Triple combination of interferon beta-1b, lopinavir – ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomized, phase 2 trial

1. Dr. Rakesh Verma
1st Year Junior Resident
Department of Clinical Pharmacology &Therapeutics
Triple combination of
interferon beta-1b, lopinavir – ritonavir, and ribavirin
in the treatment of patients admitted to hospital with COVID-19:
an open-label, randomized, phase 2 trial

2. Ivan Fan-Ngai Hung, Kwok-Cheung Lung, Eugene Yuk-Keung Tso, Raymond Liu, Tom Wai-Hin Chung, Man-Yee Chu, et al.
1) Department of Medicine, Queen Mary Hospital
2) State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection
3) The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China; Department of
Medicine, Department of Microbiology, and Department of Intensive Care
The Lancet. May 30, 2020; 395: 1695–704.

3. INTRODUCTION
▸ COVID-19:
▹ Spreads quickly from person to person
▹ Primarily an acute viral pneumonia leading to respiratory failure as
reported in autopsy studies and animal models
▹ Cytokine storm and extrapulmonary involvements have been
occasionally reported.
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Cytokine storm and extrapulmonary involvements have been
occasionally reported.

5. INTRODUCTION
▸ Lopinavir and many interferons (interferon beta):
▹ Have modest activity in vitro against SARS-CoV and Middle East
respiratory syndrome (MERS)-CoV
▹ Can be used synergistically with ribavirin.
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6. ▸ The first phase 2 randomised controlled trial on the triple combination of
interferon beta-1b, lopinavir–ritonavir, and ribavirin, compared with single-
drug lopinavir–ritonavir in the treatment of patients admitted to hospital with
COVID-19.
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INTRODUCTION

7. OBJECTIVES
▸ To assess the efficacy and safety of combined interferon beta-1b, lopinavir–
ritonavir, and ribavirin for treating patients with COVID-19
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8. METHOD
▸ Phase 2, multicentric, open-label, randomized trial
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9. Trial Settings
▸ Adult patients aged ≥18 years admitted to hospital from Feb 10, 2020, for
virologically confirmed COVID-19, were recruited from the Queen Mary
Hospital, Pamela Youde Nethersole Hospital, Ruttonjee Hospital, United
Christian Hospital, Queen Elizabeth Hospital, and Tuen Mun Hospital in
Hong Kong.
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10. ELIGIBILITY CRITERIA
▸ Age ≥18 years,
▸ A national early warning score 2 (NEWS2) of at least 1,
▸ Symptom duration of 14 days or less upon recruitment.
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11. RANDOMISATION
▸ Simple randomisation
▸ Open-label
▸ Patients assigned to a serial number and each serial number was linked to
a computer-generated randomisation list assigning the antiviral treatment
regimens.
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12. RANDOMISATION
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Randomization (2:1)
Group 1
Lopinavir-Ritonavir
+
Ribavirin
+
Interferon beta-1b
Group 2
Lopinavir-Ritonavir

13. TRIAL PROFILE
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Lopinavir–ritonavir +
ribavirin+
Interferon beta-1b
Lopinavir–ritonavir
14 days
BD

14. Standard of care
▸ Oxygen
▸ Non-invasive and Invasive ventilator support
▸ Extracorporeal membrane oxygenation support
▸ Dialysis support &
▸ Antimicrobial treatment for secondary bacterial infection as indicated
clinically.
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15. Clinical and laboratory monitoring
▸ History and Physical examination:
▸ Investigation:
- Chest radiograph and ECG,
- High resolution CT,
- Nasopharyngeal swab, posterior oropharyngeal saliva, throat swab – DAILY
- Stool or rectal swab
- Urine (if available)
- CBC, LFT, RFT, LDH, CK, CRP, ESR, and cytokine profile
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16. Outcomes
▸ Primary Endpoint:
▸ Time to achieve a negative RT-PCR result for SARS-CoV-2 in a
nasopharyngeal swab sample
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17. Outcomes
Secondary Endpoints-
▸ Time to resolution of symptoms defined as a NEWS2 of 0 maintained
for 24 h;
▸ Daily NEWS2 and sequential organ failure assessment (SOFA) score;
▸ Length of hospital stay; and
▸ 30-day mortality.
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18. Statistical analysis
▸ Sample size calculation referencing
Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical
findings. Thorax 2004; 59: 252–56.
 Designed on the basis of
▸ an estimated difference of 26·4% in the 21-day mortality or ARDS rate in
severe SARS-CoV-2 infection,
▸ when treated with lopinavir–ritonavir (2·4%) versus historical controls
without antiviral treatment (28·8%)
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19. Statistical analysis
▸ Necessary Sample size/Group- 30
▸ 2 sided α level of significance- 0.05
▸ Power of study- 80%
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20. Statistical analysis
▸ Categorical variables were compared using the χ² test and continuous
variables were compared using the Mann-Whitney U test, for both intention-
to-treat and subgroup analyses.
▸ Hazard ratios (HRs) with 95% CIs were calculated by Cox proportional
hazards model.
▸ Statistical analysis was performed using SPSS, version 26.0 and PRISM,
version 8. 20

21. Results
▸ The median number of days from symptom onset to start of study
treatment was 5 days (IQR 3–7).
▸ The combination group had a significantly shorter median time from
start of study treatment to negative nasopharyngeal swab (7 days [IQR
5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI
1·86–10·24], p=0·0010).
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22. Baseline demographics of the study population-
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23. CONTINUED…
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28. Adverse events in the study population-
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29. DISCUSSION
▸ A triple combination of an injectable interferon (interferon beta-1b)
oral protease inhibitor (lopinavir–ritonavir) and
an oral nucleoside analogue (ribavirin)
▸ given within 7 days of symptom onset
▸ is effective in suppressing shedding of SARS-CoV-2
▸ not just in a nasopharyngeal swab, but in all clinical specimens, compared
with lopinavir–ritonavir alone.
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30. ▸ So far, only two open label non-randomised trials have been reported.
One trial used a combination of
▸ oral hydroxychloroquine and azithromycin in 20 patients with COVID-19
▸ it reduced viral load significantly by day 6 after treatment,
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DISCUSSION

31. ▸ In other trial, small retrospective analysis showed that viral load was
negative at day 7 post-treatment in 75% of patients with COVID-19
treated with Arbidol( Umifenovir) and Lopinavir– Ritonavir.
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DISCUSSION

32. CONCLUSION
▸ Most patients treated with the triple combination were RT-PCR negative in
all specimens by day 8.
▸ The side-effects were generally mild and self-limiting.
▸ Triple antiviral therapy were safe and superior to lopinavir–ritonavir alone.
▸ Shortening of virus shedding, alleviation of symptoms, and
▸ Facilitating discharge of patients with mild to moderate COVID-19.
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33. LIMITATIONS
▸ This trial was open label, without a placebo group, and confounded by a
subgroup omitting interferon beta-1b within the combination group,
depending on time from symptom onset.
▸ Absence of critically ill patients did not allow the generalisation of our
findings to severe cases.
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34. RECOMMENDATION
▸ A subsequent phase 3 trial with interferon beta-1b as a backbone treatment
with a placebo control group should be considered, because subgroup
comparison suggested that interferon beta-1b appears to be a key
component of combination treatment.
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