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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 322
- 试验地点
- 4
- 主要终点
- Time specific disease severity
研究概览
简要总结
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.
详细描述
COVID-19 that is caused by SARS-CoV-2 infection is a rapidly escalating global pandemic(9). The pandemic is on an upward and escalating trajectory in most countries though some countries like China have shown a substantial decrease in the number of new cases being recorded. It is unclear if there will be a second wave of the epidemic.
Most cases of COVID-19 are either asymptomatic or have minimal symptoms (~80%) and act as carriers for disease transmission. Recent longitudinal studies indicate that the SARS-COV-2 viral load in the pharynx is highest during the prodromal phase of COVID-19. Thus, early therapeutic intervention, prior to respiratory tract dissemination and disease amplification, is likely to be a promising strategy. Although such persons are advised to be in self isolation, many, especially in resource-poor settings (due to several factors including poverty, overcrowding, environmental conditions, personal beliefs, stigma and human fallibility), continue to have contact with others thus fuelling the epidemic. Therefore, reducing the period of infectiousness in ambulatory patients will have major public health impact by shortening the epidemic, thereby reducing morbidity and mortality.
Retarding the progression of the 15 to 20% that will develop more severe disease will have benefits for the public health system, which is struggling to cope with a surge in cases and will thus have a likely impact on mortality. Thus, therapeutic agents that can reduce viral load, viral shedding, the duration of illness and progression to severe disease are urgently needed. It is important to note that HIV-infected persons and certain sub-groups (including those > 35 years of age, and with comorbidities like diabetes and hypertension etc.) may have 'enhanced risk' of disease progression. Collectively such persons would constitute an enhanced risk group and are at the highest risk of disease progression. The risk of disease progression in HIV-infected persons and whether they will respond to the NTZ intervention to the same extent as HIV uninfected persons remains unknown.
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.
A Phase 2b/3 clinical trial recently published in The Lancet Infectious Diseases found that oral administration of NTZ slow release formulation 600 mg twice daily for five days reduced the duration of clinical symptoms and reduced viral shedding compared to placebo in persons with laboratory-confirmed influenza. These dosages are suitable for treating viral respiratory infections caused by influenza and other viruses as in vitro IC50s are typically between 0.1 and 1ug/mL. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
double-blind
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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
排除标准
- •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
研究组 & 干预措施
Nitazoxanide
Nitazoxaninde, 1000mg (2pills), oral, twice daily for 7 days. To be taken with food.
干预措施: Nitazoxanide (Drug)
Placebo
Placebo, 2 pills, oral, twice daily for 7 days. To be taken with food.
干预措施: Placebo (Drug)
结局指标
主要结局
Time specific disease severity
时间窗: 60 days
Time-specific (30- and 60-day) disease severity based on the WHO clinical progression scale
次要结局
- In-hospital and 30- and 60-day all-cause mortality.(60 days)
- Duration and severity of symptoms.(60 days)
- Time-specific antibody titres (IgG and IgM).(60 days)
- Adverse events(60 days)
- COVID-19 incidence rates in contacts.(60 days)
- Cough aerosol sampling positivity(60 days)
- 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)
- Time-specific viral load as measured by RT-PCR using NP swabs and sputum (where available).(60 days)
研究者
Keertan Dheda
Professor
University of Cape Town