IDSMB recommendation

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.

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