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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
Sponsor:
Collaborators:
Medical Research Council, South Africa
Aurum Institute
National Institutes of Health (NIH)
Texas Tech University Health Sciences Center
University of KwaZulu
Perinatal HIV Research Unit of the University of the Witswatersrand
Information provided by (Responsible Party):
Keertan Dheda, University of Cape Town

Brief 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.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Nitazoxanide Drug: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A single-stage, double-blinded, randomised, placebo-controlled trial.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: double-blind
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Nitazoxanide
Nitazoxaninde, 1000mg (2pills), oral, twice daily for 7 days. To be taken with food.
Drug: Nitazoxanide
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.
Drug: Placebo
Placebo pills with no active ingredient.




Primary Outcome Measures :
  1. Time specific disease severity [ Time Frame: 60 days ]
    Time-specific (30- and 60-day) disease severity based on the WHO clinical progression scale


Secondary Outcome Measures :
  1. 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).

  2. 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.

  3. In-hospital and 30- and 60-day all-cause mortality. [ Time Frame: 60 days ]
    Time-specific all cause of mortality

  4. 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)

  5. 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)

  6. Duration and severity of symptoms. [ Time Frame: 60 days ]
    Duration and severity of COVID-19 symptoms experienced by the participant.

  7. Time-specific antibody titres (IgG and IgM). [ Time Frame: 60 days ]
    Antibody titres at pre-specified time-points.

  8. COVID-19 incidence rates in contacts. [ Time Frame: 60 days ]
    The incidence of COVID-19 infection in the contacts of index cases.

  9. Adverse events [ Time Frame: 60 days ]
    Rate and severity of adverse events experienced by participants



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

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


Contacts
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Contact: Keertan Dheda, MD/PhD +27214047654 Keertan.Dheda@uct.ac.za
Contact: Ali Esmail, MD +27214044430 A.Esmail@uct.ac.za

Locations
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South Africa
The Aurum Institute Recruiting
Tembisa, Gauteng, South Africa
Contact: Modulakgotla Sebe    0871351645    msebe@auruminstitute.org   
Contact: Gavin Churchyard    0105901306    gchurchyard@auruminstitute.org   
University of KwaZulu-Natal Recruiting
Durban, KwaZulu-Natal, South Africa
Contact: Kennedy Nyamande       nyamandek@ukzn.ac.za   
Perinatal HIV Research Unit Recruiting
Klerksdorp, North West, South Africa
Contact: Nadia Dr Sabet    0184653751    sabet@phru.co.za   
University of Cape Town Recruiting
Cape Town, Western Cape, South Africa
Contact: Keertan Dheda, MD/PhD       keertan.dheda@uct.ac.za   
Contact: Ali Esmail, MD       a.esmail@uct.ac.za   
Sponsors and Collaborators
University of Cape Town
Medical Research Council, South Africa
Aurum Institute
National Institutes of Health (NIH)
Texas Tech University Health Sciences Center
University of KwaZulu
Perinatal HIV Research Unit of the University of the Witswatersrand
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Responsible Party: Keertan Dheda, Professor, University of Cape Town
ClinicalTrials.gov Identifier: NCT04523090    
Other Study ID Numbers: C3-RCT
First Posted: August 21, 2020    Key Record Dates
Last Update Posted: June 7, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Keertan Dheda, University of Cape Town:
COVID-19
Nitazoxanide
Mild to moderate COVID-19
Additional relevant MeSH terms:
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Nitazoxanide
Antiparasitic Agents
Anti-Infective Agents