Ivermectin Effect on SARS-CoV-2 Replication in Patients With COVID-19
Condition: COVID-19 Drug Treatment
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 2

Summary: 
      In the context of COVID-19 pandemic, a report on ivermectin suppression of SARS-CoV-2 viral
      replication in cell cultures has been published, and the use of this medication seems to be
      potentially useful for the therapy. IVM safety profile and IVM wide spectrum enables to move
      forward with the investigation in patients infected by SARS-CoV-2 as a proof-of-concept of
      its possible use in the management of patients with COVID-19, given the current pandemic
      situation.
    

Detailed description: 
      Ivermectin (IVM) is a semisynthetic antiparasitic agent belonging to the avermectin group,
      drugs isolated from Streptomyces avermitilis. Ivermectin is widely used for humans and
      animals, with millions of doses annually administered through mass drug distribution programs
      held by the World Health Organization (WHO - 2016). Since 1980, Ivermectin has been included
      in the Essential Medicines List of the World Health Organization (WHO - 2019).

      This medicine is orally administered and is usually used for the treatment against nematodes
      and ectoparasites, making this drug the first-choice medication for onchocerciasis, lymph
      filariasis, itch and strongylosis.

      Until now, SARS-CoV-2 viral load dynamics has not been clearly determined. However, works
      tending to a preliminary characterization of the viral load (VL) behavior have emerged. One
      of them, the most substantial one, includes the work done by Kai-Wang showing the VL behavior
      during the 30 days before the onset of COVID-19 symptoms (Kai-Wang To et al; 2020). In this
      work, an average of 7.5 oropharyngeal samples of individuals with severe (n=10) and moderate
      (n=13) COVID-19 have been assessed. Time between the onset of symptoms and hospitalization
      ranged between 0 and 13 days, with a mean of 4 days. VL median at day 0 in all patients was
      5.2 log10 copies/mL, and no significant differences between severe and moderate COVID-19
      groups occurred. The viral load peak observed during the first week from the onset of
      symptoms had a median equal to 6.91 (Q1-Q3: 4.27-7.40) and 5.29 (Q1-Q3: 3.91-7.56) log10
      copies/mL in severe and moderate COVID-19 patients, respectively. There was no significant
      difference between both groups (p=0.52). Likewise, no difference between patients with and
      without comorbidities has been observed (n of patients equal to 12 and 11, respectively) as
      per initial VL (p=0.49) and peak VL (p=0.29). However, it has been observed that the VL peak
      was directly associated with the age of the patient (R2=0.48 and p=0.02). In a combined
      analysis of all patients (n=23), it has been observed that the VL grows in the first days
      following the onset of symptoms and that, in the 5-6 days, VL falls sharply, reaching a lower
      mean value, yet similar to that of the day 0. General VL behavior from day 9 to 30 showed a
      negative slope (VL fall) equal to -0.15 (95% confidence interval: -0.19 to -0.11) log10 per
      daya. It must be emphasized that by day 20 from the onset of symptoms, VL mean continues to
      be quantifiable (4 log10 copies/mL), and that 7/23 (30%) patients show viral RNA detection
      after such day.

      In other paper, the VL of 17 patients with an age median of 59 (range 26-76 years) has been
      studied, who tested positive for SARS-CoV-2 (Zou et al; 2020). Nonetheless, VL measurement by
      nasal swab was performed in 16 patients and quantification was conducted relatively,
      expressed in Ct values (cycle threshold), which is related with the VL copies detected in the
      molecular reaction: the lower the Ct value, the greater the VL, and vice versa. The feature
      worth noting of such work is that VL dynamics varies widely from one patient to another.
      Contrary to the work of Kai-Wang To et al. [1], the VL peak seems to occur earlier (first
      three days), whereas the sharp VL fall is at day 6 approximately, from which day the VL is
      undetectable in most patients. Only very few patients show detectable viral RNA after 10 days
      from the onset of symptoms.

      In other work, pharyngeal swabs performed in 67 patients have been studied (Pan et al; 2020).
      VL dynamics similar to that reported by Kai-Wang To et al. is observed, with a VL of
      approximately 4 to 5 log10 copies/mL at day 0 of the onset of symptoms, a peak at day 6/7 (8
      log10 copies/mL) and a sharp fall from day 8 of the onset of symptoms. A temporary onset of
      viremia is observed with a VL of 4 log10 copies/mL up to day 15 from the onset of symptoms.

      Finally, in the work published by Wölfel et al. [4] much more accelerated dynamics than that
      in the work of Kai-Wang To et al. and Pan et al. (Wölfel et al; 2020) is observed, and the
      peak appearing much earlier than the day 4 from the onset of symptoms in the nine studied
      patients. Additionally, in 8 patients, the VL falls sharply reaching values below the
      quantification limit (2 log10 copies/mL) at day 10-11 following the onset of symptoms.
      Although there are transient VL relapses after day 10, this value remains very close to the
      study quantification limit.

      In conclusion, if the works of Kai-Wang and Pan are considered, a greater viral RNA half-life
      is expected at day 10 following the onset of symptoms. Even though in the works of Zou and
      Wölfel the peak occurs much earlier than the first five days and viral negativity occurs
      after day 10-11 following the onset of symptoms. Method variability among the many works is a
      limiting factor when comparing the outcomes. That is why, due to the sample size in Kai Wang
      et al (n=23) and Zou et al (n=67), it is suggested to use these works as reference and to
      consider the works of Pan (n=17) and Wölfel (n=9) as part of behavior diversity. It is
      important to define the period in which therapy is to be initiated from the onset of symptoms
      so that the sharp fall observed post-peak is not a factor that biases the potential antiviral
      effect of the drug.

      Considering these backgrounds along with the preliminary study with ivermectin, it is not
      possible to define a specific, progressive outcome for the reduction of the VL, but it may be
      expressed in a variation percentage with respect to the control population (without therapy)
      at the end of treatment. This percentage difference between the treated population and the
      untreated population must be greater than the variation observed for the study day or period
      in the patients included in the above mentioned works, since such percentage difference would
      replicate the behavior in our control population.
    

Intervention name(s): IVERMECTIN (IVER P®) arm will receive IVM 600 µg / kg once daily plus standard care. CONTROL arm will receive standard care.
Intervention type(s): Drug
Intervention description(s): IVERMECTIN (IVER P®) arm will receive IVM 600 µg / kg once daily plus standard care. CONTROL arm will receive standard care.
Intervention MeSH terms: Ivermectin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomized to receive Ivermectin 600 µg / kg / once daily plus standard care or standard care upon diagnosis of COVID-19.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: COVID-19; IVERMECTIN; SARS-CoV-2 viral load