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

Abstract

Objectives To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19. Trial design This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial. Participants Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward. Inclusion criteria Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening. Intervention and comparator Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria. Main outcome measures Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs. Randomisation Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities. Blinding None, this is an open-label trial. Number to be randomised (sample size) 98 patients (49 per arm). Trial status Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021. Trial registration The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534. Full protocol The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Efficacy and safety of nitazoxanide combined with ritonavir-boosted atazanavir for the treatment of mild to moderate COVID-19

“…However, we only achieved 64% of the target sample size of 89 required to show or exclude 60% improvement in time to SARS-CoV-2 PCR negativity. 20 Additionally, the limited number of patients with detectable SARS-CoV-2 in saliva at baseline requires that our finding of no difference in viral load change in this trial be interpreted with caution. The choice of saliva for SARS-CoV-2 viral load in this trial was based on observed concordance with nasopharyngeal swabs in the testing laboratory and similar early reports.…”

“…Further details about the trial design, inclusion and exclusion criteria are provided in the published protocol. 20 The trial is registered on ClinicalTrials.gov (NCT04459286) and Pan African Clinical Trials Registry (PACTR202008855701534).…”

Uso de ivermectina e nitazoxanida para tratamento e profilaxia da COVID-19: Uma revisão sistemática

“…Após a triagem de títulos e resumos, 25 estudos foram analisados quanto aos critérios de inclusão e 16 foram excluídos. Os artigos foram excluídos por não apresentarem o desenho de estudo previamente definido Campos, Fulco, et al, 2020;Chitsike & Duerksen-Hughes, 2021;Cicka & Sukhatme, 2021;Duru et al, 2021;García-Álvarez & García-Vigil, 2020;Kelleni, 2020Kelleni, , 2021Lisi et al, 2020;Martins-Filho et al, 2020;Mostafa et al, 2020;Olagunju et al, 2021;Paumgartten et al, 2020;Rajoli et al, 2020;Ribeiro et al, 2021).…”

A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19

“…All patients provided written informed consent as per the ethics committee’s approved process. Further details about the trial design, inclusion and exclusion criteria are provided in the published protocol ( 19 ). The trial is registered on ClinicalTrials.gov (NCT04459286) and Pan African Clinical Trials Registry (PACTR202008855701534).…”