydrogenase OR Odds ratio SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SMD Standardized mean difference * Yoko Shibata

Author contribution Conception and design: YS and YS. Analysis and drafting the manuscript: YS and YS. Data curation: all authors. Final approval of the manuscript: all authors. Declarations Conflict of interest Y Shibata and H Minemura received lecture fees and research grants from Chugai Pharmaceutical Co., Ltd. Y Shibata and J Saito received lecture fees from GlaxoSmithKline K.K. The other authors report no conflicts of interest related to this study. Ethic approval This study was performed in line with the principles of the Declaration of Helsinki. The protocol was approved by the local ethical committee. Consent to publication The authors have seen the final version of the manuscript and approved submission for publication. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the..

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' 'Accessed 1 June 2022.'}, { 'key': '949_CR13', 'unstructured': 'Japan Ministry of Health Labor and Welfare. Clinical Management of ' 'patients with COVID-19: A guide for front-line healthcare workers. ' 'Available at: ' 'https://www.niph.go.jp/h-crisis/wp-content/uploads/2020/07/20200706103735_content_000646531.pdf. ' 'Accessed 1 June 2022.'}, { 'key': '949_CR14', 'doi-asserted-by': 'publisher', 'first-page': '3775', 'DOI': '10.3390/jcm10173775', 'volume': '10', 'author': 'A Yamamoto', 'year': '2021', 'unstructured': 'Yamamoto A, Wada H, Ichikawa Y, et al. Evaluation of biomarkers of ' 'severity in patients with COVID-19 infection. J Clin Med. 2021;10:3775. ' 'https://doi.org/10.3390/jcm10173775.', 'journal-title': 'J Clin Med'}, { 'key': '949_CR15', 'doi-asserted-by': 'publisher', 'unstructured': 'Shibata Y, Minemura H, Suzuki Y, et al. Development and external ' 'validation of the DOAT and DOATS scores: simple decision support tools ' 'to identify disease progression among nonelderly patients with ' 'mild/moderate COVID-19. medRxiv [Preprint] December 14 2021. Available ' 'from:\u3000' 'https://www.medrxiv.org/content/https://doi.org/10.1101/2021.12.13.21267698v1.', 'DOI': '10.1101/2021.12.13.21267698v1'}, { 'key': '949_CR16', 'doi-asserted-by': 'publisher', 'first-page': '457', 'DOI': '10.2188/jea.JE20210145', 'volume': '31', 'author': 'K Shiba', 'year': '2021', 'unstructured': 'Shiba K, Kawahara T. using propensity scores for causal inference: ' 'pitfalls and tips. J Epidemiol. 2021;31:457–63. ' 'https://doi.org/10.2188/jea.JE20210145.', 'journal-title': 'J Epidemiol'}, { 'key': '949_CR17', 'doi-asserted-by': 'publisher', 'first-page': '150', 'DOI': '10.1002/pst.433', 'volume': '10', 'author': 'PC Austin', 'year': '2011', 'unstructured': 'Austin PC. 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' 'https://doi.org/10.1177/1179551421990675.', 'journal-title': 'Clin Med Insights Endocrinol Diabetes', 'DOI': '10.1177/1179551421990675'}, { 'key': '949_CR20', 'doi-asserted-by': 'crossref', 'unstructured': 'Austin PC, Stuart EA. Moving towards best practice when using inverse ' 'probability of treatment weighting (IPTW) using the propensity score to ' 'estimate causal treatment effects in observational studies. Stat Med ' '2015; 34:3661–79.', 'DOI': '10.1002/sim.6607'}, { 'key': '949_CR21', 'doi-asserted-by': 'publisher', 'first-page': '319', 'DOI': '10.1038/s41422-022-00619-9', 'volume': '32', 'author': 'D Bojkova', 'year': '2022', 'unstructured': 'Bojkova D, Widera M, Ciesek S, Wass MN, Michaelis M, Cinatl J Jr. ' 'Reduced interferon antagonism but similar drug sensitivity in Omicron ' 'variant compared to Delta variant of SARS-CoV-2 isolates. Cell Res. ' '2022;32:319–21. https://doi.org/10.1038/s41422-022-00619-9.', 'journal-title': 'Cell Res'}, { 'key': '949_CR22', 'doi-asserted-by': 'publisher', 'unstructured': 'Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antiviral ' 'Agents against the SARS-CoV-2 Omicron Subvariant BA.2. N Engl J Med ' '2022; 386:1475–7. https://doi.org/10.1056/NEJMc2201933.', 'DOI': '10.1056/NEJMc2201933'}, { 'key': '949_CR23', 'doi-asserted-by': 'publisher', 'unstructured': 'Ohashi H, Hishiki T, Akazawa D, et al. Different efficacies of ' 'neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron ' 'subvariants, BA.1 and BA.2. Antiviral Res. 2022. ' 'https://doi.org/10.1016/j.antiviral.2022.105372.', 'DOI': '10.1016/j.antiviral.2022.105372'}, { 'key': '949_CR24', 'doi-asserted-by': 'publisher', 'unstructured': 'Rosenke K, Okumura A, Lewis MC, et al. Molnupiravir (MK-4482) is ' 'efficacious against Omicron and other SARS-CoV-2 variants in the Syrian ' 'hamster COVID-19 model. medRxiv [Preprint] February 24 2022 Available ' 'from: ' 'https://www.biorxiv.org/content/https://doi.org/10.1101/2022.02.22.481491v1.', 'DOI': '10.1101/2022.02.22.481491v1'}, { 'key': '949_CR25', 'doi-asserted-by': 'publisher', 'first-page': '2603', 'DOI': '10.1056/NEJMoa2034577', 'volume': '383', 'author': 'FP Polack', 'year': '2020', 'unstructured': 'Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the ' 'BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–15. ' 'https://doi.org/10.1056/NEJMoa2034577.', 'journal-title': 'N Engl J Med'}], 'container-title': 'Clinical and Experimental Medicine', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1007/s10238-022-00949-3.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1007/s10238-022-00949-3/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1007/s10238-022-00949-3.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 12, 5]], 'date-time': '2022-12-05T09:08:00Z', 'timestamp': 1670231280000}, 'score': 1, 'resource': {'primary': {'URL': 'https://link.springer.com/10.1007/s10238-022-00949-3'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 12, 5]]}, 'references-count': 25, 'alternative-id': ['949'], 'URL': 'http://dx.doi.org/10.1007/s10238-022-00949-3', 'relation': {}, 'ISSN': ['1591-9528'], 'subject': ['General Biochemistry, Genetics and Molecular Biology', 'General Medicine'], 'container-title-short': 'Clin Exp Med', 'published': {'date-parts': [[2022, 12, 5]]}, 'assertion': [ { 'value': '30 September 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '11 November 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '5 December 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Y Shibata and H Minemura received lecture fees and research grants from Chugai ' 'Pharmaceutical Co., Ltd. Y Shibata and J Saito received lecture fees from ' 'GlaxoSmithKline K.K. The other authors report no conflicts of interest related ' 'to this study.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Conflict of interest'}}, { 'value': 'This study was performed in line with the principles of the Declaration of ' 'Helsinki. The protocol was approved by the local ethical committee.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethic approval'}}, { 'value': 'The authors have seen the final version of the manuscript and approved ' 'submission for publication.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent to publication'}}]}

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