Clinical trial NCT04920942: Ivermectin Treatment Efficacy in Covid-19 High Risk Patients
Official title: Ivermectin Treatment Efficacy in Covid-19 High Risk Patients (I-TECH Study): A Multicenter Open-label Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Ivermectin
COVID-19
Lead sponsor: Clinical Research Centre, Malaysia
Sponsor class: OTHER
First posted: 2021-06-10
Enrollment: 500
Sex: ALL
Minimum age (years): 50
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Patients who Progressed to Severe Disease (Clinical stage 4 or 5)
timeFrame: Within 28 days since administered Ivermectin
measure: Time Required for Patients on Treatment Arm to Progressed to Severe Disease (Clinical stage 4 or 5)
timeFrame: Within 28 days since administered Ivermectin
Secondary outcomes:
measure: Mortality
timeFrame: Through study completion, an average of 28 days
measure: Number of Participants with Complete Resolution of Symptoms by day 5 of Enrolment
timeFrame: 5 days since time of recruitment
measure: Chest Radiograph Changes Pertaining to COVID-19 by Day 5 of Enrolment
timeFrame: 5 days since time of recruitment
measure: Changes in Serum Absolute Lymphocyte Count
timeFrame: From starting to the end of ivermectin therapy (0 to end of 5th day)
measure: Changes in Serum Absolute Neutrophil Counts
timeFrame: From starting to the end of ivermectin therapy (0 to end of 5th day)
measure: Changes in Serum C-Reative Protein (CRP)
timeFrame: From starting to the end of ivermectin therapy (0 to end of 5th day)
measure: Changes in Serum Creatinine
timeFrame: From starting to the end of ivermectin therapy (0 to end of 5th day)
measure: Changes in Serum Alanine Aminotransferase (ALT)
timeFrame: From starting to the end of ivermectin therapy (0 to end of 5th day)
measure: Numbers of Participants Admitted to the Intensive Care Unit
timeFrame: Through study completion, an average of 28 days
measure: Numbers of Participants who Require Mechanical Ventilation
timeFrame: Through study completion, an average of 28 days
measure: The Length of Hospital Stay (in Calendar days)
timeFrame: Through study completion, an average of 28 days
measure: Treatment-Related Adverse Events as Assessed by CTCAE v4.0
timeFrame: From the 6th day of study to the 28th day of study
Other outcomes:
Locations:
city: Johor Bahru
country: Malaysia
facility: Sultanah Aminah Hospital
state: Johor
city: Alor Setar
country: Malaysia
facility: Sultanah Bahiyah Hospital
state: Kadah
city: Sungai Petani
country: Malaysia
facility: Sultan Abdul Halim Hospital
state: Kedah
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun, Ipoh
state: Perak
city: Taiping
country: Malaysia
facility: Taiping Hospital
state: Perak
city: Kangar
country: Malaysia
facility: Tuanku Fauziah Hospital
state: Perlis
city: George Town
country: Malaysia
facility: Pulau Pinang Hospital
state: Pulau Pinang
city: Tawau
country: Malaysia
facility: Lahad Datu Hospital
state: Sabah
city: Kuching
country: Malaysia
facility: Sarawak General Hospital
state: Sarawak
city: Shah Alam
country: Malaysia
facility: Sungai Buloh Hospital
state: Selangor
city: Kempas
country: Malaysia
facility: Permai Hospital
city: Kepala Batas
country: Malaysia
facility: Kepala Batas Hospital
city: Kuala Kangsar
country: Malaysia
facility: Kuala Kangsar Hospital
city: Kuala Lumpur
country: Malaysia
facility: Kuala Lumpur Hospital
city: Kuala Terengganu
country: Malaysia
facility: Sultanah Nur Zahirah
city: Melaka
country: Malaysia
facility: Melaka Hospital
city: Putrajaya
country: Malaysia
facility: Putrajaya Hospital
city: Sandakan
country: Malaysia
facility: Duchess of Kent Hospital
city: Serdang
country: Malaysia
facility: Low Risk COVID-19 Quarantine & Treatment Centre - Malaysia Agro Exposition Park Serdang (MAEPS)
city: Sungai Siput
country: Malaysia
facility: Sg Siput Hospital
city: Tumpat
country: Malaysia
facility: Tumpat Hospital
Study officials:
affiliation: Ministry of Health, Malaysia
name: CHEE L LIM, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lim SCL, Hor CP, Tay KH, Mat Jelani A, Tan WH, Ker HB, Chow TS, Zaid M, Cheah WK, Lim HH, Khalid KE, Cheng JT, Mohd Unit H, An N, Nasruddin AB, Low LL, Khoo SWR, Loh JH, Zaidan NZ, Ab Wahab S, Song LH, Koh HM, King TL, Lai NM, Chidambaram SK, Peariasamy KM; I-TECH Study Group. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial. JAMA Intern Med. 2022 Apr 1;182(4):426-435. doi: 10.1001/jamainternmed.2022.0189.