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The Nitazoxanide Plus Atazanavir for COVID-19 Study (NACOVID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04459286
Recruitment Status : Recruiting
First Posted : July 7, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborators:
University of Liverpool
African Centre of Excellence for Genomics of Infectious Diseases
Infectious Disease Hospital Olodo
Obafemi Awolowo University Teaching Hospitals Complex
Osun State Ministry of Health
Olabisi Onabanjo University Teaching Hospital
Information provided by (Responsible Party):
Obafemi Awolowo University

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.


Condition or disease Intervention/treatment Phase
Covid-19 Drug: Nitazoxanide and atazanavir/ritonavir Other: Standard of Care Phase 2

Detailed Description:

COVID-19 caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an unprecedented global public health challenge which as at July 1, 2020 has spread to over 210 countries with over 10.6 million cases resulting in 514,808 deaths. More than 1500 clinical trials are currently ongoing in an unprecedented global search for potential therapeutics and vaccines. With increasing number of cases reported in low- and middle-income countries and and the possibility of a second wave of infections in countries where the pandemic appears to have slowed, studies to investigate promising therapies are urgently needed, especially those that can significantly reduce time to viral clearance and mortality. Shortening SARS-CoV-2 clearance time will lower treatment cost and reduce the economic impact of the pandemic.

The purpose of this phase 2 trial is to investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in achievement of SARS-CoV-2 PCR negativity and shorten the time to clinical improvement in patients diagnosed with moderate to severe COVID-19. The selection of candidates for this COVID-19 drug repurposing trial was guided by three pharmacological considerations: (1) demonstration of in-vitro anti-SARS-CoV-2 activity at doses shown or predicted to be tolerated by humans, (2) the feasibility of achieving effective concentration in relevant compartments, and (3) established human safety record.

This is a pilot phase 2, open label randomized controlled trial. A total of 98 patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 polymerase chain reaction (PCR) positive nasopharyngeal swab) will be recruited from participating treatment centres. Participants will be randomised to receive either the standard of care (SOC) plus nitazoxanide for 14 days, starting from day 1 or the SOC alone for 14 days.

Participants will be recruited within 2 days of admission into COVID-19 treatment centre. Before enrollment, they will be given adequate information about the trial, opportunity to ask questions, and sufficient time to consider participation. Before any screening procedures, a written consent will be obtained from each eligible subject who agrees to participate in the trial. Participants will then be randomly allocated 1:1 to receive either the SOC alone (control group) or SOC plus study drug (intervention group). Parallel assignment will be used to prevent sample size imbalance between groups and control for important covariates (e.g. age, comorbidities, gender) that may affect trial results. Participants in the intervention group will receive 1000 mg nitazoxanide (two tablets of 500 mg each) with meal two times daily (8 am and 8 pm) and one tablet of 300/100 mg atazanavir/ritonavir with meal once daily (8 pm) in addition SOC. Participants in the control arm will receive the SOC alone. 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.

The treatment duration for participants in the intervention group will be 14 days. However, follow up will continue until day 28 after study entry at the end of which all participants will exit the study. Evaluations at follow up visits will include daily symptoms monitoring using inFLUenza Patient-Reported Outcome (FLU-PRO) questionnaire, daily vitals, daily clinical improvement assessment, and swab and/or sputum collection for SARS-CoV-2 on days 2, 4, 6, 7, 14, and 28.

Sample size estimation is based on the assumption that an improvement of at least 60-80% in time to SARS-CoV-2 PCR negativity and symptoms resolution can be achieved in the intervention group compared with the control group. Hence, a total sample size of 89 will provide at least 80% power to show or exclude 60% improvement in time to SARS-CoV-2 PCR negativity. This assumes a two-sided and 5% type 1 error rate. Therefore, providing for a 10% loss to follow up rate, a total of 98 patients will be recruited.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Open Label Trial to Investigate the Efficacy and Safety of Nitazoxanide Plus Atazanavir/Ritonavir for the Treatment of COVID-19: a Pilot Study
Actual Study Start Date : October 9, 2020
Estimated Primary Completion Date : January 21, 2021
Estimated Study Completion Date : March 21, 2021


Arm Intervention/treatment
Active Comparator: Standard of Care (SOC)
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 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

Experimental: SOC plus Intervention
Participants in this arm will receive SOC plus study intervention composed of orally administered nitazoxanide and atazanavir/ritonavir tablets
Drug: Nitazoxanide and atazanavir/ritonavir
1000 mg nitazoxanide tablets twice daily and 300/100 mg atazanavir/ritonavir tablets once daily with meal

Other: Standard of Care
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




Primary Outcome Measures :
  1. Time to clinical improvement [ Time Frame: 28 days ]
    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.

  2. Time to SARS-CoV-2 negativity [ Time Frame: 28 days ]
    Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at Days 7, 10, 14 and 28

  3. Difference in SARS-CoV-2 AUC [ Time Frame: 28 days ]
    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


Secondary Outcome Measures :
  1. Time to symptoms resolution [ Time Frame: 28 days ]
    Time to symptoms resolution as monitored by the Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) questionnaire with some modifications for COVID-19

  2. Clinical status as assessed with the seven-category ordinal scale on days 7 and 14 [ Time Frame: 14 days ]
  3. Duration of hospitalization in survivors [ Time Frame: 28 days ]
  4. Day 28 mortality [ Time Frame: 28 days ]
  5. Time from treatment initiation to death [ Time Frame: 28 days ]
  6. Proportion with viral RNA detection over time [ Time Frame: 28 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04459286


Contacts
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Contact: Adeniyi Olagunju, PhD +2349068858698 aeolagunju@oauife.edu.ng

Locations
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Nigeria
Olabisi Onabanjo University Teaching Hospital Not yet recruiting
Sagamu, Ogun State, Nigeria
Contact: Bolanle Adefuye, MBBS, FWACP, MSc    +2348023851428    bolaadefuye@yahoo.com   
Obafemi Awolowo University Teaching Hospitals Complex Recruiting
Ile-Ife, Osun State, Nigeria
Contact: Temitope Ojo, MBChB, MPH    +2348035798224    linktopeojo@yahoo.com   
Contact: Adedeji Onayade, MBBS, MPH, FWACP, FMCPH    +2348037184015    aonayade@oauife.edu.ng   
State Specialist Hospital Asubiaro Recruiting
Osogbo, Osun State, Nigeria
Contact: Ajibola Olagunoye, MBBS, MPH, FEP, FWACP    +2348030850030    jiblow112@gmail.com   
Infectious Disease Hospital, Olodo Not yet recruiting
Ibadan, Oyo State, Nigeria
Contact: Adeola Fowotade, MBBS, MSc, PhD    +234817 755 7039    temilabike@gmail.com   
Contact: Olabode Ladipo, MBBS       tladops@yahoo.com   
Sponsors and Collaborators
Obafemi Awolowo University
University of Liverpool
African Centre of Excellence for Genomics of Infectious Diseases
Infectious Disease Hospital Olodo
Obafemi Awolowo University Teaching Hospitals Complex
Osun State Ministry of Health
Olabisi Onabanjo University Teaching Hospital
Additional Information:
Publications:

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Responsible Party: Obafemi Awolowo University
ClinicalTrials.gov Identifier: NCT04459286    
Other Study ID Numbers: NACOVID
First Posted: July 7, 2020    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Obafemi Awolowo University:
SARS-CoV infection
COVID-19
coronavirus
Additional relevant MeSH terms:
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Ritonavir
Atazanavir Sulfate
Nitazoxanide
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antiparasitic Agents