Ivermectin Treatment Efficacy in Covid-19 High Risk Patients

Study Overview
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Brief Summary
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This is a multicenter study, which is aimed to investigate the efficacy of the Ivermectin drug in high risk COVID-19 patients. This study will compare Ivermectin treatment efficacy with standard of care alone. Target cohort is mild to moderate symptomatic Covid-19 (Stage 2-3), high risk patients aged 50 years and above with comorbidity, who presented to hospitals within first 7 days of illness.

Detailed Description
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Objectives Primary Objective: To assess the effectiveness of Ivermectin in preventing progression of Covid-19 to severe disease (clinical stage 4 or 5), which is defined as severe pneumonia requiring oxygen supplement or critically ill requiring intensive care. Secondary Objectives: To assess the efficacy of Ivermectin in reducing mortality rate among high risk COVID-19 patients. To compare difference in resolution of symptoms, chest radiograph, laboratory investigations, ICU admission, mechanical ventilation and length of hospital stay. Methodology Study Type and Design This is a multicenter, open-label, randomized controlled clinical trial involving COVID-19 designated hospitals in Malaysia. Patients are randomized at ratio of 1:1 to groups receiving ivermectin for 5 days plus standard-of-care versus standard-of-care only. Patients will be assigned to stratified randomized treatments based on a central, computer-generated randomization scheme coordinated by an independent third party. Based on national guidelines, all high risk COVID-19 patients will be admitted to hospitals, and allow discharge once criteria are met. Rationale of ivermectin dose and duration in this study: The dose regimens used in various randomized control trials with positive results range from 0.2mg/kg single dose to 0.6mg/kg/day for 5 days 10-15. PK/PD studies have shown that the antiviral effect of Ivermectin is dose dependent 9,15. As SARS-CoV-2 viral load peaks during the first week of illness and may prolong in severe disease 18, we believe a high dose of ivermectin 0.4mg/kg/day for 5 days would be reasonable and safe to achieve our study objectives. Standard of care: Based on the current Malaysian guidelines, standard of care for mild to moderate Covid-19 patients includes isolation, infection control, close monitoring (clinical findings, laboratory tests, chest imaging) and symptomatic treatment. Study Population The population for this clinical trial will be comprised of adults with a polymerase chain reaction (PCR) confirmed diagnosis of COVID-19 admitted to any of the participating hospitals. Participants who Treatment group: Ivermectin 0.4mg/kg/day for 5 days + standard-of-care Control group: Standard-of-care only Patients who fulfil the inclusion criteria and do not meet the exclusion criteria will be enrolled. Identification of eligible participants will be done prospectively at each study site. Sample Size Sample size calculation was performed using ScalexProp Version 1.0.2 (Naing, 2016). The calculation is based on superiority trial design and the primary outcome measure of the need to have supplemental oxygen therapy during the hospital admission. We regard a 9% difference between intervention arm and control arm as a clinically important outcome. Based on local data, 17.5% of COVID-19 aged 50 years and above, with stage 2 and 3 disease and comorbidity, progressed to severe disease 3. The need of supplemental oxygen therapy is expected to be about 8.8% in intervention arm and 17.5% in control arm. With a margin of superiority set to be 1%, the study requires 231 patients for each arm or in total 462 patients. Considering potential dropouts during the trial, we would require up to 500 patients or 250 patients each arm. The sample size provides a level of significance at 5% with 80% power (2-sided test).

Official Title
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Ivermectin Treatment Efficacy in Covid-19 High Risk Patients (I-TECH Study): A Multicenter Open-label Randomized Controlled Trial

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Ivermectin 0.4mg/kg/day for 5 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RT-PCR or antigen test confirmed COVID-19 cases Aged 50 years and above,with at least one co-morbidities* Within the first 7 days of illness (from symptom onset) Mild to moderate clinical severity Exclusion Criteria: Asymptomatic stage 1 patients Patients with SpO2 less than 95% at rest. (unless it is an expected baseline SpO2 due to preexisting disease, eg. COAD or pulmonary fibrosis) Patients who need oxygen supplements Patients with concomitant bacterial, fungal, parasitic or other viral infections prior to enrollment. Patients with severe hepatic impairment (>Grade 3: ALT >10 times of upper normal limit) Malabsorptionsyndromeorotherclinicallysignificantgastrointestinaldisease that may affect absorption of the study drug (non-correctable vomiting, diarrhea, ulcerative colitis, and others). Pregnant or nursing women. Female patients of reproductive age who cannot consent to contraceptive use of oral contraceptives, mechanical contraceptives such as intrauterine devices or barrier devices (pessaries, condoms), or a combination of these devices from the start of ivermectin administration to 7 days after the end of ivermectin administration. Male patient who has female partner of reproductive age and he cannot agree to use contraception from the start of ivermectin treatment till 7 days after treatment. Patients receiving chemotherapy Patients who received interferon or drugs with reported antiviral activity against COVID-19 (favipiravir, hydroxychloroquine sulfate, chloroquine phosphate, lopinavir-ritonavir combination, remdesivir) in the past 7 days before enrollment. Patients in whom this episode of infection is a recurrence or reinfection of COVID- 19. Patients who have previously received ivermectin. Patient receiving warfarin or any medications known to interact with ivermectin. Acute medical or surgical emergency (eg. DKA/MI/stroke). Other patients judged ineligible by the principal investigator or sub-investigator.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 100 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: This is a multicenter, open-label, randomized controlled clinical trial involving COVID-19 designated hospitals in Malaysia. Patients are randomized at ratio of 1:1 to groups receiving ivermectin for 5 days plus standard-of-care versus standard-of-care only. Patients will be assigned to stratified randomized treatments based on a central, computer-generated randomization scheme coordinated by an independent third party. Based on national guidelines, all high risk COVID-19 patients will be admitted to hospitals, and allow discharge once criteria met
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Ivermectin 0.4mg/kg/day for 5 days + standard-of-care | Drug: Ivermectin 0.4mg/kg/day for 5 days<br>* Ivermectin 0.4mg/kg/day for 5 days with standard-of-care<br>|
| No Intervention: Control group<br>Standard-of-care only | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients who Progressed to Severe Disease (Clinical stage 4 or 5) | The number of patients recruited who clinically deteriorated to clinical stage 4 or 5. The differences between two study arms will be assessed via chi-square test. Estimates will be reported in proportions and 95% confidence intervals, together with their corresponding p-values. A logistic regression will also be performed, to enable estimates to be presented in the form of odds ratio and its corresponding 95% confidence interval, potentially adjusting for clinically relevant and statistically significant variable | Within 28 days since administered Ivermectin | 
| Time Required for Patients on Treatment Arm to Progressed to Severe Disease (Clinical stage 4 or 5) | The time duration for patients in the treatment arm to deteriorated to clinical stage 4 or 5. The differences between two study arms will be assessed via chi-square test. Estimates will be reported in proportions and 95% confidence intervals, together with their corresponding p-values. A logistic regression will also be performed, to enable estimates to be presented in the form of odds ratio and its corresponding 95% confidence interval, potentially adjusting for clinically relevant and statistically significant variable | Within 28 days since administered Ivermectin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | The number of died patients were evaluated in study and control groups. The differences between two study arms will be assessed via chi-square test. Estimates will be reported in proportions and 95% confidence intervals, together with their corresponding p-values. A logistic regression will also be performed, to enable estimates to be presented in the form of odds ratio and its corresponding 95% confidence interval, potentially adjusting for clinically relevant and statistically significant variable | Through study completion, an average of 28 days | 
| Number of Participants with Complete Resolution of Symptoms by day 5 of Enrolment | The total numbers of patients with complete resolution of symptoms were evaluated in study and control groups. The differences between two study arms will be assessed via chi-square test. Estimates will be reported in proportions and 95% confidence intervals, together with their corresponding p-values. A logistic regression will also be performed, to enable estimates to be presented in the form of odds ratio and its corresponding 95% confidence interval, potentially adjusting for clinically relevant and statistically significant variable | 5 days since time of recruitment | 
| Chest Radiograph Changes Pertaining to COVID-19 by Day 5 of Enrolment | Radiological Changes Pertaining to COVID-19 is recorded at day 1 of enrolment and compared with day 5 of enrolment. The differences between two study arms will be assessed via chi-square test. Estimates will be reported in proportions and 95% confidence intervals, together with their corresponding p-values. A logistic regression will also be performed, to enable estimates to be presented in the form of odds ratio and its corresponding 95% confidence interval, potentially adjusting for clinically relevant and statistically significant variable | 5 days since time of recruitment | 
| Changes in Serum Absolute Lymphocyte Count | For changes in Serum Absolute Lymphocyte counts (cell/mm3), baseline values, value at each post baseline analysis, changes from baseline at each post baseline analysis will be provided descriptively by each study arm either in mean and SD or median and interquartile range. | From starting to the end of ivermectin therapy (0 to end of 5th day) | 
| Changes in Serum Absolute Neutrophil Counts | For changes in Serum Absolute Neutrophil counts (cell/mm3), baseline values, value at each post baseline analysis, changes from baseline at each post baseline analysis will be provided descriptively by each study arm either in mean and SD or median and interquartile range. | From starting to the end of ivermectin therapy (0 to end of 5th day) | 
| Changes in Serum C-Reative Protein (CRP) | For changes in Serum C-Reative Protein (mg/L), baseline values, value at each post baseline analysis, changes from baseline at each post baseline analysis will be provided descriptively by each study arm either in mean and SD or median and interquartile range. | From starting to the end of ivermectin therapy (0 to end of 5th day) | 
| Changes in Serum Creatinine | For changes in Serum Creatinine (micro mol/L), baseline values, value at each post baseline analysis, changes from baseline at each post baseline analysis will be provided descriptively by each study arm either in mean and SD or median and interquartile range. | From starting to the end of ivermectin therapy (0 to end of 5th day) | 
| Changes in Serum Alanine Aminotransferase (ALT) | For changes in Serum Alanine Aminotransferase (U/L), baseline values, value at each post baseline analysis, changes from baseline at each post baseline analysis will be provided descriptively by each study arm either in mean and SD or median and interquartile range. | From starting to the end of ivermectin therapy (0 to end of 5th day) | 
| Numbers of Participants Admitted to the Intensive Care Unit | The number of patients admitted to the intensive care unit were evaluated in study and control groups | Through study completion, an average of 28 days | 
| Numbers of Participants who Require Mechanical Ventilation | The number of patients who require mechanical ventilation were evaluated in study and control groups | Through study completion, an average of 28 days | 
| The Length of Hospital Stay (in Calendar days) | The average number of hospitalisation required for both groups. | Through study completion, an average of 28 days | 
| Treatment-Related Adverse Events as Assessed by CTCAE v4.0 | Adverse effects of ivermectin | From the 6th day of study to the 28th day of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ivermectin, COVID-19