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.
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.
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
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
Olabisi Onabanjo University Teaching Hospital
Sagamu, Ogun State, Nigeria
Infectious Disease Hospital, Olodo
Ibadan, Oyo State, Nigeria