Dual Therapy With Interferon Beta-1b and Clofazimine for COVID-19

Study Overview
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Brief Summary
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To conduct an open-label randomized controlled trial on a short course of interferon β-1b and clofazimine combination treatment for patients hospitalized for COVID-19 infection. To assess its safety and clinical efficacy.

Detailed Description
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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.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 HKU9-1, 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 1 July 2020, more than 10 million people been confirmed to have infected by SARS-CoV-2, resulting in more than 500,000 deaths. 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.2 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 β-1b, 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.7 More recently, the investigators have demonstrated that the triple combination of interferon β-1b, lopinavir/ ritonavir and ribavirin was significantly more effective in alleviating symptoms and respiratory SARS-CoV-2 viral load than lopinavir/ ritonavir with ribavirin or lopinavir/ ritonavir alone, suggesting that interferon β-1b might be the most potent antiviral among the three. Another in-vitro study on an oral antimicrobial clofazimine for treatment of non-tuberculous mycobacterium infection has been proven to reduce SARS-CoV-2 viral load. Therefore, the investigators propose to perform a prospective open-label randomised controlled trial among adult patients hospitalised after July 2020 for virologically confirmed SARS-CoV-2 infection. Patients will be randomly assigned to one of the three groups: group A: a 3-day course of 3 doses of subcutaneous injection of interferon β-1b 1mL (0.5mg; 16 million IU) consecutively on day 1 to day 3 and oral clofazimine 100mg twice daily on day 1, then 100mg daily for 2 days plus standard care, or group B: oral clofazimine 100mg twice daily on day 1, then 100mg daily for 2 days plus standard care, or group C: standard care alone (1:1:1).

Official Title
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An Open-label Randomised Controlled Trial on Dual Therapy With Interferon Beta-1b and Clofazimine Combination, as Treatment for COVID-19 Infection

Conditions
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COVID-19

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recruited subjects include all adult patients 18 years or above hospitalized for virologic confirmed SARS-CoV-2 infection. 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 or clofazimine Patients with known history of severe depression 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
Interventional Model Description: Open-label randomised controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFN beta-1b and clofazimine<br>A 3-day course of 3 doses of subcutaneous injection of interferon β-1b 1mL (0.5mg; 16 million IU) consecutively on day 1 to day 3 and oral clofazimine 100mg twice daily on day 1, then 100mg daily for 2 days plus standard care | Drug: Interferon beta-1b<br>* Subcutaneous injection of interferon β-1b 1mL (0.5mg; 16 million IU) for 3 days<br>Drug: Clofazimine<br>* Oral 100mg twice daily on day 1, then 100mg daily for 2 days<br>|
| Active Comparator: Clofazimine<br>A 3-day course of oral clofazimine 100mg twice daily on day 1, then 100mg daily for 2 days plus standard care | Drug: Clofazimine<br>* Oral 100mg twice daily on day 1, then 100mg daily for 2 days<br>|
| No Intervention: Control<br>Standard care alone | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical alleviation of symptoms | Time to complete alleviation of symptoms as defined by NEWS of 0 maintained for 24 hours | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalisation | Length of hospitalisation | 14 days | 
| Time to negative viral load | Time to negative nasopharyngeal swab, throat saliva and sputum viral load by RT-PCR | 7 days | 
| Inflammatory changes | Cytokine/ chemokine changes | 7 days | 
| Mortality | One month mortality rate | 30 days | 
| Adverse events | Adverse events during and shortly after treatment | 30 days | 

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