High-Dose Ivermectin for Mild-to-Moderate COVID-19 - The (HD)IVACOV Trial
试验速览
- 阶段
- 2 期
- 入组人数
- 294
- 主要终点
- World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
研究概览
简要总结
Ivermectin, a classical antiparasitic and anti-scabies agent, has demonstrated antiviral activity for a variety of viruses including chikungunya virus, zyka virus and dengue virus and was tested as a potentially effective for COVID-19.
Although ivermectin demonstrated potent in vitro action by reducing viral load by 5000x after 48 hours of incubation, simultaneous pharmacokinetics simulations suggested that the minimum effective concentrations would be unfeasible to be reached within safety range (EC-50 = 2 Micromol).
However, despite the theoretical unfeasible concentrations to be achieved, preliminary observational yet well-structured studies followed by randomized clinical trials (RCTs) demonstrated ivermectin efficacy when combined with hydroxychloroquine, doxycycline or azithromycin, which was corroborated by a recent systematic review and metanalysis. In common, a dose-response effect for effectiveness was observed, and no adverse effects was reported at any dose between 0.2mg/kg/day and 1.0mg/kg/day.
Based on the scientific rationale combined with the preliminary evidence, ivermectin has sufficient evidence to be tested in higher doses in a RCT for COVID-19. The investigators propose to test ivermectin at high doses as a treatment for patients recently diagnosed with COVID-19, aiming to explore the possible protective role of high-dose ivermectin in SARS-CoV-2 infection in terms of reduction of clinic and virologic disease duration, and prevention of oxygen use, hospitalization, mechanical ventilation, death, and post-COVID persisting symptoms.
详细描述
Overall
COVID-19 is a multisystemic disease caused by SARS-CoV-2 that has become a pandemic largely due to a combination of favorable transmission and infection characteristics for its spread, including prolonged preclinical or also asymptomatic yet transmitting period, relatively highly resistant to mechanical and physical barriers and prolonged survival in the air, and transmission patterns not yet fully elucidated.
While vaccines are not widely available, the number of new cases should not decrease dramatically, unfortunately, since a large percentage of the population has not been infected by the SARS-CoV-2 yet, reinfection becomes increasingly plausible with mutations in the virus, and virus contention policies failed to be 100% effective.
Considering potential antiviral approaches for COVID-19, their effectiveness only make sense if tested and given early in the disease, during viral dissemination. The learning that oseltamivir is only effective for Influenza A in the first three days of disease finds strong plausibility, and reinforces the expected lack of effectiveness of any drug with in vitro or preliminary antiviral activity reported when tested in hospitalized or non-mild patients, once COVID-19 presents tend to present mild symptoms during the viral dissemination stage.
An actual early detection of COVID-19, i.e., before its progression to further inflammatory stages, is challenging, once the earliest symptoms tend to be unspecific, mild, and hardly attributable to COVID-19. By suspecting of COVID-19 in the presence of any symptom, specific to COVID-19 or not, sensitivity was met to be above 90% while specificity was also relatively high (above 50%). In addition, time-to-treat, rather than which drug to choose, could better determine the effectiveness of a specific approach.
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)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Laboratory or clinically confirmed positive SARS-CoV-2 rtPCR test (AndroCoV Clinical Scoring for COVID-19 Diagnosis1) within 7 days prior to randomization
- •≥18 years old
- •Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to randomization
- •Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 to 3
- •Subject (or legally authorized representative) gives written informed consent prior to performing any study procedures
- •Subject (or legally authorized representative) agree that subject will not participate in another COVID-19 trial while participating in this study
排除标准
- •Subject enrolled in a study to investigate a treatment for COVID-19
- •Require oxygen use, hospitalization or mechanical ventilation
- •Tachycardia (HR > 150 bpm) or hypotension (BP < 90/60 mmHg)
- •Patients who are allergic to the investigational product or similar drugs (or any excipients);
- •Subjects with QTcF > 450 ms
- •Subjects with uncontrolled medical conditions that could compromise participation in the study - uncontrolled hypertension (BP > 220/120 mmHg), uncontrolled hypothyroidism (TSH > 10 iU/L), uncontrolled diabetes mellitus (HbA1c > 12%)
- •Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.
- •Estimated glomerular filtration rate (eGFR) < 30 ml/min or requiring dialysis
- •Subject (or legally authorized representative) not willing or unable to provide informed consent
研究组 & 干预措施
Ivermectin 0.6mg/kg/day
干预措施: Ivermectin 0.6mg/kg/day (Drug)
Ivermectin 0.6mg/kg/day
干预措施: Hydroxychloroquine (Drug)
Ivermectin 1.0mg/kg/day
干预措施: Ivermectin 1.0mg/kg/day (Drug)
Ivermectin 1.0mg/kg/day
干预措施: Hydroxychloroquine (Drug)
Placebo
干预措施: Placebo (Drug)
Placebo
干预措施: Hydroxychloroquine (Drug)
结局指标
主要结局
World Health Organization (WHO) Clinical Progression Scale [0 to 10; 0 = uninfected; 10 = death]
时间窗: Day 14
Treatment efficacy of high-dose Ivermectin relative to placebo arm as assessed by World Health Organization (WHO) Clinical Progression Scale \[0 to 10; 0 = uninfected; 10 = death\]
次要结局
- World Health Organization (WHO) COVID=19 Ordinal Scale for Clinical Improvement [1 to 8; 1 = not hospitalized, no limitation on activities; 8 = death] [Time Frame: Day 7](Day 7)
- Time-to-recovery(Day 28)
- Viral load(Day 5)
- Proportion of post-COVID physical symptoms(Day 90)
- Proportion of post-COVID overall symptoms(Day 90)
- Duration of new oxygen use(Day 28)
- Positivity rate of rtPCR-SARS-CoV-2 (qualitative analysis)(Day 5)
- Duration of fatigue(Day 14)
- Overall duration of clinical manifestations(Day 14)
- Proportion of post-COVID mental symptoms(Day 90)
- Duration of anosmia(Day 14)
- Proportion of subjects needing additional drugs or interventions(Day 28)
- Proportion of subjects needing high-flow oxygen therapy or non-invasive ventilation(Day 28)
- Disease duration(Day 14)
- Proportion of subjects needing oxygen use(Day 28)
- Proportion of pressors use(Day 28)
- Proportion of deaths(Day 28)
- Proportion of hospitalizations(Day 28)
- Proportion of mechanical ventilation use(Day 28)
- Duration of hospitalization(Day 28)
- Duration of mechanical ventilation(Day 28)
- Proportion of increased ultrasensitive C-reactive protein (usCRP) (defined as usRCP > 7 mg/L)(Day 7)
- Proportion of decrease in erythrocyte sedimentation rate (ESR) (defined as ESR decrease > 50% compared to Day 1)(Day 7)
- Proportion of increase in eosinophils (defined as eosinophils increase > 50% compared to Day 1)(Day 7)
- Proportion of increased d-dimer (defined as d-dimer > 500 mg/dL)(Day 7)
- Change in viral load from baseline to Day 5(Day 30)