IFN-beta 1b and Remdesivir for COVID19

• ClinicalTrials.gov Identifier: NCT04647695
• Recruitment Status: Unknown
• First Posted: December 1, 2020
• Last Update Posted: December 10, 2020
• Sponsor: The University of Hong Kong
• Information provided by (Responsible Party): The University of Hong Kong

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Covid19	Drug: Interferon beta-1b; Drug: Remdesivir	Phase 2

Detailed Description:

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Randomized Controlled Trial on Interferon β-1b and Remdesivir Combination Versus Remdesivir as Treatment for COVID-19 Infection
• Actual Study Start Date: November 20, 2020
• Estimated Primary Completion Date: July 31, 2021
• Estimated Study Completion Date: September 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: IFN-beta 1b and remdesivir; 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; 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; Other Name: Remdesivir
Active Comparator: Remdesivir; 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; a 5-day course of IV remdesivir 200mg loading on day 1 followed by remdesivir 100mg daily on day 2 to day 5

Outcome Measures

Primary Outcome Measures :

1. Clinical improvement [ Time Frame: 30 days ]
   Time to complete alleviation of symptoms as defined by NEWS of 0 maintained for 24 hours

Secondary Outcome Measures :

1. Hospitalisation [ Time Frame: 30 days ]
   Length of hospitalization
2. NPS viral load [ Time Frame: 7 days ]
   Time to negative nasopharyngeal swab (NPS) SARS-CoV-2 RT-PCR
3. TS viral load [ Time Frame: 7 days ]
   Time to negative throat saliva (TS) SARS-CoV-2 RT-PCR
4. Inflammatory markers [ Time Frame: 7 days ]
   Cytokine/ chemokine changes
5. Adverse events [ Time Frame: 5 days ]
   Adverse events during treatment
6. Mortality [ Time Frame: 30 days ]
   30-day mortality

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Recruited subjects include all adult patients ≥18 years hospitalized for virologic confirmed SARS-CoV-2 infection.
2. 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)
3. 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.
4. 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:

1. Inability to comprehend and to follow all required study procedures.
2. Allergy or severe reactions to the study drugs
3. Patients taking medication that will potentially interact with l interferon beta-1b and remdesivir
4. Patients with known history of severe depression
5. Estimated glomerular filtration rate <30 mL/min
6. 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.
7. 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.
8. Have a history of alcohol or drug abuse in the last 5 years.
9. Have any condition that the investigator believes may interfere with successful completion of the study.

Contacts and Locations

Contacts

Contact: Ivan FN Hung, MD FRCP; 22554049; ivanhung@hku.hk

Contact: Kelvin KW To, MD FRCPath; 22553111; kelvinto@hku.hk

Locations

Hong Kong

Queen Mary Hospital; Recruiting

Hong Kong, Hong Kong, 852

Contact: Ivan FN Hung, MD FRCP 22554049 ivanhung@hku.hk

Contact: Kelvin KW To, MD FRCPath 22553111 kelvinto@hku.hk

Sponsors and Collaborators

The University of Hong Kong

Investigators

• Principal Investigator: Ivan FN Hung, MD FRCP; The University of Hong Kong

More Information

Publications of Results:

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fatkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8.

Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, Ng YY, Lo J, Chan J, Tam AR, Shum HP, Chan V, Wu AK, Sin KM, Leung WS, Law WL, Lung DC, Sin S, Yeung P, Yip CC, Zhang RR, Fung AY, Yan EY, Leung KH, Ip JD, Chu AW, Chan WM, Ng AC, Lee R, Fung K, Yeung A, Wu TC, Chan JW, Yan WW, Chan WM, Chan JF, Lie AK, Tsang OT, Cheng VC, Que TL, Lau CS, Chan KH, To KK, Yuen KY. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-1704. doi: 10.1016/S0140-6736(20)31042-4. Epub 2020 May 10.

Other Publications:

Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15.

Chu H, Chan JF, Wang Y, Yuen TT, Chai Y, Hou Y, Shuai H, Yang D, Hu B, Huang X, Zhang X, Cai JP, Zhou J, Yuan S, Kok KH, To KK, Chan IH, Zhang AJ, Sit KY, Au WK, Yuen KY. Comparative Replication and Immune Activation Profiles of SARS-CoV-2 and SARS-CoV in Human Lungs: An Ex Vivo Study With Implications for the Pathogenesis of COVID-19. Clin Infect Dis. 2020 Sep 12;71(6):1400-1409. doi: 10.1093/cid/ciaa410.

Yuan S, Chan CC, Chik KK, Tsang JO, Liang R, Cao J, Tang K, Cai JP, Ye ZW, Yin F, To KK, Chu H, Jin DY, Hung IF, Yuen KY, Chan JF. Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19). Viruses. 2020 Jun 10;12(6):628. doi: 10.3390/v12060628.

Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, Cai JP, Chu H, Zhou J, Chen H, Qin C, Yuen KY. Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015 Dec 15;212(12):1904-13. doi: 10.1093/infdis/jiv392. Epub 2015 Jul 21.

Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, Tsoi HW, Lo SK, Chan KH, Poon VK, Chan WM, Ip JD, Cai JP, Cheng VC, Chen H, Hui CK, Yuen KY. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020 Feb 15;395(10223):514-523. doi: 10.1016/S0140-6736(20)30154-9. Epub 2020 Jan 24.

• Responsible Party: The University of Hong Kong
• ClinicalTrials.gov Identifier: NCT04647695
• Other Study ID Numbers: UW 20-535
• First Posted: December 1, 2020
• Last Update Posted: December 10, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymous IPD will be shared upon request to the HKU IRB and approved by the panel
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Upon study publication for 12 months
• Access Criteria: Approval by the IRB panel

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The University of Hong Kong:

COVID-19; IFN-beta 1b; remdesivir; hospitalised

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Interferons; Interferon-beta; Remdesivir; Interferon beta-1b; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Adjuvants, Immunologic