Abstract: RESEARCH ARTICLE www.advancedscience.com Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19 Ozlem Altay, Muhammad Arif, Xiangyu Li, Hong Yang, Mehtap Aydın, Gizem Alkurt, Woonghee Kim, Dogukan Akyol, Cheng Zhang, Gizem Dinler-Doganay, Hasan Turkez, Saeed Shoaie, Jens Nielsen, Jan Borén, Oktay Olmuscelik, Levent Doganay, Mathias Uhlén, and Adil Mardinoglu* COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+ ) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems. Dr. O. Altay, M. Arif, Dr. X. Li, H. Yang, Dr. W. Kim, Dr. C. Zhang, Dr. S. Shoaie, Prof. M. Uhlén, Prof. A. Mardinoglu Science for Life Laboratory KTH—Royal Institute of Technology Stockholm, SE-100 44, Sweden E-mail: adilm@scilifelab.se Dr. O. Altay Department of Clinical Microbiology Dr Sami Ulus Training and Research Hospital University of Health Sciences Ankara 06080, Turkey The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/advs.202101222 © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202101222 Adv. Sci. 2021, 8, 2101222