Randomized Phase IIA Clinical Trial to Evaluate the Efficacy of Ivermectin to Obtain Negative PCR Results in Patients With Early Phase COVID-19

Study Overview
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Brief Summary
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SAINT-PERU is a triple-blinded, randomized placebo-controlled trial with two parallel arms to evaluate the efficacy of ivermectin in negativizing nasopharyngeal PCR in patients with SARS-CoV-2 infection. The trial is conducted in two national hospitals at Lima-Peru.

Detailed Description
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SAINT is a triple-blinded, randomized placebo-controlled trial with two parallel arms to evaluate the efficacy of ivermectin in negativizing nasopharyngeal PCR in patients with SARS-CoV-2 infection. The trial is conducted in two national hospitals at Lima-Peru. The planned sample size is 186 SARS-CoV-2 PCR positive patients: 93 patients to treatment and 93 to the placebo group. Participants will be randomized to receive one dose of 300 mcg/kg ivermectin or placebo daily for three consecutive days. The epidemiologist will generate a list of correlative numbers, in randomized blocks of size 4, with the assignment to the treatment groups (a and b). The randomization list will be kept in an encrypted file accessible only to the trial statistician. This list will be handed directly to the pharmacist. Independently, the principal investigator will randomly assign the intervention (ivermectin) to one of the two groups (a or b) by tossing a coin, and will inform the pharmacist of the result of this process. The pharmacist will prepare and label the treatment vials according to the randomization list prepared by the epidemiologist and the treatment assignment given by the principal investigator. Eligible patients will be allocated in a 1:1 ratio using this randomization list. Participants are expected to remain in the trial for a period of 21 days. In the interests of public health and containing transmission of infection, follow-up visits will be conducted by the trial medical staff at the participant's home or at a hospital in case of hospitalization. Follow-up visits will assess clinical and laboratory parameters of the patients.

Official Title
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Randomized Phase IIA Clinical Trial to Evaluate the Efficacy of Ivermectin to Obtain Negative PCR Results in Patients With Early Phase COVID-19

Conditions
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Covid19, Coronavirus Infection, SARS-CoV Infection

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with COVID-19 typical symptoms (cough, fever, anosmia) present for not more than 96 hours. 18 years or older. No use of ivermectin prior to the study. No known history of ivermectin allergy. The patient can give his consent to take part in the study. Not current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate drugs such as warfarin. Exclusion Criteria: COVID-19 pneumonia Diagnosed by the attending physician (oxygen saturation < 95% or lung crackles) Positive pregnancy test for women of childbearing age* Positive IgG against SARS-CoV-2 by rapid diagnostic test. Negative SARS-CoV-2 PCR from a nasopharyngeal swab. Women of child bearing age may participate if they use a safe contraceptive method for the entire period of the study. A woman is considered to not have childbearing capacity if she is post-menopausal (minimum of 2 years without menstruation) or has undergone surgical sterilization (at least one month before the study)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: SAINT-PERU is a triple-blinded, randomized, placebo-controlled trial with two parallel arms to evaluate the efficacy of one daily dose of ivermectin during three consecutive days, administered to patients with a positive PCR test for SARS-CoV-2 in a nasopharyngeal specimen, symptomatic for 96 hours or less, with non-severe COVID-19 disease at baseline, regardless of the presence of risk factors for progression to severity. The efficacy of the drug-based strategy to reduce or block transmission involves treating during early phases of infection, when viral replication is yet limited.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivermectin<br>Participants on this arm will receive orally one (1) daily dose of ivermectin 300 mcg/kg for three (3) consecutive days, starting at the enrolment visit. | Drug: Ivermectin<br>* One daily dose of NOXAL-Ivermectin Oral Solution (6 mg/mL) at 300mcg/kg for three (3) consecutive days. A weight-equivalence table will be used to determine each participant´s dose (number of oral drops/day).<br>* Other names: Noxal;|
| Placebo Comparator: Placebo<br>Participants on this arm will receive orally one (1) daily dose of placebo for three (3) consecutive days, starting at the enrolment visit. | Drug: Placebo<br>* The placebo presentation will be an oral drop solution undistinguishable from ivermectin, but without this device pharmaceutical ingredient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a positive SARS-CoV-2 PCR. | Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment | 7 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean viral load | Change from baseline quantitative and semi-quantitative PCR in nasopharyngeal swab | Baseline and on days 4, 7, 14 and 21 | 
| Fever and cough progression | Proportion of patients with fever and cough at days 4, 7, 14 and 21 as well as proportion of patients progressing to severe disease or death during the trial | Up to and including day 21 | 
| Seroconversion at day 21 | Proportion of participants with positive IgG at day 21 | Up to and including day 21 | 
| Proportion of drug-related adverse events | Proportion of drug-related adverse events | 7 days post treatment | 
| Levels of IgG, IgM and IgA |  | Up to and including day 21 | 
| Frequency of innate immune cells | Frequency (% over total PBMC) of innate immune cells (myeloid and plasmacytoid dendritic cells, NK cell, classical, intermediate and pro-inflammatory macrophages) measured in cryopreserved PBMC by flow cytometry | Up to and including day 7 | 
| Frequency SARS-CoV-2-specific CD4+ T and and CD8+ T cells | Frequency of CD4+ T and CD8+ T cells (% over total CD4+T and CD8+ T) expressing any functional marker upon in vitro stimulation of PBMC with SARS-CoV-2 peptides, measured by flow cytometry | Up to and including day 7 | 
| Results from cytokine Human Magnetic 30-Plex Panel | Concentration (all in pg/mL) of epidermal growth factor (EGF), fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1RA, IL-1β, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p40/p70), IL-13, IL-15, IL-17, IFN-γ induced protein (IP-10), monocyte chemoattractant protein (MCP-1), monokine induced by IFN-γ (MIG), macrophage inflammatory protein (MIP)-1α, MIP-1β in plasma measured by a Luminex assay using a commercially available kit (Cytokine Human Magnetic 30-Plex Panel from ThermoFisher) | Up to and including day 21 | 
| Presence of intestinal helminths | Proportion and parasitic load of intestinal helminths by spontaneous sedimentation method. | Baseline and on day 14. |