Effect of combination of interferon alpha-2b and interferon-gamma or interferon alpha-2b alone for elimination of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial
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Abstract
Objectives
An IFN-α2b and IFN-γ combination has demonstrated favorable pharmacodynamics for genes underlying antiviral activity which might be involved in the defense of a host from a SARS-CoV-2 infection. Considering this synergy, we conducted a randomized controlled clinical trial for efficacy and safety evaluation of subcutaneous IFN - α2b and IFN-γ administration in patients positive for SARS-CoV-2.
Methods
We enrolled 19-82 years-old inpatients at the Military Central Hospital Luis Diaz Soto, Havana, Cuba. They were hospitalized after confirmed diagnosis for SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction. Patients were randomly assigned in a 1:1 ratio to receive either, subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-α2b and 0.5 MIU IFN-γ (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks, or thrice a week intramuscular injection of 3.0 MIU IFN-α2b (Heberon® Alpha R, CIGB, Havana, Cuba). Additionally, all patients received lopinavir-ritonavir (200/50 mg every 12 h) and chloroquine (250 mg every 12 h, i.e.standard of care). The primary endpoints were, from the start of treatment, the time to elimination of viral RNA and the time to progression to severe COVID-19. The protocol was approved by the Ethics Committee on Clinical Investigation from the Hospital and the Center for the State Control of Medicines, Equipment and Medical Devices in Cuba. Informed consent was obtained from each participant (INSTITUTION PROTOCOL IG/IAG/CV/2001).
Results
A total of 79 patients with laboratory-confirmed SARS-CoV-2 infection, including symptomatic or asymptomatic conditions, fulfilled the inclusion criteria and underwent randomization. Thirty-three subjects were assigned to the HeberFERON group, and 33 to the Heberon Alpha R group. Sixty-three patients were analyzed for viral elimination, of these 78.6% in the HeberFERON group eliminated the virus after 4 days of treatment versus 40.6% of patients in the Heberon Alpha R groups (p=0.004). Time to reach the elimination of SARS-CoV-2, as measured by RT-PCR was 3.0 and 5.0 days for the HeberFERON and Heberon Alpha R groups, respectively. A significant improvement in the reduction of time for virus elimination was attributable to HeberFERON (p=0.0027, Log-rank test) with a Hazard Ratio of 3.2 and 95% CI of 1.529 to 6.948, as compared to the Heberon Alpha R treated group.
Worsening of respiratory symptoms was detected in two (6.6%) and one (3.3%) patients in HeberFERON and IFN-α2b groups, respectively. However, none of the subjects transited to severe COVID-19 during the study or during the following clinical evaluation (21 more days).
RT-PCR on day 14 after the start of the treatment was negative to SARS-CoV-2 in 100% and 91% of patients of the combination of IFNs and IFN-α2b, respectively. Elimination in HeberFERON treated patients was related to a significant increase in lymphocytes counts and also a significant reduction in CRP as early as 7 days after commencing the therapeutic schedule.
All the patients in both cohorts recovered and had their laboratory parameters return to normal values by day 14 after treatment initiation. Adverse events were identified in 31.5% of patients, 28.5% in the control group, and 34.4% in the HeberFERON group, with the most frequent adverse event being headaches (17.4%).
Conclusions
In a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly eliminated the virus on day 4 of treatment when compared to treatment with IFN-α2b alone. However, Heberon Alpha R alone also showed efficacy for the treatment of the viral infection. Both treatments were safe and positively impacted on the resolution of the symptoms. None of the patients developed severe COVID-19.
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SciScore for 10.1101/2020.07.29.20164251: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Adult (≥19 years-old) patients with RT-PCR confirmed SARS-CoV-2, ECOG functional status ≥ 2 (Karnofsky ≥ 70%), and who volunteered by signing the informed consent were included.
IRB: The clinical trial protocol was approved by the Ethics Committee on Clinical Investigation of Military Central Hospital Luis Diaz Soto, and the Center for the State Control of Medicines, Equipment and Medical Devices (CECMED) in Cuba.Randomization Study design: Hospitalized adult patients with RT-PCR confirmed SARS-CoV-2 were enrolled in this open-labeled, single center, prospective, randomized and controlled clinical trial at Military Central Hospital Luis Diaz Soto … SciScore for 10.1101/2020.07.29.20164251: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Adult (≥19 years-old) patients with RT-PCR confirmed SARS-CoV-2, ECOG functional status ≥ 2 (Karnofsky ≥ 70%), and who volunteered by signing the informed consent were included.
IRB: The clinical trial protocol was approved by the Ethics Committee on Clinical Investigation of Military Central Hospital Luis Diaz Soto, and the Center for the State Control of Medicines, Equipment and Medical Devices (CECMED) in Cuba.Randomization Study design: Hospitalized adult patients with RT-PCR confirmed SARS-CoV-2 were enrolled in this open-labeled, single center, prospective, randomized and controlled clinical trial at Military Central Hospital Luis Diaz Soto Hospital, Havana, Cuba. Blinding not detected. Power Analysis (Heberon Alpha R, CIGB, Havana, Cuba) based on a power of 80%, and a level of confidence set at 95%, while also considering a dropout rate of 5%. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analysis was performed using the Windows software package SPSS (version 25) and GraphPad Prism v8.0. SPSSsuggested: (SPSS, RRID:SCR_002865)GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study had several limitations. This trial was open label, without a placebo group with unbalanced demographics (age years) between treatment arms. In addition, sampling methods were most likely suboptimal using the throat sampling procedure, because of the inability to do sampling of lower respiratory tract secretions. Previous studies have shown that throat-swab specimens have lower viral loads43. Irrespective of these limitations the HeberFERON showed efficacy and was safe in shortening virus shedding, eliminating symptoms, and permitting discharge of patients with COVID-19. Based in our analyses of the clinical data and their correlation with the patient outcome, we hypothesized that a potent antiviral response based in coordinated innate and adaptive immune responses was mediated by the combination of type I and type II IFNs. Thus an anti-inflammatory response in the early steps of the disease may be the main reason for the control of COVID-19 by HeberFERON treatment. The use of HeberFERON in COVID-19 patients could also be an effective therapeutic option to halt a second stage of the disease. This stage, characterized by a respiratory worsening approximately 9-12 days after onset of symptoms58, is apparently related to an imbalance of inflammatory mediators53. Findings presented herein are the first to suggest therapeutic efficacy in COVID-19 disease of the combination of IFN-α2b and IFN-γ with individual and a public health impact, resulting in a shorter duration of...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
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