Ivermectin for Severe COVID-19 Management

Sponsor
Afyonkarahisar Health Sciences University (Other)
Overall Status
Completed
CT.gov ID
NCT04646109
Collaborator
NeuTec Pharma (Industry)
66
4
2
3.7
16.5
4.4

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Patients with severe COVID-19 pneumonia were included in the study. Two groups, the study group and the control group, took part in the study.

Ivermectin 200 mcg/kg/day for five days (9 mg between 36-50 kg, 12 mg between 51-65 kg, 15 mg between 66-79 kg and 200 microgram/kg in > 80 kg) in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine (2x400mg loading dose followed by 2x200mg, po, 5 days) + favipiravir (2x1600mg loading dose followed by 2x600mg maintenance dose, po, total 5 days) + azithromycin (first day 500mg followed by 4 days 250mg/day, po, total 5 days)- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin.

The mutations in 29 pairs of primers in mdr1/abcab1 gene by sequencing analysis using Sanger method, and the haplotypes and mutations of the CYP3A4 gene that cause the function losing were investigated among the patients who meet criteria and who were included in the study group according to randomization. Mutation screening was done when the first dose of the research drug ivermectin was given, ivermectin treatment was not continued in patients with mutations detected as a result of genetic examination and these patients were excluded from the study.

Patients were followed for 5 additional days after treatment. At the end of the treatment and follow-up period (At the end of 10th day), clinical response and changes in oxygenation and laboratory parameters were evaluated.

Study Design

Study Type:
Interventional
Actual Enrollment :
66 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
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 groupPatients 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
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
The Effectiveness and Safety of Ivermectin as add-on Therapy in Severe COVID-19 Management
Actual Study Start Date :
May 11, 2020
Actual Primary Completion Date :
Sep 2, 2020
Actual Study Completion Date :
Sep 2, 2020

Arms and Interventions

Arm Intervention/Treatment
No Intervention: Control Group

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.

Experimental: Study Group

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
Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
Other Names:
  • Hydroxychloroquine, favipiravir and azithromycin
  • Outcome Measures

    Primary Outcome Measures

    1. Gender Distribution of the Patients [At the first day of the study]

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

    2. Age Distribution of the Patients [At the first day of the study]

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

    3. Percentage of Patients With Accompanying Diseases [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

    4. Percentage of Patients With Baseline Clinical Symptoms [At the first day of the study]

      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

    5. Body Temperature Means of the Patients [At the first day of the study]

      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.

    6. Heart Rate Means of the Patients [At the first day of the study]

      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.

    7. Respiratory Rate Means of the Patients [At the first day of the study]

      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.

    8. Systolic and Diastolic Pressure Means of the Patients [At the first day of the study]

      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.

    9. Number of Participants With Clinical Response [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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.

    10. Changes in Oxygen Saturation (SpO2) Values [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    11. Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    12. Changes in Serum Lymphocyte Counts [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    13. Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    14. Changes in Serum Ferritin Levels [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    15. Changes in Serum D-dimer Levels [From starting to the end of ivermectin therapy (0 to the end of 5th day)]

      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).

    16. Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism [At the first day of ivermectin therapy (1st day)]

      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.

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

    Secondary Outcome Measures

    1. Number of Participants With Clinical Response [10 days (5 days ivermectin therapy plus 5 days follow-up)]

      The presence of at least two of the following criteria in patients on the 10th 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.

    2. Mortality [Through study completion, an average of 3 months]

      The number of died patients were evaluated in study and control groups

    3. Changes in Oxygen Saturation (SpO2) Values [From 6th to the end of 10th day]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). SpO2 values at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in SpO2 values on the 6th, 8th and 10th days was calculated graphically, the change in the SpO2 value at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).

    4. 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]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). PaO2/FiO2 ratios at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in PaO2/FiO2 ratios on the 6th, 8th and 10th days was calculated graphically, the change in the PaO2/FiO2 ratio at the end of the 10th day (secondary endpoint) with the baseline ratio was compared statistically (the results were given as p value).

    5. Changes in Serum Lymphocyte Counts [From 6th to the end of 10th day]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum lymphocyte counts (cell/mm^3) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in serum lymphocyte counts on the 6th, 8th and 10th days was calculated graphically, the change in the serum lymphocyte count at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).

    6. Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) [From 6th to the end of 10th day]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). PNL/L ratios at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in PNL/L ratios on the 6th, 8th and 10th days was calculated graphically, the change in the PNL/L ratio at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).

    7. Changes in Serum Ferritin Levels [From 6th to the end of 10th day]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum ferritin levels (mg/dL) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in serum ferritin levels on the 6th, 8th and 10th days was calculated graphically, the change in the serum ferritin level at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).

    8. Changes in Serum D-dimer Levels [From 6th to the end of 10th day]

      In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum D-dimer levels (mg/L) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in Serum D-dimer levels on the 6th, 8th and 10th days was calculated graphically, the change in the serum D-dimer level at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).

    9. Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity [At the end of 10th day]

      At the end of the follow-up period (10th day), patients in the study and control group were investigated by PCR test for SARS-CoV-2 and the negative results were recorded as percentage for both groups.

    10. Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [From the 6th day of study to the 10th 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. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • 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;

    1. Presence of tachypnea ≥ 30/minute, SpO2 level < 90% in room air, PaO2/FiO2 <300 in oxygen receiving patient

    2. Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities)

    3. Mechanical ventilation requirement

    4. Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score >2

    Exclusion Criteria:
    • Patients with the following characteristics were excluded from the study.
    1. Pediatric patients; <18 years of old

    2. Patients with chronic liver or kidney disease

    3. Pregnant women

    4. Patients with known ivermectin allergy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Afyonkarahisar Health Science University Afyonkarahisar Turkey
    2 Gulhane Faculty of Medicine, University of Health Sciences Ankara Turkey
    3 Yıldırım Beyazıt University, Ankara City Hospital Ankara Turkey
    4 Haydarpasa Sultan Abdulhamid Han Training and Research Hospital İstanbul Turkey

    Sponsors and Collaborators

    • Afyonkarahisar Health Sciences University
    • NeuTec Pharma

    Investigators

    • Study Chair: Nurullah Okumuş, Prof. Dr., Afyonkarahisar Health Science University, Afyonkarahisar, Turkey
    • Study Director: 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 Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Nurullah Okumuş, Prof. Dr., Afyonkarahisar Health Sciences University
    ClinicalTrials.gov Identifier:
    NCT04646109
    Other Study ID Numbers:
    • IVMC_03
    First Posted:
    Nov 27, 2020
    Last Update Posted:
    Jan 27, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Keywords provided by Nurullah Okumuş, Prof. Dr., Afyonkarahisar Health Sciences University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail At the beginning of the study, it was planned to have 30 patients each in the control and study groups. During the study, 6 patients were excluded from the study group because ivermectin treatments were terminated due to the detection of mutations that impairs ivermectin metabolism and new patients were added. As a result, 66 patients were included in the study, 6 patients were excluded due to mutation detection and the study was completed with 30 patients in both groups.
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Period Title: Overall Study
    STARTED 30 36
    COMPLETED 30 30
    NOT COMPLETED 0 6

    Baseline Characteristics

    Arm/Group Title Control Group Study Group Total
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions. Total of all reporting groups
    Overall Participants 30 30 60
    Age, Customized (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    66.23
    (13.31)
    58.17
    (11.52)
    62.20
    (13.00)
    Sex: Female, Male (Count of Participants)
    Female
    11
    36.7%
    9
    30%
    20
    33.3%
    Male
    19
    63.3%
    21
    70%
    40
    66.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    0
    0%
    0
    0%
    0
    0%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    30
    100%
    30
    100%
    60
    100%
    Region of Enrollment (participants) [Number]
    Turkey
    30
    100%
    30
    100%
    60
    100%

    Outcome Measures

    1. Primary Outcome
    Title Gender Distribution of the Patients
    Description The gender of patients (Male/female) in both groups were recorded at the time of inclusion.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Male
    19
    63.3%
    21
    70%
    Female
    11
    36.7%
    9
    30%
    2. Primary Outcome
    Title Age Distribution of the Patients
    Description The age of the patients (years) in both groups were recorded at the time of inclusion.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Mean (Standard Deviation) [Years]
    66.23
    (13.31)
    58.17
    (11.52)
    3. Primary Outcome
    Title Percentage of Patients With Accompanying Diseases
    Description 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
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Diabetes Mellitus
    10
    33.3%
    9
    30%
    Hypertension
    12
    40%
    15
    50%
    Coronary artery disease
    8
    26.7%
    5
    16.7%
    Cardiac failure
    1
    3.3%
    0
    0%
    Chronic obstructive pulmonary disease
    3
    10%
    6
    20%
    Malignancy
    1
    3.3%
    0
    0%
    Immunodeficiency
    1
    3.3%
    0
    0%
    4. Primary Outcome
    Title Percentage of Patients With Baseline Clinical Symptoms
    Description 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
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Fever
    13
    43.3%
    15
    50%
    Cough
    14
    46.7%
    16
    53.3%
    Sore throat
    1
    3.3%
    3
    10%
    dyspnea
    19
    63.3%
    23
    76.7%
    Headache
    2
    6.7%
    5
    16.7%
    Weakness
    11
    36.7%
    13
    43.3%
    Myalgia
    7
    23.3%
    9
    30%
    Diarrhea
    0
    0%
    1
    3.3%
    Nausea or vomiting
    0
    0%
    1
    3.3%
    5. Primary Outcome
    Title Body Temperature Means of the Patients
    Description 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.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Mean (Standard Deviation) [Degree celcius]
    36.8
    (0.8)
    36.9
    (0.7)
    6. Primary Outcome
    Title Heart Rate Means of the Patients
    Description 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.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Mean (Standard Deviation) [beats per minute]
    92
    (18)
    88
    (12)
    7. Primary Outcome
    Title Respiratory Rate Means of the Patients
    Description 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.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Mean (Standard Deviation) [breaths per minute]
    24.7
    (0.7)
    24
    (5)
    8. Primary Outcome
    Title Systolic and Diastolic Pressure Means of the Patients
    Description 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.
    Time Frame At the first day of the study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Systolic pressure
    124.61
    (15.37)
    124.39
    (15.60)
    Diastolic pressure
    73.43
    (8.47)
    75.64
    (9.79)
    9. Primary Outcome
    Title Number of Participants With Clinical Response
    Description 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.
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Count of Participants [Participants]
    11
    36.7%
    14
    46.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.43
    Comments A p<0.05 value was considered statistically significant
    Method Chi-squared
    Comments
    10. Primary Outcome
    Title Changes in Oxygen Saturation (SpO2) Values
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    89.67
    (5.09)
    89.93
    (6.51)
    TD1
    90.50
    (7.47)
    92.85
    (4.86)
    TD3
    91.90
    (4.97)
    93.07
    (4.12)
    TD5
    93.00
    (3.25)
    93.52
    (4.36)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.14
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    11. Primary Outcome
    Title Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    197.44
    (102.31)
    158.83
    (88.15)
    TD1
    181.83
    (99.62)
    147.31
    (74.15)
    TD3
    174.77
    (94.74)
    147.74
    (83.30)
    TD5
    180.13
    (95.43)
    178.94
    (98.21)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.68
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    12. Primary Outcome
    Title Changes in Serum Lymphocyte Counts
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    1010
    (438)
    932
    (483)
    TD1
    1034
    (450)
    928
    (607)
    TD3
    977
    (575)
    1021
    (648)
    TD5
    968
    (477)
    1273
    (822)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.15
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    13. Primary Outcome
    Title Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    7.48
    (6.41)
    8.77
    (8.35)
    TD1
    7.74
    (7.47)
    10.82
    (8.55)
    TD3
    9.26
    (7.58)
    9.02
    (13.08)
    TD5
    9.88
    (8.45)
    7.16
    (4.97)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.37
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    14. Primary Outcome
    Title Changes in Serum Ferritin Levels
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    747.05
    (800.54)
    682.75
    (470.08)
    TD1
    783.03
    (827.10)
    834.94
    (624.12)
    TD3
    881.17
    (779.95)
    875.90
    (694.52)
    TD5
    1028.24
    (777.08)
    875.12
    (1193.06)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.12
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    15. Primary Outcome
    Title Changes in Serum D-dimer Levels
    Description 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).
    Time Frame From starting to the end of ivermectin therapy (0 to the end of 5th day)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    1.32
    (2.04)
    1.25
    (1.71)
    TD1
    2.80
    (5.66)
    1.40
    (1.73)
    TD3
    4.14
    (9.91)
    3.24
    (11.60)
    TD5
    3.58
    (8.27)
    5.85
    (5.28)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.22
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    16. Primary Outcome
    Title Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism
    Description 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.
    Time Frame At the first day of ivermectin therapy (1st day)

    Outcome Measure Data

    Analysis Population Description
    We aimed to investigate the effectiveness/safety of adding ivermectin to the COVID-19 treatment in patients without mutation. Since ivermectin was not given to the control group, no blood sample was taken from these patients for mutation screening. The reason why there are 36 patients in the study group in this table is to indicate that there are 6 patients who were included in the study group but were removed from the study group because of a mutation and were replaced by additional patients.
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 0 36
    Mutation positive
    0
    0%
    6
    20%
    Mutation negative
    0
    0%
    30
    100%
    17. Primary Outcome
    Title Treatment-Related Adverse Events as Assessed by CTCAE v4.0
    Description 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.
    Time Frame At the first 5 days of study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Nausea and vomiting
    2
    6.7%
    0
    0%
    Increase in liver function tests
    1
    3.3%
    0
    0%
    18. Secondary Outcome
    Title Number of Participants With Clinical Response
    Description The presence of at least two of the following criteria in patients on the 10th 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.
    Time Frame 10 days (5 days ivermectin therapy plus 5 days follow-up)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Count of Participants [Participants]
    16
    53.3%
    22
    73.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.10
    Comments A p<0.05 value was considered statistically significant
    Method Chi-squared
    Comments
    19. Secondary Outcome
    Title Mortality
    Description The number of died patients were evaluated in study and control groups
    Time Frame Through study completion, an average of 3 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Count of Participants [Participants]
    9
    30%
    6
    20%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.37
    Comments A p<0.05 value was considered statistically significant
    Method Chi-squared
    Comments
    20. Secondary Outcome
    Title Changes in Oxygen Saturation (SpO2) Values
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). SpO2 values at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in SpO2 values on the 6th, 8th and 10th days was calculated graphically, the change in the SpO2 value at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    89.67
    (5.09)
    89.93
    (6.51)
    FD1
    92.43
    (2.86)
    94.54
    (2.21)
    FD3
    92.91
    (2.71)
    94.24
    (2.76)
    FD5
    93.00
    (3.93)
    95.35
    (2.72)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.03
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    21. Secondary Outcome
    Title Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). PaO2/FiO2 ratios at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in PaO2/FiO2 ratios on the 6th, 8th and 10th days was calculated graphically, the change in the PaO2/FiO2 ratio at the end of the 10th day (secondary endpoint) with the baseline ratio was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    197.44
    (102.31)
    158.83
    (88.15)
    FD1
    204.28
    (109.51)
    199.83
    (85.02)
    FD3
    211.75
    (127.62)
    227.43
    (103.71)
    FD5
    220.78
    (127.26)
    236.33
    (85.66)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.39
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    22. Secondary Outcome
    Title Changes in Serum Lymphocyte Counts
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum lymphocyte counts (cell/mm^3) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in serum lymphocyte counts on the 6th, 8th and 10th days was calculated graphically, the change in the serum lymphocyte count at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    1010
    (438)
    932
    (483)
    FD1
    916
    (411)
    1403
    (869)
    FD3
    1086
    (880)
    1668
    (819)
    FD5
    1256
    (710)
    1698
    (1438)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.24
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    23. Secondary Outcome
    Title Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). PNL/L ratios at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in PNL/L ratios on the 6th, 8th and 10th days was calculated graphically, the change in the PNL/L ratio at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    7.48
    (6.41)
    8.77
    (8.35)
    FD1
    10.49
    (7.10)
    6.90
    (11.84)
    FD3
    9.66
    (10.99)
    5.81
    (9.99)
    FD5
    6.19
    (4.85)
    7.34
    (8.09)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.56
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    24. Secondary Outcome
    Title Changes in Serum Ferritin Levels
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum ferritin levels (mg/dL) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in serum ferritin levels on the 6th, 8th and 10th days was calculated graphically, the change in the serum ferritin level at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    747.05
    (800.54)
    682.75
    (470.08)
    FD1
    1076.88
    (704.05)
    628.45
    (580.10)
    FD3
    1097.57
    (595.22)
    433.48
    (641.82)
    FD5
    1206.90
    (782.84)
    494.71
    (349.78)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    25. Secondary Outcome
    Title Changes in Serum D-dimer Levels
    Description In both groups, after the treatment period was completed (first 5 days, primary endpoint), patients were followed up for 5 more days (follow-up period). Serum D-dimer levels (mg/L) at the end of 6th (FD1), 8th (FD3) and 10th day (FD5) were also recorded. The end of the 10th day was accepted as the secondary endpoint. While the change in Serum D-dimer levels on the 6th, 8th and 10th days was calculated graphically, the change in the serum D-dimer level at the end of the 10th day (secondary endpoint) with the baseline value was compared statistically (the results were given as p value).
    Time Frame From 6th to the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Baseline
    1.32
    (2.04)
    1.25
    (1.71)
    FD1
    3.45
    (6.60)
    1.37
    (2.53)
    FD3
    1.63
    (1.38)
    0.89
    (2.45)
    FD5
    1.49
    (2.28)
    0.71
    (0.96)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.03
    Comments A p<0.05 value was considered statistically significant
    Method Wilcoxon (Mann-Whitney)
    Comments
    26. Secondary Outcome
    Title Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity
    Description At the end of the follow-up period (10th day), patients in the study and control group were investigated by PCR test for SARS-CoV-2 and the negative results were recorded as percentage for both groups.
    Time Frame At the end of 10th day

    Outcome Measure Data

    Analysis Population Description
    PCR test was applied to 8 patients in the control group and 16 patients in the study group at the end of the study (secondary endpoint).
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 8 16
    Count of Participants [Participants]
    3
    10%
    14
    46.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control Group, Study Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.01
    Comments A p<0.05 value was considered statistically significant
    Method Chi-squared
    Comments
    27. Secondary Outcome
    Title Treatment-Related Adverse Events as Assessed by CTCAE v4.0
    Description 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.
    Time Frame From the 6th day of study to the 10th day of study

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group Study Group
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
    Measure Participants 30 30
    Count of Participants [Participants]
    0
    0%
    0
    0%

    Adverse Events

    Time Frame From the beginning of the study to the end of the 10th day
    Adverse Event Reporting Description In our study, it was also aimed to detect mutations that impair ivermectin metabolism and report side effects that may occur due to these mutations, and these mutations were detected in 6 patients initially included in the study group. Since these patients were excluded from the study on the first day following the mutation detection and their ivermectin treatment was discontinued, they were evaluated separately from the other patients included in the study.
    Arm/Group Title Control Group Study Group Participants With Mutations
    Arm/Group Description 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. 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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions. Patients that were included in the study group and excluded from the study because one or both of the multidrug resistance 1 (MDR1) / ABCB1 and CYP3A4 genes were detected in the blood sample taken at the beginning of ivermectin treatment on the first day
    All Cause Mortality
    Control Group Study Group Participants With Mutations
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/30 (30%) 6/30 (20%) 0/6 (0%)
    Serious Adverse Events
    Control Group Study Group Participants With Mutations
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 0/30 (0%) 5/6 (83.3%)
    Nervous system disorders
    Encephalopathy 0/30 (0%) 0/30 (0%) 5/6 (83.3%)
    Other (Not Including Serious) Adverse Events
    Control Group Study Group Participants With Mutations
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/30 (10%) 0/30 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Nausea and vomiting 2/30 (6.7%) 2 0/30 (0%) 0 0/6 (0%) 0
    Increase in liver function tests 1/30 (3.3%) 1 0/30 (0%) 0 0/6 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Prof. Dr. Nurullah Okumuş
    Organization Afyonkarahisar Health Sciences University
    Phone +90 532 4372406
    Email drnuri@hotmail.com
    Responsible Party:
    Nurullah Okumuş, Prof. Dr., Afyonkarahisar Health Sciences University
    ClinicalTrials.gov Identifier:
    NCT04646109
    Other Study ID Numbers:
    • IVMC_03
    First Posted:
    Nov 27, 2020
    Last Update Posted:
    Jan 27, 2021
    Last Verified:
    Jan 1, 2021