Trial Outcomes & Findings for Ivermectin for Severe COVID-19 Management (NCT NCT04646109)

NCT ID: NCT04646109

Last Updated: 2021-01-27

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 66 participants
• Primary outcome timeframe: At the first day of the study
• Results posted on: 2021-01-27

Participant Flow

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.

Participant milestones

Measure	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.	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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
Overall Study STARTED	30	36
Overall Study COMPLETED	30	30
Overall Study NOT COMPLETED	0	6

Reasons for withdrawal

Measure	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.	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. Ivermectin: Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
Overall Study Mutation disrupting ivermectin metabolism was found in 6 patients	0	6

Baseline Characteristics

Ivermectin for Severe COVID-19 Management

Baseline characteristics by cohort

Measure	Control Group n=30 Participants 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 n=30 Participants 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 n=60 Participants Total of all reporting groups
Age, Customized	66.23 years STANDARD_DEVIATION 13.31 • n=5 Participants	58.17 years STANDARD_DEVIATION 11.52 • n=7 Participants	62.20 years STANDARD_DEVIATION 13.00 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	9 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	21 Participants n=7 Participants	40 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	30 Participants n=5 Participants	30 Participants n=7 Participants	60 Participants n=5 Participants
Region of Enrollment Turkey	30 participants n=5 Participants	30 participants n=7 Participants	60 participants n=5 Participants

PRIMARY outcome

Timeframe: At the first day of the study

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

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Gender Distribution of the Patients Male	19 Participants	21 Participants
Gender Distribution of the Patients Female	11 Participants	9 Participants

PRIMARY outcome

Timeframe: At the first day of the study

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

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Age Distribution of the Patients	66.23 Years Standard Deviation 13.31	58.17 Years Standard Deviation 11.52

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Percentage of Patients With Accompanying Diseases Diabetes Mellitus	10 Participants	9 Participants
Percentage of Patients With Accompanying Diseases Hypertension	12 Participants	15 Participants
Percentage of Patients With Accompanying Diseases Coronary artery disease	8 Participants	5 Participants
Percentage of Patients With Accompanying Diseases Cardiac failure	1 Participants	0 Participants
Percentage of Patients With Accompanying Diseases Chronic obstructive pulmonary disease	3 Participants	6 Participants
Percentage of Patients With Accompanying Diseases Malignancy	1 Participants	0 Participants
Percentage of Patients With Accompanying Diseases Immunodeficiency	1 Participants	0 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Percentage of Patients With Baseline Clinical Symptoms Fever	13 Participants	15 Participants
Percentage of Patients With Baseline Clinical Symptoms Cough	14 Participants	16 Participants
Percentage of Patients With Baseline Clinical Symptoms Sore throat	1 Participants	3 Participants
Percentage of Patients With Baseline Clinical Symptoms dyspnea	19 Participants	23 Participants
Percentage of Patients With Baseline Clinical Symptoms Headache	2 Participants	5 Participants
Percentage of Patients With Baseline Clinical Symptoms Weakness	11 Participants	13 Participants
Percentage of Patients With Baseline Clinical Symptoms Myalgia	7 Participants	9 Participants
Percentage of Patients With Baseline Clinical Symptoms Diarrhea	0 Participants	1 Participants
Percentage of Patients With Baseline Clinical Symptoms Nausea or vomiting	0 Participants	1 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Body Temperature Means of the Patients	36.8 Degree celcius Standard Deviation 0.8	36.9 Degree celcius Standard Deviation 0.7

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Heart Rate Means of the Patients	92 beats per minute Standard Deviation 18	88 beats per minute Standard Deviation 12

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Respiratory Rate Means of the Patients	24.7 breaths per minute Standard Deviation 0.7	24 breaths per minute Standard Deviation 5

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Systolic and Diastolic Pressure Means of the Patients Systolic pressure	124.61 mmHg Standard Deviation 15.37	124.39 mmHg Standard Deviation 15.60
Systolic and Diastolic Pressure Means of the Patients Diastolic pressure	73.43 mmHg Standard Deviation 8.47	75.64 mmHg Standard Deviation 9.79

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Number of Participants With Clinical Response	11 Participants	14 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Oxygen Saturation (SpO2) Values Baseline	89.67 percentage of peripheral capillary O2 Standard Deviation 5.09	89.93 percentage of peripheral capillary O2 Standard Deviation 6.51
Changes in Oxygen Saturation (SpO2) Values TD1	90.50 percentage of peripheral capillary O2 Standard Deviation 7.47	92.85 percentage of peripheral capillary O2 Standard Deviation 4.86
Changes in Oxygen Saturation (SpO2) Values TD3	91.90 percentage of peripheral capillary O2 Standard Deviation 4.97	93.07 percentage of peripheral capillary O2 Standard Deviation 4.12
Changes in Oxygen Saturation (SpO2) Values TD5	93.00 percentage of peripheral capillary O2 Standard Deviation 3.25	93.52 percentage of peripheral capillary O2 Standard Deviation 4.36

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) Baseline	197.44 Ratio Standard Deviation 102.31	158.83 Ratio Standard Deviation 88.15
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) TD1	181.83 Ratio Standard Deviation 99.62	147.31 Ratio Standard Deviation 74.15
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) TD3	174.77 Ratio Standard Deviation 94.74	147.74 Ratio Standard Deviation 83.30
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) TD5	180.13 Ratio Standard Deviation 95.43	178.94 Ratio Standard Deviation 98.21

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum Lymphocyte Counts Baseline	1010 cell/mm^3 Standard Deviation 438	932 cell/mm^3 Standard Deviation 483
Changes in Serum Lymphocyte Counts TD1	1034 cell/mm^3 Standard Deviation 450	928 cell/mm^3 Standard Deviation 607
Changes in Serum Lymphocyte Counts TD3	977 cell/mm^3 Standard Deviation 575	1021 cell/mm^3 Standard Deviation 648
Changes in Serum Lymphocyte Counts TD5	968 cell/mm^3 Standard Deviation 477	1273 cell/mm^3 Standard Deviation 822

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) Baseline	7.48 Ratio Standard Deviation 6.41	8.77 Ratio Standard Deviation 8.35
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) TD1	7.74 Ratio Standard Deviation 7.47	10.82 Ratio Standard Deviation 8.55
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) TD3	9.26 Ratio Standard Deviation 7.58	9.02 Ratio Standard Deviation 13.08
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) TD5	9.88 Ratio Standard Deviation 8.45	7.16 Ratio Standard Deviation 4.97

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum Ferritin Levels Baseline	747.05 mg/dL Standard Deviation 800.54	682.75 mg/dL Standard Deviation 470.08
Changes in Serum Ferritin Levels TD1	783.03 mg/dL Standard Deviation 827.10	834.94 mg/dL Standard Deviation 624.12
Changes in Serum Ferritin Levels TD3	881.17 mg/dL Standard Deviation 779.95	875.90 mg/dL Standard Deviation 694.52
Changes in Serum Ferritin Levels TD5	1028.24 mg/dL Standard Deviation 777.08	875.12 mg/dL Standard Deviation 1193.06

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum D-dimer Levels Baseline	1.32 mg/L Standard Deviation 2.04	1.25 mg/L Standard Deviation 1.71
Changes in Serum D-dimer Levels TD1	2.80 mg/L Standard Deviation 5.66	1.40 mg/L Standard Deviation 1.73
Changes in Serum D-dimer Levels TD3	4.14 mg/L Standard Deviation 9.91	3.24 mg/L Standard Deviation 11.60
Changes in Serum D-dimer Levels TD5	3.58 mg/L Standard Deviation 8.27	5.85 mg/L Standard Deviation 5.28

PRIMARY outcome

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

Population: 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.

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.

Outcome measures

Measure	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.	Study Group n=36 Participants 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.
Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism Mutation positive	0 Participants	6 Participants
Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism Mutation negative	0 Participants	30 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Treatment-Related Adverse Events as Assessed by CTCAE v4.0 Nausea and vomiting	2 Participants	0 Participants
Treatment-Related Adverse Events as Assessed by CTCAE v4.0 Increase in liver function tests	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Number of Participants With Clinical Response	16 Participants	22 Participants

SECONDARY outcome

Timeframe: Through study completion, an average of 3 months

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

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Mortality	9 Participants	6 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Oxygen Saturation (SpO2) Values Baseline	89.67 percentage of peripheral capillary O2 Standard Deviation 5.09	89.93 percentage of peripheral capillary O2 Standard Deviation 6.51
Changes in Oxygen Saturation (SpO2) Values FD1	92.43 percentage of peripheral capillary O2 Standard Deviation 2.86	94.54 percentage of peripheral capillary O2 Standard Deviation 2.21
Changes in Oxygen Saturation (SpO2) Values FD3	92.91 percentage of peripheral capillary O2 Standard Deviation 2.71	94.24 percentage of peripheral capillary O2 Standard Deviation 2.76
Changes in Oxygen Saturation (SpO2) Values FD5	93.00 percentage of peripheral capillary O2 Standard Deviation 3.93	95.35 percentage of peripheral capillary O2 Standard Deviation 2.72

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) Baseline	197.44 Ratio Standard Deviation 102.31	158.83 Ratio Standard Deviation 88.15
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) FD1	204.28 Ratio Standard Deviation 109.51	199.83 Ratio Standard Deviation 85.02
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) FD3	211.75 Ratio Standard Deviation 127.62	227.43 Ratio Standard Deviation 103.71
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) FD5	220.78 Ratio Standard Deviation 127.26	236.33 Ratio Standard Deviation 85.66

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum Lymphocyte Counts Baseline	1010 cell/mm^3 Standard Deviation 438	932 cell/mm^3 Standard Deviation 483
Changes in Serum Lymphocyte Counts FD1	916 cell/mm^3 Standard Deviation 411	1403 cell/mm^3 Standard Deviation 869
Changes in Serum Lymphocyte Counts FD3	1086 cell/mm^3 Standard Deviation 880	1668 cell/mm^3 Standard Deviation 819
Changes in Serum Lymphocyte Counts FD5	1256 cell/mm^3 Standard Deviation 710	1698 cell/mm^3 Standard Deviation 1438

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) Baseline	7.48 Ratio Standard Deviation 6.41	8.77 Ratio Standard Deviation 8.35
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) FD1	10.49 Ratio Standard Deviation 7.10	6.90 Ratio Standard Deviation 11.84
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) FD3	9.66 Ratio Standard Deviation 10.99	5.81 Ratio Standard Deviation 9.99
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L) FD5	6.19 Ratio Standard Deviation 4.85	7.34 Ratio Standard Deviation 8.09

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum Ferritin Levels Baseline	747.05 mg/dL Standard Deviation 800.54	682.75 mg/dL Standard Deviation 470.08
Changes in Serum Ferritin Levels FD1	1076.88 mg/dL Standard Deviation 704.05	628.45 mg/dL Standard Deviation 580.10
Changes in Serum Ferritin Levels FD3	1097.57 mg/dL Standard Deviation 595.22	433.48 mg/dL Standard Deviation 641.82
Changes in Serum Ferritin Levels FD5	1206.90 mg/dL Standard Deviation 782.84	494.71 mg/dL Standard Deviation 349.78

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Changes in Serum D-dimer Levels Baseline	1.32 mg/L Standard Deviation 2.04	1.25 mg/L Standard Deviation 1.71
Changes in Serum D-dimer Levels FD1	3.45 mg/L Standard Deviation 6.60	1.37 mg/L Standard Deviation 2.53
Changes in Serum D-dimer Levels FD3	1.63 mg/L Standard Deviation 1.38	0.89 mg/L Standard Deviation 2.45
Changes in Serum D-dimer Levels FD5	1.49 mg/L Standard Deviation 2.28	0.71 mg/L Standard Deviation 0.96

SECONDARY outcome

Timeframe: At the end of 10th day

Population: 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).

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.

Outcome measures

Measure	Control Group n=8 Participants 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 n=16 Participants 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.
Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity	3 Participants	14 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Control Group n=30 Participants 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 n=30 Participants 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.
Treatment-Related Adverse Events as Assessed by CTCAE v4.0	0 Participants	0 Participants

Adverse Events

Control Group

Serious events: 0 serious events

Other events: 3 other events

Deaths: 9 deaths

Study Group

Serious events: 0 serious events

Other events: 0 other events

Deaths: 6 deaths

Participants With Mutations

Serious events: 5 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Control Group n=30 participants at risk 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 n=30 participants at risk 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.	Participants With Mutations n=6 participants at risk 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
Nervous system disorders Encephalopathy	0.00% 0/30 • From the beginning of the study to the end of the 10th day 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.	0.00% 0/30 • From the beginning of the study to the end of the 10th day 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.	83.3% 5/6 • From the beginning of the study to the end of the 10th day 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.

Other adverse events

Measure	Control Group n=30 participants at risk 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 n=30 participants at risk 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.	Participants With Mutations n=6 participants at risk 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
Gastrointestinal disorders Nausea and vomiting	6.7% 2/30 • Number of events 2 • From the beginning of the study to the end of the 10th day 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.	0.00% 0/30 • From the beginning of the study to the end of the 10th day 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.	0.00% 0/6 • From the beginning of the study to the end of the 10th day 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.
Gastrointestinal disorders Increase in liver function tests	3.3% 1/30 • Number of events 1 • From the beginning of the study to the end of the 10th day 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.	0.00% 0/30 • From the beginning of the study to the end of the 10th day 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.	0.00% 0/6 • From the beginning of the study to the end of the 10th day 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.

Additional Information

Prof. Dr. Nurullah Okumuş

Afyonkarahisar Health Sciences University

Phone: +90 532 4372406

Email: drnuri@hotmail.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place