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Ivermectin Treatment Efficacy in Covid-19 High Risk Patients (I-TECH)

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ClinicalTrials.gov Identifier: NCT04920942
Recruitment Status : Completed
First Posted : June 10, 2021
Last Update Posted : November 10, 2021
Sponsor:
Information provided by (Responsible Party):
Clinical Research Centre, Malaysia

Tracking Information
First Submitted Date  ICMJE May 31, 2021
First Posted Date  ICMJE June 10, 2021
Last Update Posted Date November 10, 2021
Actual Study Start Date  ICMJE June 1, 2021
Actual Primary Completion Date October 9, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2021)
  • Number of Patients who Progressed to Severe Disease (Clinical stage 4 or 5) [ Time Frame: Within 28 days since administered Ivermectin ]
    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
  • Time Required for Patients on Treatment Arm to Progressed to Severe Disease (Clinical stage 4 or 5) [ Time Frame: Within 28 days since administered Ivermectin ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: June 8, 2021)
  • Gender Distribution of Patients [ Time Frame: Time Frame: At the first day of the study ]
    The gender of patients (Male/female) in both groups were recorded at the time of inclusion.
  • Age Distribution of the Patients [ Time Frame: Time Frame: At the first day of the study ]
    The age of the patients (years) in both groups were recorded at the time of inclusion.
  • Percentage of Patients With Underlying Illness [ Time Frame: At the first day of the study ]
    At the beginning of the study, the patients were asked whether there were any of the following accompanying diseases and the percentage of patients with accompanying disease in both groups were recorded: Diabetes mellitus Hypertension Coronary artery disease Cardiac failure Chronic obstructive pulmonary disease Malignancy Immunodeficiency
  • COVID-19 Clinical Staging at Time of Hospitalization [ Time Frame: At the first day of the study ]
    At the beginning of the study, the admission diagnosis is recorded
  • COVID-19 Clinical Staging at Time of Enrolment [ Time Frame: At the first day of the study ]
    At the beginning of the study, the current diagnosis is recorded
  • Radiograph Diagnosis of Patient Prior to Enrolment [ Time Frame: At the first day of the study ]
    Radiological Changes Pertaining to COVID-19 is Recorded at the beginning of the study
  • Laboratory Results within 48 Hours of Enrolment [ Time Frame: Laboratory values are recorded within 48 hours of recruitment ]
    Three laboratory parameters that may indicate deterioration are recorded within 48 hours of enrolment, they include the followings:
    1. Absolute lymphocyte count (ALC)
    2. Absolute Neutrophil Count (ANC)
    3. C-reactive protein (CRP)
  • Changes in Serum Absolute Lymphocyte Counts [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ]
    Baseline Serum Absolute Lymphocyte counts (cell/mm^3) of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1),and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
  • Changes in Serum Absolute Neutrophil Counts [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ]
    Baseline Serum Absolute Neutrophil counts (cell/mm^3) of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1),and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
  • Changes in Serum C-Reative Protein (CRP) [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ]
    Baseline Serum C-Reative Protein (mg/L) of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1),and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
  • Changes in Serum Creatinine [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ]
    Baseline Serum Creatinine (micro mol/L)of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1),and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
  • Changes in Serum Alanine Aminotransferase (ALT) [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ]
    Baseline Serum Alanine Aminotransferase (U/L)of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1),and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
  • Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: At the first 5 days of study ]
    Adverse effects of ivermectin and drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the study group and and the number of participants were noted.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2021)
  • Mortality [ Time Frame: Through study completion, an average of 28 days ]
    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
  • Number of Participants with Complete Resolution of Symptoms by day 5 of Enrolment [ Time Frame: 5 days since time of recruitment ]
    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
  • Chest Radiograph Changes Pertaining to COVID-19 by Day 5 of Enrolment [ Time Frame: 5 days since time of recruitment ]
    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
  • Changes in Serum Absolute Lymphocyte Count [ Time Frame: From starting to the end of ivermectin therapy (0 to end of 5th day) ]
    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.
  • Changes in Serum Absolute Neutrophil Counts [ Time Frame: From starting to the end of ivermectin therapy (0 to end of 5th day) ]
    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.
  • Changes in Serum C-Reative Protein (CRP) [ Time Frame: From starting to the end of ivermectin therapy (0 to end of 5th day) ]
    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.
  • Changes in Serum Creatinine [ Time Frame: From starting to the end of ivermectin therapy (0 to end of 5th day) ]
    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.
  • Changes in Serum Alanine Aminotransferase (ALT) [ Time Frame: From starting to the end of ivermectin therapy (0 to end of 5th day) ]
    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.
  • Numbers of Participants Admitted to the Intensive Care Unit [ Time Frame: Through study completion, an average of 28 days ]
    The number of patients admitted to the intensive care unit were evaluated in study and control groups
  • Numbers of Participants who Require Mechanical Ventilation [ Time Frame: Through study completion, an average of 28 days ]
    The number of patients who require mechanical ventilation were evaluated in study and control groups
  • The Length of Hospital Stay (in Calendar days) [ Time Frame: Through study completion, an average of 28 days ]
    The average number of hospitalisation required for both groups.
  • Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: From the 6th day of study to the 28th day of study ]
    Adverse effects of ivermectin
Original Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2021)
  • Mortality [ Time Frame: Through study completion, an average of 28 days ]
    The number of died patients were evaluated in study and control groups
  • Number of Participants With Clinical Response [ Time Frame: 28 days (including 5 days of ivermectin therapy) ]
    The presence of at least two of the following criteria in patients on the 28th day were accepted as "clinical response": Respiration rate between 22-24/min, SpO2 level in room air >95%, absence of oxygen requirement, observation of radiological improvement in control lung tomography and no need for intensive care
  • Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: From the 6th day of study to the 28th day of study ]
    Adverse effects of ivermectin and drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the study group and and the number of participants were noted.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ivermectin Treatment Efficacy in Covid-19 High Risk Patients
Official Title  ICMJE Ivermectin Treatment Efficacy in Covid-19 High Risk Patients (I-TECH Study): A Multicenter Open-label Randomized Controlled Trial
Brief Summary 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

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:

  1. To assess the efficacy of Ivermectin in reducing mortality rate among high risk COVID-19 patients.
  2. 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

  1. Treatment group: Ivermectin 0.4mg/kg/day for 5 days + standard-of-care
  2. 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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Investigator)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE Drug: Ivermectin 0.4mg/kg/day for 5 days
Ivermectin 0.4mg/kg/day for 5 days with standard-of-care
Study Arms  ICMJE
  • Experimental: Treatment group
    Ivermectin 0.4mg/kg/day for 5 days + standard-of-care
    Intervention: Drug: Ivermectin 0.4mg/kg/day for 5 days
  • No Intervention: Control group
    Standard-of-care only
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 8, 2021)
500
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 9, 2021
Actual Primary Completion Date October 9, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. RT-PCR confirmed COVID-19 cases
  2. Aged 50 years and above,with at least one co-morbidities*
  3. Within the first 7 days of illness (from symptom onset)
  4. Mild to moderate clinical severity

Exclusion Criteria:

  1. Asymptomatic stage 1 patients
  2. Patients with SpO2 less than 95% at rest. (unless it is an expected baseline SpO2 due to preexisting disease, eg. COAD or pulmonary fibrosis)
  3. Patients who need oxygen supplements
  4. Patients with concomitant bacterial, fungal, parasitic or other viral infections prior to enrollment.
  5. Patients with severe hepatic impairment (>Grade 3: ALT >10 times of upper normal limit)
  6. Malabsorptionsyndromeorotherclinicallysignificantgastrointestinaldisease that may affect absorption of the study drug (non-correctable vomiting, diarrhea, ulcerative colitis, and others).
  7. Pregnant or nursing women.
  8. 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
  9. Male patients whose partner cannot agree to use the contraception method described in (8) above
  10. Patients receiving chemotherapy
  11. 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.
  12. Patients in whom this episode of infection is a recurrence or reinfection of COVID- 19.
  13. Patients who have previously received ivermectin.
  14. Patient receiving warfarin or any medications known to interact with ivermectin.
  15. Acute medical or surgical emergency (eg. DKA/MI/stroke).
  16. Other patients judged ineligible by the principal investigator or sub-investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Malaysia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04920942
Other Study ID Numbers  ICMJE I-TECH21
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Clinical Research Centre, Malaysia
Study Sponsor  ICMJE Clinical Research Centre, Malaysia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: CHEE L LIM, MRCP Ministry of Health, Malaysia
PRS Account Clinical Research Centre, Malaysia
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP