Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment

An Open-label Randomized Controlled Trial on Lopinavir/ Ritonavir, Ribavirin and Interferon Beta 1b Combination Versus Lopinavir/ Ritonavir Alone, as Treatment for 2019 Novel Coronavirus Infection

A combination of lopinavir/ ritonavir, ribavirin and interferon beta-1b will expedite the recovery, suppress the viral load, shorten hospitalisation and reduce mortality in patients with 2019-n-CoV infection compared with to lopinavir/ ritonavir

Study Overview

• Status: Completed
• Conditions: Novel Coronavirus Infection
• Intervention / Treatment: Drug: Lopinavir/ritonavir; Drug: Ribavirin; Drug: Interferon Beta-1B

Detailed Description

Hypothesis A combination of lopinavir/ ritonavir, ribavirin and interferon beta-1b will expedite the recovery, suppress the viral load, shorten hospitalisation and reduce mortality in patients with 2019-n-CoV infection compared with to lopinavir/ ritonavir alone

Primary objective: To evaluate the safety and efficacy in mortality reduction with a combination of lopinavir/ ritonavir, ribavirin and interferon beta-1b in the treatment of patient hospitalised for 2019-n-CoV infection and compare this to lopinavir/ ritonavir alone

Subject/patient definition: Recruited subjects include adult patients ≥18 years of age, admitted to the HA Hospitals from February 2020 onwards, with laboratory confirmed 2019-n-CoV infection. All subjects give written informed consent. Subjects must be available to complete the study and comply with study procedures.

Study design: This is a prospective open-label randomised controlled trial among adult patients hospitalised after February 2020 for virologically confirmed 2019-n-CoV infection. Patients will be randomly assigned to either a 14-day course of lopinavir/ ritonavir 400mg/100mg twice daily, ribavirin 400mg bd and zero to three doses of subcutaneous injection of interferon beta-1b 1mL (0.25mg; 8 million IU) on day 1, 3 and 5 (depending on day of admission from symptoms onset) plus standard care, or a 14-day course of lopinavir/ ritonavir 400mg/100mg twice daily plus standard care alone (2:1).

Intervention/study article: lopinavir/ ritonavir, ribavirin and interferon beta-1b

Primary outcome: Time to negative nasopharyngeal swab (NPS) 2019-n-CoV coronavirus viral RT-PCR

Secondary outcome:

1. Time to negative saliva 2019-n-CoV coronavirus viral RT-PCR
2. Time to clinical improvement of NEWS2 (National Early Warning Score 2) of 0 maintained for 24 hours
3. Length of hospitalisation
4. Adverse events during treatment
5. 30-day mortality
6. Cytokine/ chemokine changes

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • University of Hong Kong, Queen Mary Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Recruited subjects include all adult patients ≥18 years hospitalised for virologically confirmed 2019-n-CoV infection.
2. NEWS of ≥1 upon recruitment
3. Auditory temperature ≥38°C with at least one of the following symptoms (cough, sputum production, sore-throat, nasal discharge, myalgia, headache or fatigue) upon admission
4. Symptom duration ≤10 days
5. All subjects give written informed consent.
6. 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 with known prolonged QT or PR interval, second- or third-degree heart block, or ventricular cardiac arrhythmias, including torsade de pointes
4. Patients taking medication that will potentially interact with lopinavir/ ritonavir, ribavirin or interferon-beta1b
5. Patients with known history of severe depression
6. Pregnant or lactation women
7. Inability to comprehend and to follow all required study procedures
8. 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. Unwilling to refuse participation in another clinical study through the end of this study.
9. Have a history of alcohol or drug abuse in the last 5 years.
10. Have any condition that the investigator believes may interfere with successful completion of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study group; triple combination	Drug: Lopinavir/ritonavir; 400mg/100mg twice daily for 14 days; Drug: Ribavirin; 400mg twice daily for 14 days; Drug: Interferon Beta-1B; 0.25mg subcutaneous injection alternate day for 3 days
Active Comparator: Control group; single	Drug: Lopinavir/ritonavir; 400mg/100mg twice daily for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to negative NPS	Time to negative NPS 2019-n-CoV RT-PCR	Up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to negative saliva	Time to negative saliva 2019-n-CoV RT-PCR	Up to 1 month
Time to clinical improvement	Time to NEWS of 0	Up to 1 month
Hospitalisation	Length of hospitalisation	Up to 1 month
Mortality	30-day mortality	Up to 1 month
Immune reaction	Cytokine/ chemokine changes	up to 1 month
Adverse events	Adverse events during treatment	up to 1 month
Time to negative all clinical specimens	Time to negative NPS, saliva, urine and stool 2019-n-CoV RT-PCR	up to 1 month

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Hospital Authority, Hong Kong

Publications and helpful links

General Publications

• Moschen AR. IBD in the time of corona - vigilance for immune-mediated diseases. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):529-530. doi: 10.1038/s41575-020-0333-5.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Actual): March 30, 2020
• Study Completion (Actual): March 31, 2020

Study Registration Dates

• First Submitted: February 11, 2020
• First Submitted That Met QC Criteria: February 17, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): April 15, 2020
• Last Update Submitted That Met QC Criteria: April 13, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: nCoV; lopinavir/ ritonavir; IFN-beta
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Coronavirus Infections; Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Adjuvants, Immunologic; HIV Protease Inhibitors; Viral Protease Inhibitors; Interferons; Ribavirin; Ritonavir; Lopinavir; Interferon-beta; Interferon beta-1b
• Other Study ID Numbers: UW-20-074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No