The Nitazoxanide Plus Atazanavir for COVID-19 Study

NCT04459286 | Terminated Phase 2 DMC

• 1 other identifier: NACOVID
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 2

Brief Summary

Since the outbreak of the novel coronavirus disease in 2019 (COVID-19), an unprecedented global search for potential therapeutics and vaccines is ongoing. In this study, a combination of two drugs that have been shown to be effective against the germ that causes COVID-19 in the laboratory will be tested in patients diagnosed with moderate to severe COVID-19. One of the drugs is called nitazoxanide and the second is atazanavir/ritonavir. Nitazoxanide has been used for the treatment of diarrhea since 2004 while atazanavir/ritonavir was approved for HIV treatment in 2003. They are known to be safe in humans. In this pilot study, 98 COVID-19 patients will be recruited into two groups. The 49 patients in group 1 will receive the standard of care determined by their primary care providers while the 49 patients in group 2 will receive both the standard of care combined with the two study drugs. Patients in group 2 will receive the study drugs for 14 days and all patients will be monitored for a total of 28 days. The time it takes for the germ that causes COVID-19 to be completely removed from the body (in nasal secretions) and the time to clinical improvement will be monitored in all patients and compared between the two groups.

Conditions

Covid-19

Keywords

SARS-CoV infection; COVID-19; coronavirus

Outcome Measures

Primary Outcomes (3)

• Time to clinical improvement

  Proportion of patients with clinical improvement, as defined by live discharge from the hospital, a decrease of at least 2 points from baseline on a 7-point ordinal scale, or both.

  28 days

• Time to SARS-CoV-2 negativity

  Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at Days 7, 10, 14 and 28

  28 days

• Difference in SARS-CoV-2 AUC

  Temporal patterns of SARS-CoV-2 viral load quantified by RT-PCR from nasal swabs or sputum of patients receiving SOC alone versus SOC plus study drug

  28 days

Secondary Outcomes (6)

• Time to symptoms resolution

  28 days

• Clinical status as assessed with the seven-category ordinal scale on days 7 and 14

  14 days

• Duration of hospitalization in survivors

  28 days

• Day 28 mortality

  28 days

• Time from treatment initiation to death

  28 days

Study Arms (2)

Standard of Care (SOC)

ACTIVE COMPARATOR

Participants in this arm will receive SOC alone, which will be as determined by the clinical team at the treatment centres in line with the current National Interim Guidelines for Clinical Management of COVID-19

Other: Standard of Care

SOC plus Intervention

EXPERIMENTAL

Participants in this arm will receive SOC plus study intervention composed of orally administered nitazoxanide and atazanavir/ritonavir tablets

Drug: Nitazoxanide and atazanavir/ritonavir; Other: Standard of Care

Interventions

Nitazoxanide and atazanavir/ritonavir DRUG

1000 mg nitazoxanide tablets twice daily and 300/100 mg atazanavir/ritonavir tablets once daily with meal

SOC plus Intervention

Standard of Care OTHER

SOC will be as determined by the clinical team at the treatment centres in line with the current National Interim Guidelines for Clinical Management of COVID-19

SOC plus Intervention; Standard of Care (SOC)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willingness and ability to provide written informed consent
• At least 18 and not more than 75 years of age at study entry
• SARS-CoV-2 infection confirmed by PCR test within 4 days before randomization
• Currently symptomatic (fever or chills, cough, myalgia, sore throat, shortness of breath, or new onset of anosmia or ageusia) and at COVID-19 isolation and treatment centre

You may not qualify if:

• Inability to take orally administered medication or food
• Known hypersensitivity to study medication
• Pregnant or lactating (unless practicing exclusive replacement feeding for the entire study duration)
• Participation in any other interventional trial for COVID-19 (observational study co-enrollment allowed)
• Concurrent treatment with other agents with actual or possible direct-acting antiviral activity against SARS-CoV-2 less than 24 hours prior to study drug dosing
• Concurrent use of agents with known or uncertain interaction with study drugs, including ritonavir
• Requiring mechanical ventilation at screening
• Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
• Creatinine clearance below 50 mL/min using the Cockcroft-Gault formula for participants above 18 years of age

Sponsors & Collaborators

• Obafemi Awolowo University: lead
• University of Liverpool: collaborator
• African Centre of Excellence for Genomics of Infectious Diseases: collaborator
• Infectious Disease Hospital Olodo: collaborator
• Obafemi Awolowo University Teaching Hospitals Complex: collaborator
• Osun State Ministry of Health: collaborator
• Olabisi Onabanjo University Teaching Hospital: collaborator

Study Sites (2)

Olabisi Onabanjo University Teaching Hospital

Sagamu, Ogun State, Nigeria

Location

Infectious Disease Hospital, Olodo

Ibadan, Oyo State, Nigeria

Location

Related Publications (7)

• Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016 May-Jun;9(3):227-30. doi: 10.1016/j.jiph.2016.04.001. Epub 2016 Apr 16.

  PMID: 27095301 BACKGROUND

• Cao J, Forrest JC, Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs. Antiviral Res. 2015 Feb;114:1-10. doi: 10.1016/j.antiviral.2014.11.010. Epub 2014 Nov 28.

  PMID: 25451075 BACKGROUND

• Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, Bardin M, Rossignol JF; US Nitazoxanide Influenza Clinical Study Group. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014 Jul;14(7):609-18. doi: 10.1016/S1473-3099(14)70717-0. Epub 2014 May 19.

  PMID: 24852376 BACKGROUND

• Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, O'Neill PM, Aljayyoussi G, Pennington SH, Ward SA, Hill A, Back DJ, Khoo SH, Bray PG, Biagini GA, Owen A. Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Clin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 10.1002/cpt.1909. Epub 2020 Jun 14.

  PMID: 32438446 BACKGROUND

• Rajoli RK, Pertinez H, Arshad U, Box H, Tatham L, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, Aljayyoussi G, Pennington SH, Hill A, Boffito M, Ward SA, Khoo SH, Bray PG, O'Neill PM, Hong WD, Biagini G, Owen A. Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. medRxiv [Preprint]. 2020 May 6:2020.05.01.20087130. doi: 10.1101/2020.05.01.20087130.

  PMID: 32511548 BACKGROUND

• Fowotade A, Bamidele F, Egbetola B, Fagbamigbe AF, Adeagbo BA, Adefuye BO, Olagunoye A, Ojo TO, Adebiyi AO, Olagunju OI, Ladipo OT, Akinloye A, Onayade A, Bolaji OO, Rannard S, Happi C, Owen A, Olagunju A. A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19. Front Med (Lausanne). 2022 Sep 8;9:956123. doi: 10.3389/fmed.2022.956123. eCollection 2022.

  PMID: 36160134 DERIVED

• Olagunju A, Fowotade A, Olagunoye A, Ojo TO, Adefuye BO, Fagbamigbe AF, Adebiyi AO, Olagunju OI, Ladipo OT, Akinloye A, Adeagbo BA, Onayade A, Bolaji OO, Happi C, Rannard S, Owen A. Efficacy and safety of nitazoxanide plus atazanavir/ritonavir for the treatment of moderate to severe COVID-19 (NACOVID): A structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Jan 4;22(1):3. doi: 10.1186/s13063-020-04987-8.

  PMID: 33397457 DERIVED

Related Links

• Nitaxoxanide Prescribing Information
• Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
• Atazanavir/ritonavir Prescribing Information

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome; Coronavirus Infections

Interventions

nitazoxanide; Atazanavir Sulfate; Ritonavir; Standard of Care

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; 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; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2020
• First Posted: July 7, 2020
• Study Start: October 9, 2020
• Primary Completion: May 2, 2021
• Study Completion: May 2, 2021
• Last Updated: March 2, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

NG (2)