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Volume 17
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10.3390/v17070982
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Article

Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial

by
Toshihiro Kita
1,*,
Norio Ohmagari
2,
Sho Saito
2,
Hiroshi Mukae
3,
Takahiro Takazono
3,
Taka-Aki Nakada
4,
Tadanaga Shimada
4,
Yuji Hirai
5,
Yuichiro Shindo
6,
Kosaku Komiya
7,
Atsushi Saito
8,
Masaya Yamato
9,
Koichiro Homma
10,
Masaki Okamoto
11,
Yoshihiro Yamamoto
12,
Yoshikazu Mutoh
13,
Chihiro Hasegawa
14,
Nobuaki Mori
15,†,
Fukumi Nakamura-Uchiyama
16,
Mitsuru Honda
17,
Keisuke Tomii
18,
Hiroshi Ishii
19,
Ichiro Takajo
20,
Koji Watanabe
1 and
Kazuo Kitamura
1add Show full author list remove Hide full author list
1
Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan
2
Disease Control and Prevention Center, National Center for Global Health and Medicine, Japan Institute for Health Security, Tokyo 162-8655, Japan
3
Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8520, Japan
4
Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
5
Department of Infectious Diseases, Tokyo Medical University Hachioji Medical Center, Hachioji 193-0998, Japan
6
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
7
Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Oita 879-5593, Japan
8
Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
9
Department of General Internal Medicine and Infectious Diseases, Rinku General Medical Center, Izumisano 598-8577, Japan
10
Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
11
Department of Respirology, NHO Kyushu Medical Center, Fukuoka 810-0065, Japan
12
Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-8555, Japan
13
Department of Infectious Diseases, Tosei General Hospital, Seto 489-8642, Japan
14
Nagoya City University East Medical Center, Nagoya 464-8547, Japan
15
Department of General Internal Medicine and Infectious Diseases, NHO Tokyo Medical Center, Tokyo 152-8902, Japan
16
Department of Infectious Diseases, Tokyo Metropolitan Bokutoh Hospital, Tokyo 130-8575, Japan
17
Critical Care Center, Toho University Omori Medical Center, Tokyo 143-8540, Japan
18
Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan
19
Department of Respiratory Medicine, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
20
Division of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-2192, Japan
 
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*
Author to whom correspondence should be addressed.
†
Current address: Department of Medicine, Division of Clinical Infectious Diseases, Showa Medical University School of Medicine, Tokyo 142-8555, Japan.
Viruses 2025, 17(7), 982; https://doi.org/10.3390/v17070982 (registering DOI)
Submission received: 23 May 2025 / Revised: 2 July 2025 / Accepted: 10 July 2025 / Published: 14 July 2025
(This article belongs to the Section Coronaviruses)
Versions Notes

Abstract

Adrenomedullin (AM) is a bioactive peptide that is strongly induced during severe inflammation, including pneumonia and sepsis, and serves as an organ-protective factor. The plasma concentration of AM is markedly increased in the novel coronavirus disease COVID-19 and is closely related to the severity of the disease and prognosis of patients. We performed two investigator-initiated trials to evaluate the efficacy and safety of AM in patients with moderate-to-severe COVID-19. This multicenter, double-blind, placebo-controlled phase-2a trial evaluated COVID-19 patients with severe (n = 33) and moderate (n = 31) pneumonia in Japan. Patients were randomly assigned to receive either 15 ng/kg/min AM or placebo. The primary endpoint was the duration of mechanical ventilation (MV) for severe pneumonia and oxygen support for moderate pneumonia. The main secondary endpoint was clinical status up to 30 days after the intervention. No differences in primary or secondary endpoints were observed between the AM and placebo groups in patients with severe or moderate pneumonia. In the severe pneumonia group, three patients in the placebo group died due to respiratory failure, and one patient in the AM group died due to respiratory failure. The respiratory function test at 30 days in the moderate pneumonia group tended to be better than that in the AM group and approached significance (p = 0.073). Although mild adverse events caused by the vasodilatory effects of AM were noted, the safety of AM for treating pneumonia was confirmed. In these trials, we did not observe a definitive efficacy of AM in moderate to severe pneumonia. Alternative strategies for the treatment of AM in pneumonia require further research.
Keywords: adrenomedullin; COVID-19; pneumonia; mechanical ventilation; phase 2a clinical trial; Japanese adrenomedullin; COVID-19; pneumonia; mechanical ventilation; phase 2a clinical trial; Japanese

Share and Cite

MDPI and ACS Style

Kita, T.; Ohmagari, N.; Saito, S.; Mukae, H.; Takazono, T.; Nakada, T.-A.; Shimada, T.; Hirai, Y.; Shindo, Y.; Komiya, K.; et al. Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial. Viruses 2025, 17, 982. https://doi.org/10.3390/v17070982

AMA Style

Kita T, Ohmagari N, Saito S, Mukae H, Takazono T, Nakada T-A, Shimada T, Hirai Y, Shindo Y, Komiya K, et al. Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial. Viruses. 2025; 17(7):982. https://doi.org/10.3390/v17070982

Chicago/Turabian Style

Kita, Toshihiro, Norio Ohmagari, Sho Saito, Hiroshi Mukae, Takahiro Takazono, Taka-Aki Nakada, Tadanaga Shimada, Yuji Hirai, Yuichiro Shindo, Kosaku Komiya, and et al. 2025. "Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial" Viruses 17, no. 7: 982. https://doi.org/10.3390/v17070982

APA Style

Kita, T., Ohmagari, N., Saito, S., Mukae, H., Takazono, T., Nakada, T.-A., Shimada, T., Hirai, Y., Shindo, Y., Komiya, K., Saito, A., Yamato, M., Homma, K., Okamoto, M., Yamamoto, Y., Mutoh, Y., Hasegawa, C., Mori, N., Nakamura-Uchiyama, F., ... Kitamura, K. (2025). Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial. Viruses, 17(7), 982. https://doi.org/10.3390/v17070982

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