Antiviral Agents Against COVID-19 Infection

NCT04468087 | Completed Phase 2 DMC

• 1 other identifier: REVOLUTIOn
• Study Type: interventional
• Target: 256
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

COVID-19

Keywords

covid-19; antivirals; atazanavir; daclatasvir; sofosbuvir; multiarm multistage study; adaptive

Outcome Measures

Primary Outcomes (3)

• Phase II first step: Change in the slope of SARS-COV 2 viral load

  Change in the slope of the SARS-COV 2 log viral load evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (isolated antiviral).

  days 3, 6 and 10 after randomization

• Phase II second step: Change in the slope of SARS-COV 2 viral load

  Change in the slope of the SARS-COV 2 log viral load curve evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (combined antiviral).

  days 3, 6 and 10 after randomization

• Phase III: Number of free days from respiratory support

  Number of days without oxygen, non-invasive ventilation/high flow nasal cannula or need for mechanical ventilation in 15 days.

  15 days

Study Arms (6)

Atazanavir

EXPERIMENTAL

600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.

Drug: Atazanavir

Daclatasvir 60 mg

EXPERIMENTAL

initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.

Drug: Daclatasvir 60 mg

Sofusbuvir + Daclatasvir 60 mg

EXPERIMENTAL

400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofosbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)

Drug: Sofusbuvir + Daclastavir 60 mg; Drug: Placebo Sofusbuvir + Daclatasvir 60 mg

Placebo Atazanavir

PLACEBO COMPARATOR

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Drug: Placebo Atazanavir

Placebo Daclatasvir

PLACEBO COMPARATOR

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Drug: Placebo Daclatasvir 60 mg

Placebo Sofusbuvir + Daclatasvir

PLACEBO COMPARATOR

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Drug: Placebo Sofusbuvir + Daclatasvir 60 mg

Interventions

Atazanavir DRUG

600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.

Also known as: Active Group

Atazanavir

Daclatasvir 60 mg DRUG

initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.

Also known as: Active Group

Daclatasvir 60 mg

Sofusbuvir + Daclastavir 60 mg DRUG

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)

Also known as: Active Group

Sofusbuvir + Daclatasvir 60 mg

Placebo Atazanavir DRUG

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Also known as: Placebo group

Placebo Atazanavir

Placebo Daclatasvir 60 mg DRUG

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Also known as: Placebo group

Placebo Daclatasvir

Placebo Sofusbuvir + Daclatasvir 60 mg DRUG

2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.

Also known as: Placebo group

Placebo Sofusbuvir + Daclatasvir; Sofusbuvir + Daclatasvir 60 mg

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Symptom duration \<= 9 days
• SpO2 \<= 94% in room air or need for supplemental oxygen to maintain SpO2\> 94%
• The patient consents to participate in the study and is willing to comply with all study procedures, including the collection of virology samples

You may not qualify if:

• Patients in need of respiratory support with invasive mechanical ventilation;
• Alanine Transaminase (ALT) or Aspartate Transaminase (AST) \> 5 times the upper limit of normal;
• Total bilirubin \> 2 mg/dL;
• Platelets \<50,000 cel/L;
• Total neutrophil count \<750 cell/L;
• 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;
• 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;
• 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;
• Pregnant or breast feeding patients;
• Known allergy or hypersensitivity to any study drug;
• 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;
• Patients currently using nucleoside or nucleotide analog drugs for any indication;
• Corrected Q interval T\> 480 on the electrocardiogram;
• Heart rate \<55 bpm;
• Patients in use or who recently used (\<90 days) amiodarone;

Sponsors & Collaborators

• Hospital do Coracao: lead

Study Sites (1)

Hospital do Coracao

São Paulo, São Paulo, 04005-000, Brazil

Location

Related Publications (2)

• Maia IS, Marcadenti A, Veiga VC, Miranda TA, Gomes SPC, Carollo MBS, Negrelli KL, Gomes JO, Tramujas L, Abreu-Silva EO, Westphal GA, Fernandes RP, Horta JGA, Oliveira DC, Flato UAP, Paoliello RCR, Fernandes C, Zandonai CL, Coelho JC, Barros WC, Lemos JC, Bolan RS, Dutra MM, Gebara OCE, Lopes ATA, Alencar Filho MS, Arraes JA, Hamamoto VA, Hernandes ME, Golin NA, Santos TM, Santos RHN, Damiani LP, Zampieri FG, Gesto J, Machado FR, Rosa RG, Azevedo LCP, Avezum A, Lopes RD, Souza TML, Berwanger O, Cavalcanti AB; BRICNet. Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial. Lancet Reg Health Am. 2023 Apr;20:100466. doi: 10.1016/j.lana.2023.100466. Epub 2023 Mar 8.

  PMID: 36908503 DERIVED

• Maia IS, Marcadenti A, Zampieri FG, Damiani LP, Santos RHN, Negrelli KL, Gomes SPDC, Gomes JO, Carollo MBDS, Miranda TA, Santucci E, Valeis N, Laranjeira LN, Westphal GA, Horta JGA, Flato UAP, Fernandes C, Barros WC, Bolan RS, Gebara OCE, Alencar Filho MS, Hamamoto VA, Hernandes ME, Golin NA, Olinda RT, Machado FR, Rosa RG, Veiga VC, Azevedo LCP, Avezum A, Lopes RD, Souza TML, Berwanger O, Cavalcanti AB. Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan. Rev Bras Ter Intensiva. 2022 Jan-Mar;34(1):44-55. doi: 10.5935/0103-507X.20220002-pt.

  PMID: 35766657 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Atazanavir Sulfate; daclatasvir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Israel S Maia, MSc

  HCor Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, multicenter, multi-arm, multi-stage, study. Adults, COVID-19 confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or SARS-Cov2 Antigen hospitalized patients with ≤ 9 days duration of symptoms and SpO2\<=94% will be randomly assigned to receive antivirals with potential effectiveness for SARS-CoV-2. The study is planned to be an adaptive phase II / III study. The phase II will be divided into 2 stages: first and second stages. First stage will allocate patients into a 3:3:3:1:1:1 allocation ratio (5 for each treatment group and 1 for placebo) and second stage will allocate into 2:2:1:1 (2 for each treatment group and 1 for placebo). The phase 3 study will then proceed in a 2:1 allocation (2 treatments for each placebo).

Study Record Dates

• First Submitted: July 3, 2020
• First Posted: July 13, 2020
• Study Start: February 15, 2021
• Primary Completion: August 4, 2021
• Study Completion: August 4, 2021
• Last Updated: March 22, 2024

Record last verified: 2022-02

Locations

BR (1)