Ivermectin for Severe COVID-19 Management

NCT04646109 | Completed Phase 3 Results

• 1 other identifier: IVMC_03
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 4

Brief Summary

In this multicenter study; it was aimed to investigate the effectiveness and safety of ivermectin use in the treatment of patients with severe COVID-19 pneumonia that have no mutations which alter ivermectin metabolism and cause side effects.

Conditions

COVID-19

Keywords

Ivermectin; SARS-CoV-2; Treatment

Outcome Measures

Primary Outcomes (17)

• Gender Distribution of the Patients

  The gender of patients (Male/female) in both groups were recorded at the time of inclusion.

  At the first day of the study

• Age Distribution of the Patients

  The age of the patients (years) in both groups were recorded at the time of inclusion.

  At the first day of the study

• Percentage of Patients With Accompanying Diseases

  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

  At the first day of the study

• Percentage of Patients With Baseline Clinical Symptoms

  At the beginning of the study, the patients were asked whether there were any of the following clinical symptoms and the percentage of patients with any of the clinical symptoms in both groups were recorded: * Fever * Cough * Sore throat * Dispnea * Headache * Weakness * Myalgia * Diarrhea * Nausea or vomiting

  At the first day of the study

• Body Temperature Means of the Patients

  At the beginning of the study, the body temperatures (as degree celcius) of the patients were measured and the mean body temperature values of both groups were recorded.

  At the first day of the study

• Heart Rate Means of the Patients

  At the beginning of the study, the heart rates (as per minute) of the patients were measured and the mean heart rate values of both groups were recorded.

  At the first day of the study

• Respiratory Rate Means of the Patients

  At the beginning of the study, the respiratory rates (as per minute) of the patients were measured and the mean respiratory rate values of both groups were recorded.

  At the first day of the study

• Systolic and Diastolic Pressure Means of the Patients

  At the beginning of the study, the systolic and diastolic pressures (as mmHg) of the patients were measured and the mean systolic and diastolic pressure values of both groups were recorded.

  At the first day of the study

• Number of Participants With Clinical Response

  The presence of at least two of the following criteria in patients at the end of 5th day were accepted as "clinical response": Extubation in mechanically ventilated patients, respiratory rate \<26/min, SpO2 level in room air \>90%, PaO2/FiO2 \>300 in patients receiving oxygen, presence of at least two of the 2-point reduction criteria in "Sequential Organ Failure Assessment (SOFA)" score.

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in Oxygen Saturation (SpO2) Values

  Baseline SpO2 values of the patients were recorded in both groups. Then, their treatments were started and SpO2 values at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in SpO2 values on the 1st, 3rd and 5th days after the basal value calculated graphically, the change in the SpO2 value at the end of the 5th day (primary endpoint) with the baseline value was compared statistically (the results were given as p value).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)

  Baseline PaO2/FiO2 ratios of the patients were recorded in both groups. Then, their treatments were started and PaO2/FiO2 ratios at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in PaO2/FiO2 ratios on the 1st, 3rd and 5th days after the basal ratio was calculated graphically, the change in the PaO2/FiO2 ratio at the end of the 5th day (primary endpoint) with the baseline value was compared statistically (the results were given as p value).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in Serum Lymphocyte Counts

  Baseline Serum 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), 3rd (TD3) 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, 3rd 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).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)

  Baseline PNL/L ratio of the patients were recorded in both groups. Then, their treatments were started and PNL/L ratios at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in PNL/L ratios on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the PNL/L ratio at the end of the 5th day (primary endpoint) with the baseline ratio was compared statistically (the results were given as p value).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in Serum Ferritin Levels

  Baseline serum ferritin levels (mg/dL) of the patients were recorded in both groups. Then, their treatments were started and serum ferritin levels at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in serum ferritin levels on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the serum ferritin level at the end of the 5th day (primary endpoint) with the baseline level was compared statistically (the results were given as p value).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Changes in Serum D-dimer Levels

  Baseline serum D-dimer levels (mg/L) of the patients were recorded in both groups. Then, their treatments were started and serum D-dimer levels at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in serum D-dimer levels on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the serum D-dimer level at the end of the 5th day (primary endpoint) with the baseline level was compared statistically (the results were given as p value).

  From starting to the end of ivermectin therapy (0 to the end of 5th day)

• Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism

  A blood sample was taken from the patients included in the study group, after taking or during the first dose of ivermectin. From the blood samples, haplotypes and mutations that cause the function losing were investigated by performing sequence analysis of multidrug resistance 1 (MDR1)/ABCB1 and CYP3A4 genes with Sanger method. In case of detection of mutation, the patient were excluded from the study and if observed, side effects of ivermectin were noted.

  At the first day of ivermectin therapy (1st day)

• Treatment-Related Adverse Events as Assessed by CTCAE v4.0

  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. Adverse effects of drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the control group and and the number of participants were noted.

  At the first 5 days of study

Secondary Outcomes (10)

• Number of Participants With Clinical Response

  10 days (5 days ivermectin therapy plus 5 days follow-up)

• Mortality

  Through study completion, an average of 3 months

• Changes in Oxygen Saturation (SpO2) Values

  From 6th to the end of 10th day

• Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)

  From 6th to the end of 10th day

• Changes in Serum Lymphocyte Counts

  From 6th to the end of 10th day

Study Arms (2)

Control Group

NO INTERVENTION

Patients who were hospitalised with a pre-diagnosis of severe COVID-19 pneumonia and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the control and study group, respectively. Hydroxychloroquine, favipiravir and azithromycin (HFA) standard treatment protocol were given to the control group as recommended in the "COVID-19 (SARS-CoV-2 Infection) Guide" prepared by the Republic of Turkey Ministry of Health.

Study Group

EXPERIMENTAL

In addition to HFA treatment, ivermectin 200 micrograms/kg/day (9mg between 36-50 kg, 12mg between 51-65 kg, 15mg between 66-79 kg and 200 micrograms/kg in \> 80 kg) in the form of a solution prepared for enteral use was added (HFA+I) to the treatment protocol of the study group's for five days. Blood sample was taken with the first dose of ivermectin and haplotype analysis was performed in ABCB1 and CYP3A4 genes in the whole study group.

Drug: Ivermectin

Interventions

Ivermectin DRUG

Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.

Also known as: Hydroxychloroquine, favipiravir and azithromycin

Study Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who were hospitalised with a pre-diagnosis of "severe COVID-19 pneumonia" and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively.
• Patients with at least one of the criteria below were accepted as patients with severe COVID-19 pneumonia;
• Presence of tachypnea ≥ 30/minute, SpO2 level \< 90% in room air, PaO2/FiO2 \<300 in oxygen receiving patient
• Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities)
• Mechanical ventilation requirement
• Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score \>2

You may not qualify if:

• Patients with the following characteristics were excluded from the study.
• Pediatric patients; \<18 years of old
• Patients with chronic liver or kidney disease
• Pregnant women
• Patients with known ivermectin allergy

Sponsors & Collaborators

• Afyonkarahisar Health Sciences University: lead
• NeuTec Pharma: collaborator

Study Sites (4)

Afyonkarahisar Health Science University

Afyonkarahisar, Turkey (Türkiye)

Location

Gulhane Faculty of Medicine, University of Health Sciences

Ankara, Turkey (Türkiye)

Location

Yıldırım Beyazıt University, Ankara City Hospital

Ankara, Turkey (Türkiye)

Location

Haydarpasa Sultan Abdulhamid Han Training and Research Hospital

Istanbul, Turkey (Türkiye)

Location

Related Publications (5)

• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.

  PMID: 32109013 BACKGROUND

• Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020 Jun;53(3):436-443. doi: 10.1016/j.jmii.2020.03.034. Epub 2020 Apr 4.

  PMID: 32307245 BACKGROUND

• Croci R, Bottaro E, Chan KW, Watanabe S, Pezzullo M, Mastrangelo E, Nastruzzi C. Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin. Int J Biomater. 2016;2016:8043983. doi: 10.1155/2016/8043983. Epub 2016 May 8.

  PMID: 27242902 BACKGROUND

• Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo). 2020 Sep;73(9):593-602. doi: 10.1038/s41429-020-0336-z. Epub 2020 Jun 12.

  PMID: 32533071 BACKGROUND

• Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.

  PMID: 32251768 BACKGROUND

Related Links

• World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard

MeSH Terms

Conditions

COVID-19

Interventions

Ivermectin; Hydroxychloroquine; favipiravir; Azithromycin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Polyketides; Lactones; Organic Chemicals; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Erythromycin

Results Point of Contact

• Title: Prof. Dr. Nurullah Okumuş
• Organization: Afyonkarahisar Health Sciences University

drnuri@hotmail.com

+90 532 4372406

Study Officials

• Nurullah Okumuş, Prof. Dr.

  Afyonkarahisar Health Science University, Afyonkarahisar, Turkey

  STUDY CHAIR

• Neşe Demirtürk, A. Prof. Dr.

  Afyonkarahisar Health Science University, Afyonkarahisar, Turkey

  STUDY DIRECTOR

• Rıza A. Çetinkaya, Prof. Dr.

  Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey

  STUDY DIRECTOR

• Rahmet Güner, Prof. Dr.

  Yıldırım Beyazıt University, Ankara City Hospital, Ankara, Turkey

  STUDY DIRECTOR

• İsmail Y. Avcı

  Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: Patients who were hospitalised with a pre-diagnosis of severe COVID-19 pneumonia and thereafter diagnosis of COVID-19 was also confirmed microbiologically with polymerase chain reaction (PCR) positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively. Single numbered patients were accepted as study group and double numbered patients as control group

Study Record Dates

• First Submitted: November 15, 2020
• First Posted: November 27, 2020
• Study Start: May 11, 2020
• Primary Completion: September 2, 2020
• Study Completion: September 2, 2020
• Last Updated: January 27, 2021
• Results First Posted: January 27, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

TU (4)