IFN-beta 1b and Remdesivir for COVID19

Study Overview
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Brief Summary
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A 5-day combination of interferon β-1b and remdesivir will expedite the recovery, suppress the viral load and shorten hospitalisation in patients with SARS-CoV-2 infection compare to the control arm

Detailed Description
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Introduction The novel coronavirus (SARS-CoV-2), is a single-stranded RNA coronavirus. The virus was first isolated from patients presented with pneumonia in Wuhan in December 2019. It is believed that the virus first emerged from patients working in the Wuhan Seafood Market which also sold contaminated wild animals, consumed as a local delicacy. Sequences of the Wuhan betacoronavirus show similarities to betacoronaviruses found in bats, sharing a common ancestor with the 2003 SARS coronavirus (SARS-CoV) and the bat coronavirus HKU, a virus found in fruit bats. Similar to SARS-CoV, it is a member of Beta-CoV lineage B. Five genomes of the novel coronavirus have been initially isolated and reported including BetaCoV/Wuhan/IVDC-HB-01/2019, BetaCoV/Wuhan/IVDC-HB-04/2020, BetaCoV/Wuhan/IVDC-HB-05/2019, BetaCoV/Wuhan/WIV04/2019, and BetaCoV/Wuhan/IPBCAMS-WH-01/2019 from the China CDC. The SARS-CoV-2 has since spread from China to the rest of the world. As of 20 November 2020, more than 50 million people been confirmed to have infected by SARS-CoV-2, resulting in more than 1,000,000 deaths. Remdesivir has been shown to clinically effective in severe Covid-19 patients but virological data is lacking. FDA has approved the use of remdesivir for the treatment of severe Covid-19 infection. Apart from remdesivir, no specific antiviral treatment for the SARS-CoV-2 is currently available, but existing medication could be repurposed. Genetic sequencing demonstrated similarity of the SARS-CoV-2 to the SARS-CoV and MERS CoV. We expect patients infected with the SARS-CoV-2 will also present similarly with initial upper respiratory tract symptoms including fever, cough, sputum, myalgia and shortness or breath. More severe cases might complicate with pneumonia and required ventilatory or ECMO support. According to our previous studies in 2003 on patients hospitalized for severe SARS-CoV, the viral load peaked between day 7 from symptoms onset and coincided with clinical deterioration of pneumonia and respiratory failure, with majority of the patients required intensive care support. Higher viral load isolated from different human system also correlated with worsened SARS manifestation and complications. Previously, the investigators have demonstrated that interferon-beta1b, commonly used in the treatment of multiple sclerosis and lopinavir/ ritonavir, also demonstrated to improve the outcome of MERS-CoV infection in a non-human primate model of common marmoset. A more recent open-label, randomized controlled trial by our team has proven that interferon beta-1b, in combination with lopinavir/ ritonavir and ribavirin reduced the SARS-CoV-2 viral load in the respiratory tract and resulted in faster alleviation of clinical symptoms when compared to lopinavir/ ritonavir alone or with ribavirin, suggesting that interferon beta-1b was likely to be the backbone of this triple therapy. Therefore, the investigators propose to conduct an open-label randomized controlled trial on interferon beta-1b and remdesivir combination versus remdesivir as treatment for patients hospitalized for COVID-19 infection Patients will be randomly assigned to one of the two groups: Group A: a 5-day course of subcutaneous injection of interferon β-1b 2mL (16 million IU) consecutively and IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5, or Group B: a 5-day course of IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5 (1:1).

Official Title
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An Open-label Randomized Controlled Trial on Interferon β-1b and Remdesivir Combination Versus Remdesivir as Treatment for COVID-19 Infection

Conditions
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Covid19

Intervention / Treatment
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* Drug: Interferon beta-1b
* Drug: Remdesivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recruited subjects include all adult patients ≥18 years hospitalized for virologic confirmed SARS-CoV-2 infection. Fulfilling one of the following criteria associated with high risk of clinical deterioration: age 65 years or above, radiological evidence of pneumonia, oxygen desaturation <94% on room air, comorbidity including hypertension, diabetes, cardiovascular diseases, chronic obstructive lung disease, chronic liver diseases, chronic kidney diseases, malignancy, haematological diseases, rheumatological diseases, immunocompromised hosts and obesity (BMI > 30) All subjects give written informed consent. For patients who are critically ill, requiring ICU, ventilation or confused, informed consent will be obtained from spouse, next-of-kin or legal guardians. Subjects must be available to complete the study and comply with study procedures. Willingness to allow for serum samples to be stored beyond the study period, for potential additional future testing to better characterize immune response. Exclusion Criteria: Inability to comprehend and to follow all required study procedures. Allergy or severe reactions to the study drugs Patients taking medication that will potentially interact with l interferon beta-1b and remdesivir Patients with known history of severe depression Estimated glomerular filtration rate <30 mL/min Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to recruitment in this study or expect to receive an experimental agent during this study. To participate in an unrelated trial during the current clinical trial. Nevertheless, the patients have the right to withdraw from the current clinical trial to join another clinical trial. Have a history of alcohol or drug abuse in the last 5 years. Have any condition that the investigator believes may interfere with successful completion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFN-beta 1b and remdesivir<br>a 5-day course of subcutaneous injection of interferon β-1b 2mL (16 million IU) consecutively and IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5 | Drug: Interferon beta-1b<br>* a 5-day course of subcutaneous injection of interferon β-1b 2mL (16 million IU) consecutively and IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5<br>* Other names: Remdesivir;|
| Active Comparator: Remdesivir<br>a 5-day course of IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5 | Drug: Remdesivir<br>* a 5-day course of IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement | Time to complete alleviation of symptoms as defined by NEWS of 0 maintained for 24 hours | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalisation | Length of hospitalization | 30 days | 
| NPS viral load | Time to negative nasopharyngeal swab (NPS) SARS-CoV-2 RT-PCR | 7 days | 
| TS viral load | Time to negative throat saliva (TS) SARS-CoV-2 RT-PCR | 7 days | 
| Inflammatory markers | Cytokine/ chemokine changes | 7 days | 
| Adverse events | Adverse events during treatment | 5 days | 
| Mortality | 30-day mortality | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, IFN-beta 1b, remdesivir, hospitalised