An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19

Abstract

Background Epidemic outbreaks caused by SARS-CoV-2 are worsening around the world, and there are no target drugs to treat COVID-19. IFN-κ inhibits the replication of SARS-CoV-2; and TFF2 is a small secreted polypeptide that promotes the repair of mucosal injury and reduces the inflammatory responses. We used the synergistic effect of both proteins to treat COVID-19. Methods We conducted an open-label, randomized, clinical trial involving patients with moderate COVID-19. Patients were assigned in a 1:1 ratio to receive either aerosol inhalation treatment with IFN-κ and TFF2 every 24 h for six consecutive dosages in addition to standard care (experimental group) or standard care alone (control group). The primary endpoint was the time until a viral RNA negative conversion for SARS-CoV-2 in all clinical samples. The secondary clinical endpoint was the time of CT imaging improvement. Data analysis was performed per protocol. This study was registered with chictr.org.cn, ChiCTR2000030262. Findings Between March 23 and May 23 of 2020, 86 COVID-19 patients with symptoms of moderate illness were recruited, and 6 patients were excluded due to not matching the inclusion criteria (patients with pneumonia through chest radiography). Among the remaining 80 patients, 40 patients were assigned to experimental group, and the others were assigned to control group to only receive standard care. Efficacy and safety were evaluated for both groups. The time of viral RNA negative conversion in experimental group (Mean, 3·80 days, 95% CI 2·07–5·53), was significantly shorter than that in control group (7·40 days, 95% CI 4·57 to 10·23) ( p = 0.031), and difference between means was 3·60 days. The percentage of patients in experimental group with reversion to negative viral RNA was significantly increased compared with control group on all sampling days (every day during the 12-day observation period) ( p = 0·037). For the secondary endpoint, the experimental group had a significantly shorter time until improvement was seen by CT (Mean 6·21 days, N = 38/40, 95% CI 5·11–7·31) than that in control group (8·76 days, N = 34/40, 95% CI 7·57–9·96) ( p = 0.002), and difference between means was 2·55 days. No discomfort or complications during aerosol inhalation were reported to the nurses by any experimental patients. Interpretation In conclusion, we found that aerosol inhalation of IFN-κ plus TFF2 in combination with standard care is safe and superior to standard care alone in shortening the time up to viral RNA negative conversion in all clinical samples. In addition, the patients in experimental group had a significantly shortened CT imaging improvement time than those in control group. This study suggested that this combination treatment is able to facilitate clinical improvement (negative for virus, impr...

Type I interferon: From innate response to treatment for COVID‐19

“…Nebulized IFN was also shown to decrease mortality in COVID‐19 patients in other studies 38,39 . Fu et al 40 showed that nebulized IFN‐k plus trefoil factor 2 (TFF2) was associated with clinical improvement in COVID‐19 patients and their consequent early discharge from hospital. A study involving about 100 COVID‐19 patients (NCT04385095) reported that nebulized IFN‐β1a might be highly effective, with a 79% lower risk of developing severe disease.…”

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider

“…Safety concerns were raised by one of the studies with increased liver enzymes in leflunomide-treated patients. 70 IFN-alpha 71 and IFN-kappa 72 reduced the time to negative conversion of SARS-CoV-2 in two studies. Two prospective studies on baricitinib at high RoB provided conflicting results for every assessed outcome and only agreed on the fact that addition of baricitinib to SOC did not worsen the safety profile of the therapeutic strategy.…”

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

“…It has been demonstrated that early administration of type I IFNs inhibits viral replication in vitro by partially restoring innate immune response to SARS-CoV-2 infection [ 156 ]. A randomized clinical trial of 80 patients with moderate COVID-19 and pneumonia found that aerosol inhalation of IFN-ĸ (a type I IFN) combined with TFF2 anti-inflammatory polypeptide led to faster SARS-CoV-2 clearance and facilitated clinical resolution of pneumonia [ 199 ]. A phase 2 clinical trial assessing the efficacy of IFN-β (a type I IFN) treatment in 127 COVID-19 patients found that IFN-β in combination with lopinavir-ritonavir and ribavirin shortened viral shedding time and hospital stay [ 200 ].…”