Ivermectin Treatment Efficacy in Covid-19 High Risk Patients

Phase 3

Completed

• Conditions: COVID-19
• Interventions: Drug: Ivermectin 0.4mg/kg/day for 5 days

• Registration Number: NCT04920942
• Lead Sponsor: Clinical Research Centre, Malaysia

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 Timeline

• Study Start: 2021-05-31
• Study First Submitted: 2021-05-31
• Study First Submitted QC: 2021-06-08
• Study First Posted: 2021-06-10
• Primary Completion: 2021-10-31
• Study Completion: 2021-10-31
• Status Verified: 2021-11
• Last Update Submitted: 2023-05-30
• Last Update Posted: 2023-06-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

1. RT-PCR or antigen test 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 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.
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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment group	Ivermectin 0.4mg/kg/day for 5 days	Ivermectin 0.4mg/kg/day for 5 days + standard-of-care

Primary Outcome Measures

Name	Time	Method
Number of Patients who Progressed to Severe Disease (Clinical stage 4 or 5)	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)	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

Secondary Outcome Measures

Name	Time	Method
Number of Participants with Complete Resolution of Symptoms by day 5 of Enrolment	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	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	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	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)	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	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.
Mortality	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
Changes in Serum Alanine Aminotransferase (ALT)	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	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	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)	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	From the 6th day of study to the 28th day of study	Adverse effects of ivermectin

Trial Locations

Locations (21)

Sultanah Aminah Hospital; 🇲🇾 Johor Bahru, Johor, Malaysia

Tuanku Fauziah Hospital; 🇲🇾 Kangar, Perlis, Malaysia

Kepala Batas Hospital; 🇲🇾 Kepala Batas, Malaysia

Sarawak General Hospital; 🇲🇾 Kuching, Sarawak, Malaysia

Pulau Pinang Hospital; 🇲🇾 George Town, Pulau Pinang, Malaysia

Sg Siput Hospital; 🇲🇾 Sungai Siput, Malaysia

Tumpat Hospital; 🇲🇾 Tumpat, Malaysia

Low Risk COVID-19 Quarantine & Treatment Centre - Malaysia Agro Exposition Park Serdang (MAEPS); 🇲🇾 Serdang, Malaysia

Sultanah Bahiyah Hospital; 🇲🇾 Alor Setar, Kadah, Malaysia

Sultan Abdul Halim Hospital; 🇲🇾 Sungai Petani, Kedah, Malaysia

Hospital Raja Permaisuri Bainun, Ipoh; 🇲🇾 Ipoh, Perak, Malaysia

Taiping Hospital; 🇲🇾 Taiping, Perak, Malaysia

Lahad Datu Hospital; 🇲🇾 Tawau, Sabah, Malaysia

Permai Hospital; 🇲🇾 Kempas, Malaysia

Sungai Buloh Hospital; 🇲🇾 Shah Alam, Selangor, Malaysia

Melaka Hospital; 🇲🇾 Melaka, Malaysia

Sultanah Nur Zahirah; 🇲🇾 Kuala Terengganu, Malaysia

Kuala Kangsar Hospital; 🇲🇾 Kuala Kangsar, Malaysia

Kuala Lumpur Hospital; 🇲🇾 Kuala Lumpur, Malaysia

Putrajaya Hospital; 🇲🇾 Putrajaya, Malaysia

Duchess of Kent Hospital; 🇲🇾 Sandakan, Malaysia