A randomized phase 2 study on demeclocycline in patients with mild-to-moderate COVID-19

Abstract

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/μL in the number of CD4⁺ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/μL-377.6/μL) (p = 0.023), whereas that in the control group was 47.8/μL (95% CI - 151.2/μL to 246.8/μL), which was not significant (p = 0.271). The change rates of CD4⁺ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).

Figure 1

Flow diagram.

Figure 2

(A) Kaplan–Meier curves for the cumulative incidence of the dexamethasone treatment due to COVID-19 exacerbations. (B) Kaplan–Meier curves for the cumulative incidence of continuous oxygen therapy due to respiratory failure in COVID-19.

Figure 3

Relationships between change rates of T cells and cytokines in demeclocycline treatment groups (n = 9). (A) Correlations between the change rates of CD8⁺ T cells and cytokines (IL-6, TNF-α, and IFN-γ) in the demeclocycline treatment groups. (B) Correlations between the change rates of CD4⁺ T cells and cytokines (IL-6, TNF-α, and IFN-γ) in the demeclocycline treatment groups.