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
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