Outcomes of COVID-19 among patients treated with subcutaneous interferon beta-1a for multiple sclerosis.

BACKGROUND: In accordance with expert guidance, patients have typically continued to receive treatment with subcutaneous interferon beta-1a (sc IFN ß-1a) for relapsing multiple sclerosis (MS) during the COVID-19 pandemic. METHODS: We provide a summary of outcomes among sc IFN ß-1a-treated patients with adverse events related to confirmed or suspected COVID-19, as reported to the Merck Global Patient Safety Database (as of 2 February 2021). Serious COVID-19-related adverse events (as classified by the reporting clinician) included those leading to hospitalization, admission to intensive care, or death. Outcomes were classified per usual pharmacovigilance practice. RESULTS: The evaluable cohort comprised 603 patients of median age 43 (range, 13-84) years and 75.1% were female. COVID-19 was experienced at a median of 33.0 (range, 0-321.8) months after start of treatment with sc IFN ß-1a. A total of 136 (22.6%) patients experienced serious COVID-19 events, including 59 hospitalizations (4 patients admitted to intensive care) and 5 deaths (fatality rate, 0.8%). Regarding non-fatal outcomes, 47.8% of patients (289/603) with COVID-19 adverse events were recovered or recovering at time of analysis; similar findings were apparent for the serious and hospitalized cohorts. CONCLUSION: Findings of this analysis from the Merck Global Patient Safety Database suggest that, compared with available statistics for the general population and those with MS, patients receiving sc IFN ß-1a for treatment of relapsing MS have relatively low rates of serious disease and/or severe outcomes with COVID-19.

An investigation into the beneficial effects of high-dose interferon beta 1-a, compared to low-dose interferon beta 1-a in severe COVID-19: The COVIFERON II randomized controlled trial.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been a serious obstacle in front of public health. Interferon-beta 1a (IFN-ß 1a) has been used to treat patients with COVID-19. We aimed to compare the effectiveness of high-dose IFN-ß 1a compared to low dose IFN-ß 1a in severe COVID-19 cases. METHODS: In this randomized, controlled, and clinical trial, eligible patients with confirmed SARS-CoV-2 infections were randomly assigned to receive one of the two following therapeutic regimens: The intervention group was treated with high-dose IFN-ß 1a (Recigen) (Subcutaneous injections of 88 µg (24 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally) and the control group was treated with low-dose IFN-ß 1a (Recigen) (Subcutaneous injections of 44 µg (12 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally). RESULT: A total of 168 COVID- 19 confirmed patients underwent randomization; 83 were assigned to the intervention group and 85 were assigned to the control group. Median Time To Clinical Improvement (TTIC) for cases treated with low-dose IFN-ß1a was shorter than that for cases treated with high-dose IFN-ß1a (6 vs 10 days; P = 0.018). The mortality rates in intervention and control group were 41% and 36.5%, respectively. CONCLUSION: The use of high-dose IFN-ß 1a did not improve TTCI in hospitalized patients with moderate to severe COVID-19. Also, it did not have any significant effect on mortality reduction compared with treating with low-dose IFN-ß 1a. TRIAL REGISTRATION: This trial has been registered as ClinicalTrials.gov, NCT04521400.

Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed. FINDINGS: Between March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 [95% CI 1·07-5·04]; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03-4·69]; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group. INTERPRETATION: Patients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials. FUNDING: Synairgen Research.

The efficacy and safety of Ivermectin in patients with mild and moderate COVID-19: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We will evaluate the efficacy and safety of Ivermectin in patients with mild and moderately severe COVID-19. TRIAL DESIGN: This is a phase 3, single-center, randomized, open-label, controlled trial with a 2-arm parallel-group design (1:1 ratio). PARTICIPANTS: The Severe Acute Respiratory Syndrome Departments of the Shahid Mohammadi Hospital, Bandar Abbas, Iran, will screen for patients age ≥ 20 years and weight ≥35 kg for the following criteria: Inclusion criteria for patients with mild COVID-19 symptoms (outpatients) 1. Diagnosed mild pneumonia using computed tomography (CT) and/or chest X-ray (CX-R) imaging, not requiring hospitalization. 2. Signing informed consent. Inclusion criteria for patients with moderate COVID-19 symptoms (inpatients) 1. Confirmed infection using PCR. 2. Diagnosed moderate pneumonia using CT and/or CXR imaging, requiring hospitalization. 3. Hospitalized ≤ 48 hours. 4. Signing informed consent. Exclusion criteria 1. Severe and critical pneumonia due to COVID-19. 2. Underlying diseases, including AIDS, asthma, loiasis, and severe liver and kidney disease. 3. Use of anticoagulants (e.g., warfarin) and ACE inhibitors (e.g., captopril). 4. History of drug allergy to Ivermectin. 5. Pregnancy or breastfeeding. INTERVENTION AND COMPARATOR: Intervention groups: Outpatient and inpatient groups will receive the standard treatment regimen for mild and moderate COVID-19, based on the Iranian Ministry of Health and Medical Education's protocol, along with oral Ivermectin (MSD Company, France) at a single dose of 0.2 mg/kg. Control groups: The outpatient group will receive hydroxychloroquine sulfate (Amin Pharmaceutical Company, Iran) at a dose of 400 mg twice a day for the first day and 200 mg twice a day for seven subsequent days. The inpatient group will receive 200/50 mg Lopinavir/Ritonavir (Heterd Company, India) twice a day for the seven days, plus five doses of 44 mcg Interferon beta-1a (CinnaGen, Iran) every other day. Other supportive and routine care will be the same in both outpatient and inpatient groups. MAIN OUTCOME: The primary outcomes are composite and include the improvement of clinical symptoms and need for hospitalization for outpatient groups, and the length of hospital stay until discharge, the need for ICU admission until discharge, and the need for mechanical ventilation for inpatient groups within seven days of randomization. The secondary outcome is the incidence of serious adverse drug reactions within seven days of randomization. RANDOMIZATION: Patients in both outpatient (mild) and inpatient (moderate) groups will be randomized into the treatment and control groups based on the following method. A simple randomization method and table of random numbers will be used. If the selected number is even, the patient is allocated to the treatment group, and if it is odd, the patient is allocated to the control group in a 1:1 ratio. BLINDING (MASKING): This is an open-label study, and there is not blinding. Numbers to be randomized (sample size) A total number of 120 patients (60 outpatients and 60 patients) will be randomized into two groups (30 patients in each of the intervention groups and 30 patients in each of the control groups). TRIAL STATUS: The protocol is Version 1.0, November 17, 2020. Recruitment began November 25, 2020, and is anticipated to be completed by February 25, 2021. TRIAL REGISTRATION: This clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20200506047323N6 ". The registration date is November 17, 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 the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Effectiveness of Interferon Beta 1a, compared to Interferon Beta 1b and the usual therapeutic regimen to treat adults with moderate to severe COVID-19: structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We will investigate the effectiveness of Interferon Beta 1a, compared to Interferon Beta 1b and the usual therapeutic regimen in COVID-19 in patients that have tested positive and are moderately to severely ill. TRIAL DESIGN: This is a single center, open label, randomized, controlled, parallel group, clinical trial that will be conducted at Loghman Hakim Medical Education Center in conjunction with Shahid Beheshti University of Medical Sciences. PARTICIPANTS: Sixty COVID-19 confirmed cases (using the RT-PCR test) will be enrolled in the trial between April 9th to April 14th 2020. Patients will be randomly assigned to the intervention groups or the control group with the following eligibility criteria: ≥ 18 years of age AND (oxygen saturation (SPO2) ≤ 93% OR respiratory rate ≥ 24) AND at least one of the following: Contactless infrared forehead thermometer temperature of ≥37.8, cough, sputum production, nasal discharge, myalgia, headache or fatigue on admission, and time of onset of the symptoms should be acute (Days ≤ 14). Although Hydroxychloroquine will be administered in a single dose, patients with heart problems (prolonged QT or PR intervals, second- or third-degree heart block, and arrhythmias including torsade de pointes) will be excluded. Other exclusion criteria include using drugs with potential interaction with Hydroxychloroquine + Lopinavir/Ritonavir, Interferon-ß 1a, Interferon-ß 1b, pregnant or lactating women, history of alcohol or drug addiction in the past 5 years, blood ALT/AST levels > 5 times the upper limit of normal on laboratory results and refusal to participate. This study will be undertaken at the Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences and Health Services. INTERVENTION AND COMPARATOR: COVID-19 confirmed patients will be randomly assigned to one of three groups, with 20 patients in each. The first group (Arm 1) will receive Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra) + Interferon-ß 1a (Recigen), the second group (Arm 2) will be administered Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra) + Interferon-ß 1b (Ziferon), and the control group (Arm 3) will be treated by Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra). MAIN OUTCOMES: 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 include 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. If any patient dies, we have reached an important secondary outcome. SpO2 Improvement between the last and first day of hospitalization, using pulse-oximetry. Duration of hospitalization from date of randomization until the date of hospital discharge or date of death from any cause, whichever comes first. Incidence of new mechanical ventilation uses from date of randomization until the last day of the study. Please note that we are trying to add further secondary outcomes and this section of the protocol is still evolving. Statistical analysis will be performed by R version 3.6.1 software. We will use Kaplan-Meier to analyze the time to clinical improvement (compared with a log-rank test). Hazard ratios with 95% confidence intervals will be calculated using the Cox proportional-hazards model in crude and adjusted analysis. RANDOMIZATION: Eligible patients will be randomly assigned in a 1:1:1 ratio to receive either Interferon Beta 1a, Interferon Beta 1b or standard care only. Patients will be randomly allocated to three 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 RANDOMIZED (SAMPLE SIZE): Of the 60 patients who underwent randomization, 20 patients were assigned to receive Interferon beta-1a, 20 patients were assigned to receive Interferon beta 1b plus standard care and the rest of patients were assigned to receive the standard care alone. TRIAL STATUS: Protocol version 1.2.1. Recruitment is finished, the start date of recruitment was on 9th April 2020 and the end date was on 14th April 2020. Last point of data collection will be the last day on which all of the 60 participants have had an outcome of clinical improvement or death, completing the study's follow-up time window. TRIAL REGISTRATION: This study was registered with National Institutes of Health Clinical trials (www.clinicaltrials.gov; identification number NCT04343768, registered April 8, 2020 and first available online April 13, 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.

Interferons in the Therapy of Severe Coronavirus Infections: A Critical Analysis and Recollection of a Forgotten Therapeutic Regimen with Interferon Beta.

The pharmacological and immunological properties of interferons, especially those of interferon beta, and the corresponding treatment strategies are described, and the results of studies with different interferons in coronavirus infections are analysed. Furthermore, the data obtained with high-dosed native interferon beta in life-threatening acute viral diseases as well as the results of clinical pilot studies with high-dosed recombinant interferon beta-1a are provided because they serve as the rationale for the proposed therapeutic regimen to be applied in acute viral infections. This regimen differs from those approved for treatment of multiple sclerosis and consists of interferon beta-1a administered as a 24 hour intravenous infusion at a daily dose of up to 90 µg for 3-5 consecutive days. Since under this regimen transient severe side effects can occur, it is analysed which patients are suitable for this kind of treatment in general and if patients with severe coronavirus infections could also be treated accordingly.