Study Protocol
June 2020
Study Protocol Title:
A prospective open label trial on the use of triple combination therapy of (Lopinavir–
Ritonavir) , Ribavirin, and nebulized Interferon Beta-1b in the management of moderate
COVID-19 pneumonia .
Principal investigator
:
Dr.Oghowan Abdelrahman Osman
Contact
:
+971565573503
:
:
United Arab Emirates, Rashid Hospital
+9714219100
Oabashir@dha.gov.ae
Address
Tel
E-mail
June 2020
Introduction
The ongoing COVID-19 disease pandemic (caused by SARS-Cov2), with associated mortality and
morbidity, has forced scientists to rework strategies to combat infectious diseases through drugs and control
measures. COVID-19 treatment requires both limiting viral multiplication and neutralizing tissue damage
induced by inappropriate immune reaction. The current standard treatment guidelines for COVID19
include pharmaceutical and other supportive care treatments.
Early treatment with a triple combination of antiviral drugs, is appropriate for the treatment of COVID-19
because the viral load of SARS-CoV-2 peaks at around the time of symptom onset. This is unlike the
situation of SARS and MERS when the antiviral treatment has time to suppress the viral load before it
peaks at around days 7–10 after symptom onset. The viral load profile of COVID-19 is similar to that of
influenza, which has a high viral load at the time of initiation of anti-influenza treatment. Thus, the antiviral
combination was considered a reasonable option to improve the outcome of severe influenza and the
combination of lopinavir–ritonavir and ribavirin did significantly reduce the mortality and respiratory
failure in patients during the 2003 SARS outbreak. Thus, we hypothesized that a triple combination of
antiviral drugs might rapidly suppress the high initial viral load, improve the clinical parameters, and reduce
risk of health-care workers by reducing the duration and quantity of virus shedding from these treated
patients.
This study aims to look for the efficacy and safety of the triple combination therapy of (Lopinavir–
Ritonavir), Ribavirin, and nebulized Interferon Beta-1b. It will evaluate the effect of triple therapy on
reducing the mortality and the need for intensive respiratory support and mechanical ventilation. It will
assess its effect on the biomarkers of Inflammation post treatment in comparison to pre-treatment. It will
correlate the triple therapy effect in alleviating symptoms, and facilitating the discharge of patients by
accelerating viral clearance and shorten the duration of viral shedding. Success may not only benefit the
individual infected patient but, by reducing duration of viral shedding it will even benefit the overall public
health and may help at slowing the tide of this pandemic.
This form of treatment modality is FDA approved and it is one of the approved options in UAE COVID19
National treatment guidelines.
June 2020
Study Objectives:
The study aims to evaluate the following objectives related to the triple combination therapy of
(Lopinavir–Ritonavir) , Ribavirin, and nebulized Interferon Beta-1b:

Requirement of invasive ventilation (and\or) ICU admission. [Time Frame: within 14 days from
the date of enrollment in the study] (Efficacy).

Time to viral clearance. [Noval corona swab/gene xpert tests will be done on admission
and then on day 5, day 7 , day 10 and day 14 ] (Efficacy).

Reduce the mortality rate. [ Mortality event will be traced until discharge from the hospital
or a maximum of 28 days after admission whichever comes first]. (Efficacy).

To assess the effects of the triple therapy on the biomarkers of Inflammation (C reactive
protein, Procalcitonin, lactate dehydrogenase, Dimer and Ferritin), which will be done on
admission and then on day3, day7, day10 and day 14. (Efficacy).

Improvement in radiological findings on day 5, day 7 and day14 post treatment.

Incidence of Adverse Events related to the medications under investigation (Lopinavir–
Ritonavir) , Ribavirin, and nebulized Interferon Beta-1b) . [Time Frame: within 14 days from
the date of enrollment in the study] (Safety).
Study Design
 Pre-treatment initiation steps :
o Eligible recipients admitted to study hospitals in phase one of the study will be chosen
according to inclusion criteria.
o Consent will be taken by attending physician from the patient or next of kin which explains
indications and possible side effects
o Baseline blood tests and Chest X ray will be performed prior to initiation on the triple
therapy.
 Method and management steps:
o Patients within the inclusion criteria, will be randomly assigned to a 7-days combination of
lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and
Nebulized interferon (IFN-α2b ) 250 mcg every 12 hours .
o The Triple therapy can be given in the Emergency Department, isolation units or Intensive
Care Unit for patients fulfilling the criteria.
June 2020
o Patient’s general condition as well as oxygen requirement and the need for mechanical
ventilation will be closely followed and documented.
o Patients will be observed for any of the drug’s related side effects.
o Circulating biomarkers of Inflammation will be followed (C-reactive protein, procalcitonin,
Ferritin, LDH and Dimer levels ) on admission and then on day3, day7, day10 and day 14
o Chest X ray will be performed as per the study protocol, baseline and then on Day 5, day7 and day
14.
o The patient will be followed by (Noval corona test PCR swabs /gene xpert tests) , baseline and then
on Day 5 , Day 7 , Day 10 and 14- to assess the time to viral clearance .
Study Population
o Adult patients, 18 to 70 years old with conformed COVID-19 infection and moderate Pneumonia
admitted in Rashid Hospital during the study period.
o Male and female patients meeting inclusion criteria will constitute study population
Subject Selection
Inclusion Criteria
 Age 18years to 70 years , male or female
 Laboratory confirmed COVID-19, diagnosed using PCR or gene xpert tests.
 Patients with radiological findings of moderate to severe Pneumonia, with > 50% of lung
field opacification
Exclusion Criteria:
 Pregnant Women
 Children below the age of 18 years
 Age more than 70 years
 Refusal to consent or withdraw from the study after consent
 Patients with hypersensitivity or contraindications to any of the drug included in this
study (Lopinavir–Ritonavir) , Ribavirin, or Interferon Beta-1b.
Study Protocol
It is interventional open label study for COVID patients who will receive the combined triple
therapy with (Lopinavir–Ritonavir) , Ribavirin, and nebulized Interferon Beta-1b.
Outcome Measures
June 2020
The study aims to measure safety and efficacy of the combined triple therapy (Lopinavir–
Ritonavir) , Ribavirin, and nebulized Interferon Beta-1b in moderate to severe COVID-19
Pneumonia
Safety measures parameters: Any cause mortality or known drug related side effects - within 14
days from the date of enrollment in the study.
Efficacy measures parameters: Reduce the mortality and the need for invasive ventilation.
Improvement in the inflammatory markers (CRP, procalcitonin, LDH, Dimer and Ferritin) as measured on
admission and then on day3, day7, day10 and day 14 . Improvement in radiological findings on day 5,
day 7 and day14 post treatment. The study will assess the effect of triple therapy in accelerating viral
clearance (measured by Time-to-viral clearance with two consecutive negative PCR swabs) .
Time-to-viral clearance: Time-to-viral clearance, defined as the number of days elapsed from the onset of
symptoms to the time of the first of two consecutive negative PCR tests at least 24 h
apart, was compared among the treatment groups using time-to-event analysis. Date of
onset of symptoms was considered as date of onset of disease, an appropriate time point
to allow for interrogation of disease course for all patients in this COVID-19 cohort.
References:
1. Hung IF, Lung KC, Tso EY, et al. 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 8:[Epub ahead of print].
2.Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterization and epidemiology of
2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. (2020)
395:565–74. doi: 10.1016/S0140-6736(20)30251-8
CrossRef Full Text
3. Wang BX, Fish EN. Global virus outbreaks: interferons as 1st responders. Semin Immunol.
(2019) 43:101300. doi: 10.1016/j.smim.2019.101300
PubMed Abstract | CrossRef Full Text
June 2020
4. Loutfy M, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon alfacon-1plus
corticosteroids in severe acute respiratory syndrome. JAMA. (2003) 290:3222–8. doi:
10.1001/jama.290.24.3222 CrossRef Full Text
5. Blaising A, Polyak SJ, Pécheur E-I. Arbidol as a broad spectrum antiviral: an update. Antiviral
Res. (2014) 107:84–94. doi: 10.1016/j.antiviral.2014.04.006
PubMed Abstract | CrossRef Full Text
6. https://www.cdc.gov/coronavirus/2019-ncov/lab/rt-pcr-detection-instructions.html
7. Kassamnara A, Kosinski M, Biecek P, Fabian S. Drawing Survival Curves Using “ggplot2.”
2018. (2019). Available online at: https://CRAN.R-project.org/package=survminer.
8. Huang X, Xu Y, Yang Q, Chen J, Zhang T, Li Z, et al. Efficacy and biological safety of
lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of
randomized controlled trials. Sci Rep. (2015) 5:8528. doi: 10.1038/srep08528
PubMed Abstract | CrossRef Full Text
9. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of
lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax.
(2004) 59:252–6. doi: 10.1136/thorax.2003.012658
PubMed Abstract | CrossRef Full Text
June 2020