A key strategy in the treatment of COVID-19 would be to find an effective antiviral agent that would decrease the peak viral load and, consequently, the associated degree of immunopathological damage that follows this phase. The clinically approved substances considered for this study are used for treatment of other virus diseases, like HIV (atazanavir) and HCV (sofosbuvir and daclatasvir). Severe progression of COVID-19 among patients under treatment for these aforementioned viruses is empirical less common. Besides, the clinical rationale, there are pre-clinical evidence pointing out that patients with COVID-19 could benefit from treatments with atazanavir, sofosbuvir and daclatasvir.
We have planned an randomized, adaptive, placebo-controlled, double-blind study to be carried
out in 3 seamless stages. The first two stages are phase 2 studies with a third stage phase 3
to be conducted conditional to success of the first phase 2 and second phase 2 stages
including efficacy and safety.
In particular, there is great interest in the possibility of combining the phase II and phase
III stages of the development process and this is the focus here. Phase II trials can be
thought of as part of the learning stage where dose selection and appropriate treatment
groups are assessed together with initial indications of their effects. Phase III trials are
usually more confirmatory in nature where the treatment effects of the selected treatments
are assessed in a full-scale trial. Seamless phase II/III trials are concerned with combining
these two aspects into a single trial. There are a clearly advantages of speed in that the
dose selection and treatment effects are assessed within a single trial rather than
establishing separate trials. In addition, all data available for the selected dose are used
in the analysis rather than just those from the second stage with a consequent gain in power.
The savings in the number of patients is achieved by applying a form of screening of
competing treatments in the initial phase and abandoning those that are ineffective before
the end of the study following pre-established premises of futility. Effect estimates,
confidence intervals and p values need some statistical adjustments to allow for this,
otherwise they will be biased towards a benefit of the treatment. This study design, starting
with a phase II, could give us a treatment regimen composed of one or more repurposed
antivirals drugs that could improve the clinical outcomes of those hospitalized with COVID-19
reducing time to recovery and the need for respiratory support. It will be conducted in about
60 Brazilian hospitals.
Selection of drugs rationale
- Atazanavir: Atazanavir is a potent inhibitor of HIV-1 protease and is not associated
with significant dyslipidemia, as observed with other protease inhibitors.15 It was
approved by the FDA on January 29, 201516,17 as a combination of atazanavir and
cobicistat. Atazanavir can also be combined with ritonavir18 In a protease-free cell
assay, atazanavir blocked the major protease activity of SARS-Cov-2 at a concentration
of 10 μM. In in vitro models of viral infection/replication performed on Vero cells, a
human pulmonary epithelial cell line and primary human monocytes, atazanavir inhibited
SARS-CoV-2 replication; in addition, the concentrations of interleukin 6 (IL-6) and
tumor necrosis factor type alpha (TNF-α) induced by the virus were reduced.10 Currently,
no clinical study is registered on the ClinicalTrials.com website to assess the effects
of atazanavir in the context of COVID-19.
- Daclastavir: Daclatasvir is a direct-acting antiviral that inhibits HCV replication by
binding to the N- terminal of the NS5A protein, affecting viral RNA replication. NS5A is
a multifunctional protein in the HCV replicative cycle, involved in the enrollment of
cell lipid bodies, RNA binding and replication, protein phosphorylation, cell signaling
and antagonism of interferon pathways.19 In an in vitro study, daclatasvir consistently
inhibited the production of SARS-CoV-2 infectious particles in Vero cells, in the HuH-7
cell line and in Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively.
Daclatasvir reached early events during the replication cycle of SARS-CoV-2 and
prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the
cytokine storm typical of SARS-CoV-2 infection.20
- Sofosbuvir/daclastavir:
Sofosbuvir (SOVALDI®) is a nucleotide analog directed against HCV NS5B polymerase, clinically
approved with potent antiviral effects on the hepatitis C virus with several genotypes21. It
is proposed that the drug could be a potential option in the treatment of COVID-19 especially
at the beginning of the disease and before the invasion of the virus in the cells of the lung
parenchyma, based on the similarity between the replication mechanisms of HCV and
coronavirus22. In vitro, sofosbuvir showed EC50 values of 6.2 and 9.5 µM in HuH-7 (hepatoma)
and Calu-3 (type II pneumocytes) cells respectively, although inactive in Vero cells (these
cells are unable to make this conversion sofosbuvir in the pro-drug to active form)11.
First stage - will have 6 arms with total treatment for 10 days:
First stage Phase II - 6 arms
1. Atazanavir (ATV)
2. Daclatasvir (DCV)
3. Sofusbuvir+Daclatasvir (SFV/DCV)
6. Placebo (PbO) ATV 7. (PbO) DCV 8. (PbO) SFV/DCV
Second stage Phase II - 4 arms:
1. Best from first stage
2. Best from first stage + Second best
3. PbO Best from first stage;
4. PbO Best from first stage + Pbo Second best
Phase III - 2 arms:
1. Best from phase II second stage
2. (PbO) Best from phase 2 second stage
Main questions: The aim of the Coalition IX REVOLUTIOn evaluation is to answer the following
questions:
- Are antiviral candidates (atazavir, daclatasvir/sofosbuvir) able to reduce the viral
load of SARS-CoV-2 compared to placebo in patients hospitalized with COVID-19 with ≤ 9
days of symptoms?
- Which antiviral alone has the best effect in reducing the viral load of SARS-CoV-2 in
patients hospitalized with COVID-19 with ≤ 9 days of symptoms? And which is the second
most effective?
- Are combined antiviral candidates able to reduce the viral load of SARS-CoV-2 compared
to antiviral alone and placebo in patients hospitalized with COVID-19 with ≤ 9 days of
symptoms?
- Are isolated or combined antiviral candidates safe compared to placebo?
- Does the antiviral candidate alone or in combination improve clinical outcomes (days
free of respiratory support in 15 days) compared with placebo in patients hospitalized
with COVID-19 with ≤ 9 days of symptoms?
Primary/secondary objectives Primary objectives Phase II/ 1st and 2nd stages: Assess the
effect of treatment with antivirals alone or combined with each other compared to placebo in
reducing the of viral load of SARS-CoV-2 in nasopharyngeal swab samples obtained at baseline
(d0) and days 3, 6 and 10; Phase III: Evaluate the effectiveness of best antivirals from
Phase II alone or combined compared to placebo in increasing days free of respiratory support
defined as the number of days without oxygen, non-invasive ventilation / high-flow nasal
cannula or mechanical ventilation in 15 days.
Secondary Objectives
1. Ordinal 7-stage scale for clinical outcomes on the 15th day (1. not hospitalized with
resumption of normal activities; 2. not hospitalized, but unable to resume normal
activities; 3. hospitalized, without the need for supplemental oxygen; 4. hospitalized ,
requiring supplemental oxygen; 5. hospitalized, requiring high-flow nasal oxygen
therapy, non-invasive mechanical ventilation or both; 6. hospitalized, requiring blood
oxygenation through the membrane system, invasive mechanical ventilation or both; 7.
Death);
2. Ordinal 6-stage scale for clinical outcomes on day 7 1. not hospitalized; 2.
hospitalized, without the need for supplemental oxygen; 3. hospitalized, requiring
supplemental oxygen; 4. hospitalized, requiring high-flow nasal oxygen therapy,
non-invasive mechanical ventilation, or both; 5. hospitalized, requiring blood
oxygenation through a membrane system, invasive mechanical ventilation or both; 6.
Death;
3. Mortality in 28 days
4. Days free from mechanical ventilation within 28 days;
5. Days out of hospital within 28 days;
6. Time to discharge, defined as the number of days from randomization to discharge, within
28 days
7. Evaluate free days of respiratory support in 15 days for Phase II/1 and II/2
8. Grade 2, 3 or 4 adverse events that was not present at patient's admission, defined by
the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric
Adverse Events (corrected version 2.1, July, 2017); 53
9. Evaluate Serious adverse events (SAE);
10. Evaluate discontinuation of study drug-related treatment.
Recruitment and enrollment: The randomization list will be generated electronically using
appropriate software. Randomization will be performed in blocks and stratified by center. The
allocation concealment will be maintained through a centralized, automated, internet-based
randomization system, available 24 hours a day. Hospitalized patients with the inclusion
criteria will be allocated in an allocation ratio 3: 3: 3: 1: 1: 1 (3 for each treatment
group and 1 for placebo) in Phase II / 1. The parameter of interest for the efficacy decision
will be the comparison of the decay rates (slope) of the viral load logarithm from RT-PCR to
COVID-19 in 10 days between the treatment groups in comparison with the control (placebo). In
the 2nd stage, we will allocate patients in the ratio 2: 2: 1: 1 (2 for each active arm and 1
for each placebo) and the same statistic, now comparing combined treatment against the
treatment selected in phase II / 1 and placebo, since it is already known that the treatment
of phase II / 1 is effective for reducing viral load according to the pre specified criteria.
As long as we have success on primary outcome of Phase II/2, Phase III will proceed in a 2: 1
allocation ratio (2 active treatments for each placebo).
Blinding:This is a double-blind study for participants of the same active drug and
researchers. Both participant and investigator can know, after randomization, which
medication they were allocated to. However, none will know whether the capsule to be
administered is active or placebo, ensuring blinding within that specific group to which the
participant was allocated.
Sample size and analysis: 252 patients in total in phase II first stage (189 in active groups
and 63 in placebo) and 189 patients in total in phase II second stage (126 in active groups
and 63 in placebo). In case of success in Phase II, 564 additional participants will be
recruited in phase 3 (376 in the active group and 188 in the placebo). Thus, at the end of
phase III, we will have 314 patients evaluated in the Placebo group and between 439 and 502
patients in the treatment group.
Drug: Atazanavir
600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.
Other Name: Active Group
Drug: Daclatasvir 60 mg
initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.
Other Name: Active Group
Drug: Sofusbuvir + Daclastavir 60 mg
400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofusbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)
Other Name: Active Group
Drug: Placebo Atazanavir
2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
Other Name: Placebo group
Drug: Placebo Daclatasvir 60 mg
2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
Other Name: Placebo group
Drug: Placebo Sofusbuvir + Daclatasvir 60 mg
2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
Other Name: Placebo group
Inclusion Criteria:
1. Adults (≥ 18 years) hospitalized with COVID-19:
- SARS-CoV-2 positive RT-PCR or Antigen test
- Typical clinical history and chest CT with typical findings, pending RT-PCR for
SARS-CoV-2
2. Symptom duration <= 9 days
3. SpO2 <= 94% in room air or need for supplemental oxygen to maintain SpO2> 94%
4. The patient consents to participate in the study and is willing to comply with all
study procedures, including the collection of virology samples
Exclusion Criteria:
1. Patients in need of respiratory support with invasive mechanical ventilation;
2. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit
of normal;
3. Total bilirubin > 2 mg/dL;
4. Platelets <50,000 cel/L;
5. Total neutrophil count <750 cell/L;
6. Renal dysfunction (estimated glomerular filtration rate [eGFR] <30 mL / min / 1.73 m2,
using the MDRD or CKD-EPI method); and pre-defined renal failure stage 3 according to
AKINx classification with serum creatinine> 4 mg / dl or patient already on renal
replacement therapy;
7. Previously known liver disease (liver cirrhosis), defined as a report by the
participant or written in the respective cirrhosis chart, esophageal varices, or the
presence of clinical ascites on examination;
8. Decompensated congestive heart failure defined as the presence of dyspnea, edema of
the lower limbs or rales on pulmonary auscultation, jugular turgency or chest X-ray
with signs of pulmonary congestion;
9. Pregnant or breast feeding patients;
10. Known allergy or hypersensitivity to any study drug;
11. Hepatitis C carrier (HCV RNA positive), active Hepatitis B (positive surface antigen
in the past), or HIV (ELISA and confirmatory Western Blot in the past). New screening
tests are NOT required;
12. Patients currently using nucleoside or nucleotide analog drugs for any indication;
13. Corrected Q interval T> 480 on the electrocardiogram;
14. Heart rate <55 bpm;
15. Patients in use or who recently used (<90 days) amiodarone;
16. Women of childbearing potential and men with a partner of childbearing potential who
do NOT agree to use two contraceptive methods (including barrier method) for 100 days.
Hospital do Coracao
Sao Paulo, SP, Brazil
Israel S Maia, MSc, Principal Investigator
HCor Research Institute