An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a (the base therapeutic regimen) in moderate to severe COVID-19: A structured summary of a study protocol for a randomized controlled l trial

Abstract

Objectives We will investigate the effectiveness of high dose Interferon Beta 1a, compared to low dose Interferon Beta 1a (the base therapeutic regimen) in COVID-19 Confirmed Cases (Either RT-PCR or CT Scan Confirmed) with moderate to severe disease Trial Design This is a single center, open label, randomized, controlled, 2-arm parallel group (1:1 ratio), clinical trial. Participants The eligibility criteria in this study is: age ≥ 18 years, oxygen saturation (SPO2) ≤ 93% or respiratory rate ≥ 24, at least one of the following manifestation: radiation contactless body temperature ≥37.8, Cough, shortness of breath, nasal congestion/ discharge, myalgia/arthralgia, diarrhea/vomiting, headache or fatigue on admission. The onset of the symptoms should be acute (≤ 14 days). The exclusion criteria include refusal to participate, using drugs with potential interaction with lopinavir/ritonavir or interferon-β 1a, blood ALT/AST levels > 5 times the upper limit of normal on laboratory results, pregnant or lactating women, history of alcohol or drug addiction in the past 5 years, the patients who be intubated less than one hours after admission to hospital. This study will be undertaken at the Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences. Intervention and Comparator COVID- 19 confirmed patients (using the RT-PCR test or CT scan) will be randomly assigned to one of two groups. The intervention group (Arms1) will be treated with lopinavir / ritonavir (Kaletra) + high dose Interferon-β 1a (Recigen) and the control group will be treated with lopinavir / ritonavir (Kaletra) + low dose Interferon-β 1a (Recigen) (the base therapeutic regimen). Both groups will receive standard care consisting of the necessary oxygen support, non-invasive, or invasive mechanical ventilation. Main outcomes Primary outcome: Time to clinical improvement is our primary outcome measure. This is an improvement of two points on a seven-category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization) or discharge from the hospital, whichever comes first. Secondary outcomes: mortality from the date of randomization until the last day of the study which will be the day all of the patients have had at least one of the following outcomes: 1) Improvement of two points on a seven-category ordinal scale. 2) Discharge from the hospital 3) Death. Improvement of SPO2 during the hospitalization, duration of hospitalization from date of randomization until the date of hospital discharge or death, whichever comes first. The incidence of new mechanical ventilation uses from the date of randomization until the last day of the study and the duration of it will be extracted. Please note that we are trying to add further secondary outcomes and this section of the protocol is still evolving. Randomization Eligible patients with confirmed SARS-Cov-2 infections will be randomly assigned in a 1:1 ratio to two therapeutic arms using permuted, block-randomization to balance the number of patients allocated to each group. The permuted block (three or six patients per block) randomization sequence will be generated, using Package ‘randomizeR’ in R software version 3.6.1. and placed in individual sealed and opaque envelopes by the statistician. The investigator will enroll the patients and only then open envelopes to assign patients to the different treatment groups. This method of allocation concealment will result in minimum selection and confounding biases. Blinding (Masking) The present research is open-label (no masking) of patients and health care professionals who are undertaking outcome assessment of the primary outcome - time to clinical improvement. Numbers to be randomised (sample size) Of the 100 patients randomised, 50 patients will be assigned to receive high dose Interferon beta-1a plus lopinavir/ritonavir (Kaletra), 50 patients will be assigned to receive low dose Interferon beta 1a plus lopinavir/ritonavir (Kaletra). Trial Status Protocol version 1.2.1. Recruitment is finished, the start date of recruitment was on August 20th 2020, and the end date was on September 4th 2020. Last point of data collection will be the last day on which all of the 100 participants have had an outcome of clinical improvement or death, up to 14th days after hospitalization. Trial registration This study was registered with National Institutes of Health Clinical trials (www.clinicaltrials.gov; identification number NCT04521400, https://clinicaltrials.gov/ct2/show/NCT04521400, registered August 18, 2020 and first available online August 20, 2020). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β

“…U1111-1189-1653 Compare diverse immunomodulatory treatment (IFNβ among them) REMAP-CAP trial https://www.remapcap.org/ International mullti- centric > 4000 The trial is multifactorial as it tests multiple interventions Patients admitted to ICU with acute respiratory insufficiency due to suspected pneumonia The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection [ 138 ] IFNβ-1a NCT04449380 Compare IFNb-1a+ standard care vs. standard care alone INTERCOP trial randomized, controlled, open-label, phase II trial Italy mono-centric s.c. 44 μg (12 MIU) 3 times × week at least 48h apart, for 2 weeks 126 randomized 2:1 to IFNβ-1a No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms Patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale, among others [ 139 ] IFNβ-1a NCT04521400 ongoing Compare high- vs. low-dose IFNβ Randomized open-label controlled 2-arm parallel group; phase 2a trial Iran single center Arm 1: high-dose IFN arm 2: low-dose IFN Intention to treat: 50 patients per arm All patients will receive LPV/R SPO2<93% or RR> 24 + one of the following manifestations: B.T<37.8 °C or cough, or shortness of breath or nasal congestion/discharge, or myalgia/arthralgia or diarrhea/vomiting or headache or fatigue on admission Primary outcome: time to clinical improvement Secondary outcome: (a) mortality at the end of the study; (b) Improvement of SPO2 during hospitalization; (c) duration of hospitalization; (d) incidence of mechanical ventilation [ 140 ] Previous studies IFNβ-1a NCT02622724 Efficacy and adverse events of IFNβ in patients with moderate ARDS Randomized double-blind parallel-group trial E.U. Multi-center n=74 ICU in 8 countries <...>…”

A Journey From SARS-CoV-2 to COVID-19 and Beyond: A Comprehensive Insight of Epidemiology, Diagnosis, Pathogenesis, and Overview of the Progress into Its Therapeutic Management

“…Clinical trials are being conducted to investigate its effectiveness against COVID-19 infection ( Alavi Darazam et al, 2020 ). It has also been found to be effective previously against SARS-CoV-1 and MERS-CoV and suggested presently for the treatment of SARS-CoV-2 ( Arabi et al, 2020 ; Jamilloux et al, 2020 ; Sallard et al, 2020 ).…”

Therapeutic Intervention of COVID-19 by Natural Products: A Population-Specific Survey Directed Approach

“…As numerous experimental agents progress on the pipeline, we expect the emergence of more safe and efficacious treatments to treat COVID-19. Other investigational agents with promising prospects include interferon beta [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ], and tocilizumab [ 24 , 25 ]. As of this writing, from the total number of registered COVID-19 related clinical trials, 1993 are actively recruiting or not yet recruiting participants, and we expect new treatments to be available soon.…”