Catalysing the Containment of COVID-19

NCT04523090 | Terminated Phase 2 DMC

• 1 other identifier: C3-RCT
• Study Type: interventional
• Target: 322
• Locations: 1 country
• Sites: 4

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.

Conditions

COVID-19

Keywords

COVID-19; Nitazoxanide; Mild to moderate COVID-19

Outcome Measures

Primary Outcomes (1)

• Time specific disease severity

  Time-specific (30- and 60-day) disease severity based on the WHO clinical progression scale

  60 days

Secondary Outcomes (9)

• Progression to severe disease

  60 days

• Need for respiratory support (high flow nasal oxygen, non-invasive ventilation, or intubation) in those admitted to hospital because of disease progression.

  60 days

• In-hospital and 30- and 60-day all-cause mortality.

  60 days

• Time-specific viral load as measured by RT-PCR using NP swabs and sputum (where available).

  60 days

• Cough aerosol sampling positivity

  60 days

Study Arms (2)

Nitazoxanide

EXPERIMENTAL

Nitazoxaninde, 1000mg (2pills), oral, twice daily for 7 days. To be taken with food.

Drug: Nitazoxanide

Placebo

PLACEBO COMPARATOR

Placebo, 2 pills, oral, twice daily for 7 days. To be taken with food.

Drug: Placebo

Interventions

Nitazoxanide DRUG

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.

Nitazoxanide

Placebo DRUG

Placebo pills with no active ingredient.

Placebo

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults \>18 years of age.
• 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.
• Presenting within 6 days of symptom onset.
• Not requiring immediate hospitalisation.
• 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)
• Enhanced risk and/or HIV-infected

You may not qualify if:

• Refusal or unable to sign informed consent.
• Patient who declines or will be unable to comply with follow up visits by study staff.
• Patients with advanced organ dysfunction/co-morbid conditions that in the opinion of the study doctor would compromise the patient's well-being.
• Patients who have had symptoms for \> 6 days (as at the day of recruitment).
• Patients who refuse HIV-testing.
• Patients using warfarin (Appendix A in the protocol)
• Patients with a body weight of less than 40kg.
• Women of child-bearing age (18-50 years) with a positive urine pregnancy test at randomisation.
• Female patients who are currently breastfeeding.
• Patients without HIV infection or at least one enhanced risk characteristic

Sponsors & Collaborators

• University of Cape Town: lead
• Medical Research Council, South Africa: collaborator
• Aurum Institute: collaborator
• National Institutes of Health (NIH): collaborator
• Texas Tech University Health Sciences Center: collaborator
• University of KwaZulu: collaborator
• Perinatal HIV Research Unit of the University of the Witswatersrand: collaborator

Study Sites (4)

The Aurum Institute

Tembisa, Gauteng, South Africa

Location

University of KwaZulu-Natal

Durban, KwaZulu-Natal, South Africa

Location

Perinatal HIV Research Unit

Klerksdorp, North West, South Africa

Location

University of Cape Town

Cape Town, Western Cape, South Africa

Location

MeSH Terms

Conditions

COVID-19

Interventions

nitazoxanide

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: A single-stage, double-blinded, randomised, placebo-controlled trial.

Study Record Dates

• First Submitted: August 20, 2020
• First Posted: August 21, 2020
• Study Start: August 27, 2020
• Primary Completion: December 21, 2021
• Study Completion: August 12, 2022
• Last Updated: August 16, 2022

Record last verified: 2022-08

Locations

ZA (4)