Catalysing the Containment of COVID-19

• Status: Recruiting
• Trial end date: 2022-02-01
• Target enrollment: 0
• Participant gender: All

Summary

COVID-19 due to SARS-CoV-2 infection is a rapidly escalating global pandemic for which there is no proven effective treatment. COVID-19 is multi-dimensional disease caused by viral cytopathic effects and host-mediated immunopathology. Therapeutic approaches should logically be based on interventions that have direct anti-viral effects and favourably modulate the host immune response. Thus, an optimal drug regimen in ambulatory patients should collectively (i) target and reduce viral replication, (ii) upregulate host innate immune anti-viral responses, (iii) have favourable immunomodulatory properties, and (iv) minimise disease progression to hospitalisation thus circumventing the 'cytokine storm' that likely underpins ARDS and multi-organ failure.

Nitazoxanide (NTZ) is an antiprotozoal drug that is FDA-approved for treating Cryptosporidium and Giardia and has an excellent safety record for a variety of indications, but primarily as an anti-parasitic agent. It has proven broad anti-viral activity as it amplifies cytoplasmic RNA sensing, potently augments type I interferon and autophagy-mediated anti-viral responses, has immunomodulatory properties e.g inhibits macrophage IL-6 production, and interferes with SARS-CoV-2 glycosylation. It has been shown to have anti-viral activity against several viruses including Ebola, influenza, hepatitis B and C, rotavirus and norovirus.

With regard to respiratory viral infections, NTZ was evaluated in uncomplicated influenza and demonstrated a reduction in the median time to symptom recovery. By contrast, NTZ failed to show benefit in hospitalised patients with severe influenza suggesting that, as with oseltamivir (Tamiflu), it likely needs to be administered early in the course of the disease. NTZ has proven in vitro activity against SARS-CoV-2. NTZ inhibited the SARS-CoV-2 at a low-micromolar concentrations and in vivo evaluation in patients with COVID-19 has been strongly recommended. NTZ has an excellent drug-drug interaction profile. No clinically significant interactions are expected with commonly used antihypertensive agents, anti-diabetics drugs, antiretroviral agents, steroids or commonly prescribed analgesics/anti-inflammatory agents.

The investigators propose NTZ for the treatment of mild COVID-19 in non-hospitalised patients with HIV co-infection and/or enhanced risk for progression to severe disease (age >35 years and/or with comorbidity). The investigators will perform a randomised controlled trial enrolling 440 patients with mild disease. The primary outcome measure will be the proportion progressing to severe disease (hospitalisation) based on the WHO clinical progression scale (stage 4 and beyond). Secondary outcome measures will include disease rates in contacts and effect on viral load, productive infectiousness using viral cultures, and ability to abrogate the generation of infectious aerosols using novel cough aerosol sampling technology. Recruitment is stratified and thus the study is powered to detect progression to severe disease in HIV-infected persons.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Cape Town
• Collaborators: Aurum Institute; Medical Research Council, South Africa; National Institutes of Health (NIH); Perinatal HIV Research Unit of the University of the Witswatersrand; Texas Tech University Health Sciences Center; University of KwaZulu
• Treatments: Nitazoxanide

Criteria

Inclusion Criteria:

1. Adults >18 years of age.

2. Confirmed COVID-19 on antigen testing* and/or RT-PCR using NP or OP swabs (or sputum or another sample e.g. stool).

• Only SAHPRA approved antigen tests will be used to identify COVID-19. A positive antigen detection test will be valid provided that at least one serial PCR test is positive.

3. Presenting within 6 days of symptom onset.

4. Not requiring immediate hospitalisation.

5. Patients with non-severe not requiring admission i.e. mild disease (respiratory rate <25/min), pulse rate <120 beats/min, oxygen saturation of ≥93% at sea level sites and >91% at high altitude sites)

6. Enhanced risk and/or HIV-infected

Exclusion Criteria:

1. Refusal or unable to sign informed consent.

2. Patient who declines or will be unable to comply with follow up visits by study staff.

3. Patients with advanced organ dysfunction/co-morbid conditions that in the opinion of the study doctor would compromise the patient's well-being.

4. Patients who have had symptoms for > 6 days (as at the day of recruitment).

5. Patients who refuse HIV-testing.

6. Patients using warfarin (Appendix A in the protocol)

7. Patients with a body weight of less than 40kg.

8. Women of child-bearing age (18-50 years) with a positive urine pregnancy test at randomisation.

9. Female patients who are currently breastfeeding.

10. Patients without HIV infection or at least one enhanced risk characteristic