Catalysing the Containment of COVID-19 (C3-RCT)
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|ClinicalTrials.gov Identifier: NCT04523090|
Recruitment Status : Recruiting
First Posted : August 21, 2020
Last Update Posted : June 7, 2021
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.
|Condition or disease||Intervention/treatment||Phase|
|COVID-19||Drug: Nitazoxanide Drug: Placebo||Phase 2 Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||440 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||A single-stage, double-blinded, randomised, placebo-controlled trial.|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||The C3 Nitazoxanide for Mild to Moderate COVID-19 in HIV-infected and HIV-uninfected Adults With Enhanced Risk: a Double-blind, Randomised, Placebo-controlled Trial in a Resource-poor Setting|
|Actual Study Start Date :||August 27, 2020|
|Estimated Primary Completion Date :||December 2021|
|Estimated Study Completion Date :||February 2022|
Nitazoxaninde, 1000mg (2pills), oral, twice daily for 7 days. To be taken with food.
Nitazoxanide (NTZ) is licensed in the USA for treatment of diarrhoea caused by Cryptosporidium parvum and Giardia lamblia. NTZ is a pro-drug for tizoxanide, which also has broad spectrum antiviral properties, has many viral indications and shows promising pharmacodynamics against Coronaviridae. NTZ was identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. In vitro studies evaluating tizoxanide, the active circulating metabolite of NTZ, inhibits the replication of broad range of influenza A and B, HIN1, H3N2, H3N2V, H3N8, H5N9, H7N1 and oseltamivir resistant strain and coronaviruses . It has been shown to have anti-viral activity against several viruses including Ebola, hepatitis B and C, rotavirus and norovirus.
Placebo Comparator: Placebo
Placebo, 2 pills, oral, twice daily for 7 days. To be taken with food.
Placebo pills with no active ingredient.
- Time specific disease severity [ Time Frame: 60 days ]Time-specific (30- and 60-day) disease severity based on the WHO clinical progression scale
- Progression to severe disease [ Time Frame: 60 days ]Need for hospitalisation and length of hospital stay (in those admitted to hospital because of disease progression).
- Need for respiratory support (high flow nasal oxygen, non-invasive ventilation, or intubation) in those admitted to hospital because of disease progression. [ Time Frame: 60 days ]Length of time on high flow nasal oxygen or in the ventilator.
- In-hospital and 30- and 60-day all-cause mortality. [ Time Frame: 60 days ]Time-specific all cause of mortality
- Time-specific viral load as measured by RT-PCR using NP swabs and sputum (where available). [ Time Frame: 60 days ]SARS-CoV-2 viral parameters [duration and burden of viral load and duration of viral culture positivity (viral shedding)
- Cough aerosol sampling positivity [ Time Frame: 60 days ]Assessment of SARS-CoV-2 presence in droplets and aerosols generated COVID-19 positive participants (and infectiousness)
- Duration and severity of symptoms. [ Time Frame: 60 days ]Duration and severity of COVID-19 symptoms experienced by the participant.
- Time-specific antibody titres (IgG and IgM). [ Time Frame: 60 days ]Antibody titres at pre-specified time-points.
- COVID-19 incidence rates in contacts. [ Time Frame: 60 days ]The incidence of COVID-19 infection in the contacts of index cases.
- Adverse events [ Time Frame: 60 days ]Rate and severity of adverse events experienced by participants
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04523090
|Contact: Keertan Dheda, MD/PhD||+27214047654||Keertan.Dheda@uct.ac.za|
|Contact: Ali Esmail, MD||+27214044430||A.Esmail@uct.ac.za|
|The Aurum Institute||Recruiting|
|Tembisa, Gauteng, South Africa|
|Contact: Modulakgotla Sebe 0871351645 email@example.com|
|Contact: Gavin Churchyard 0105901306 firstname.lastname@example.org|
|University of KwaZulu-Natal||Recruiting|
|Durban, KwaZulu-Natal, South Africa|
|Contact: Kennedy Nyamande email@example.com|
|Perinatal HIV Research Unit||Recruiting|
|Klerksdorp, North West, South Africa|
|Contact: Nadia Dr Sabet 0184653751 firstname.lastname@example.org|
|University of Cape Town||Recruiting|
|Cape Town, Western Cape, South Africa|
|Contact: Keertan Dheda, MD/PhD email@example.com|
|Contact: Ali Esmail, MD firstname.lastname@example.org|