COVID-19Phase 3NCT04646109
Ivermectin for Severe COVID-19 Management
A Phase 3 study testing Ivermectin in people with COVID-19, run by Afyonkarahisar Health Sciences University at 4 sites in Turkey (Türkiye).
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- COVID-19
- What is being tested?
- Ivermectin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 66 participants
- Where
- 4 sitesTurkey (Türkiye)
- Study dates
- 11 May 2020to 2 Sep 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Patients who were hospitalised with a pre-diagnosis of "severe COVID-19 pneumonia" and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively.
- Patients with at least one of the criteria below were accepted as patients with severe COVID-19 pneumonia;
- Presence of tachypnea ≥ 30/minute, SpO2 level < 90% in room air, PaO2/FiO2 <300 in oxygen receiving patient
- Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities)
- Mechanical ventilation requirement
- Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score >2
Who cannot join
- Patients with the following characteristics were excluded from the study.
- Pediatric patients; <18 years of old
- Patients with chronic liver or kidney disease
- Pregnant women
- Patients with known ivermectin allergy
Trial locations and contacts
4 sites in 1 country.
Turkey (Türkiye)4 sites
Afyonkarahisar Health Science University
Afyonkarahisar
Gulhane Faculty of Medicine, University of Health Sciences
Ankara
Yıldırım Beyazıt University, Ankara City Hospital
Ankara
Haydarpasa Sultan Abdulhamid Han Training and Research Hospital
Istanbul
About this study
Official title: The Effectiveness and Safety of Ivermectin as add-on Therapy in Severe COVID-19 Management
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.
Read the 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.
- Conditions
- COVID-19
- Being tested
- Ivermectin
- Keywords
- Ivermectin, SARS-CoV-2, Treatment
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IvermectinDrug
Also called Hydroxychloroquine, favipiravir and azithromycin
Ivermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions.
| Study group | Role | What they receive |
|---|---|---|
| Control Group | No intervention | Patients who were hospitalised with a pre-diagnosis of severe COVID-19 pneumonia and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the control and study group, respectively. Hydroxychloroquine, favipiravir and azithromycin (HFA) standard treatment protocol were given to the control group as recommended in the "COVID-19 (SARS-CoV-2 Infection) Guide" prepared by the Republic of Turkey Ministry of Health. |
| Study Group | Experimental | In addition to HFA treatment, ivermectin 200 micrograms/kg/day (9mg between 36-50 kg, 12mg between 51-65 kg, 15mg between 66-79 kg and 200 micrograms/kg in > 80 kg) in the form of a solution prepared for enteral use was added (HFA+I) to the treatment protocol of the study group's for five days. Blood sample was taken with the first dose of ivermectin and haplotype analysis was performed in ABCB1 and CYP3A4 genes in the whole study group. Receives: Drug: Ivermectin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Gender Distribution of the Patients
The gender of patients (Male/female) in both groups were recorded at the time of inclusion.
Measured: At the first day of the study
Age Distribution of the Patients
The age of the patients (years) in both groups were recorded at the time of inclusion.
Measured: At the first day of the study
Percentage of Patients With Accompanying Diseases
At the beginning of the study, the patients were asked whether there were any of the following accompanying diseases and the percentage of patients with accompanying disease in both groups were recorded:
- Diabetes mellitus
- Hypertension
- Coronary artery disease
- Cardiac failure
- Chronic obstructive pulmonary disease
- Malignancy
- Immunodeficiency
Measured: At the first day of the study
Percentage of Patients With Baseline Clinical Symptoms
At the beginning of the study, the patients were asked whether there were any of the following clinical symptoms and the percentage of patients with any of the clinical symptoms in both groups were recorded:
- Fever
- Cough
- Sore throat
- Dispnea
- Headache
- Weakness
- Myalgia
- Diarrhea
- Nausea or vomiting
Measured: At the first day of the study
Body Temperature Means of the Patients
At the beginning of the study, the body temperatures (as degree celcius) of the patients were measured and the mean body temperature values of both groups were recorded.
Measured: At the first day of the study
Heart Rate Means of the Patients
At the beginning of the study, the heart rates (as per minute) of the patients were measured and the mean heart rate values of both groups were recorded.
Measured: At the first day of the study
Respiratory Rate Means of the Patients
At the beginning of the study, the respiratory rates (as per minute) of the patients were measured and the mean respiratory rate values of both groups were recorded.
Measured: At the first day of the study
Systolic and Diastolic Pressure Means of the Patients
At the beginning of the study, the systolic and diastolic pressures (as mmHg) of the patients were measured and the mean systolic and diastolic pressure values of both groups were recorded.
Measured: At the first day of the study
Number of Participants With Clinical Response
The presence of at least two of the following criteria in patients at the end of 5th day were accepted as "clinical response": Extubation in mechanically ventilated patients, respiratory rate <26/min, SpO2 level in room air >90%, PaO2/FiO2 >300 in patients receiving oxygen, presence of at least two of the 2-point reduction criteria in "Sequential Organ Failure Assessment (SOFA)" score.
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in Oxygen Saturation (SpO2) Values
Baseline SpO2 values of the patients were recorded in both groups. Then, their treatments were started and SpO2 values at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in SpO2 values on the 1st, 3rd and 5th days after the basal value calculated graphically, the change in the SpO2 value at the end of the 5th day (primary endpoint) with the baseline value was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
Baseline PaO2/FiO2 ratios of the patients were recorded in both groups. Then, their treatments were started and PaO2/FiO2 ratios at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in PaO2/FiO2 ratios on the 1st, 3rd and 5th days after the basal ratio was calculated graphically, the change in the PaO2/FiO2 ratio at the end of the 5th day (primary endpoint) with the baseline value was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in Serum Lymphocyte Counts
Baseline Serum Lymphocyte counts (cell/mm^3) of the patients were recorded in both groups. Then, their treatments were started and Serum Lymphocyte counts at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in Serum Lymphocyte counts on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the Serum Lymphocyte count at the end of the 5th day (primary endpoint) with the baseline count was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
Baseline PNL/L ratio of the patients were recorded in both groups. Then, their treatments were started and PNL/L ratios at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in PNL/L ratios on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the PNL/L ratio at the end of the 5th day (primary endpoint) with the baseline ratio was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in Serum Ferritin Levels
Baseline serum ferritin levels (mg/dL) of the patients were recorded in both groups. Then, their treatments were started and serum ferritin levels at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in serum ferritin levels on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the serum ferritin level at the end of the 5th day (primary endpoint) with the baseline level was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Changes in Serum D-dimer Levels
Baseline serum D-dimer levels (mg/L) of the patients were recorded in both groups. Then, their treatments were started and serum D-dimer levels at the end of the 1st (TD1), 3rd (TD3) and 5th days (TD5) were also recorded. The end of the 5th day was accepted as the primary endpoint. While the change in serum D-dimer levels on the 1st, 3rd and 5th days after the basal level was calculated graphically, the change in the serum D-dimer level at the end of the 5th day (primary endpoint) with the baseline level was compared statistically (the results were given as p value).
Measured: From starting to the end of ivermectin therapy (0 to the end of 5th day)
Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism
A blood sample was taken from the patients included in the study group, after taking or during the first dose of ivermectin. From the blood samples, haplotypes and mutations that cause the function losing were investigated by performing sequence analysis of multidrug resistance 1 (MDR1)/ABCB1 and CYP3A4 genes with Sanger method. In case of detection of mutation, the patient were excluded from the study and if observed, side effects of ivermectin were noted.
Measured: At the first day of ivermectin therapy (1st day)
Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Adverse effects of ivermectin and drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the study group and and the number of participants were noted.
Adverse effects of drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the control group and and the number of participants were noted.
Measured: At the first 5 days of study
Secondary outcomes (10)
Number of Participants With Clinical Response
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.
Measured: 10 days (5 days ivermectin therapy plus 5 days follow-up)
Mortality
The number of died patients were evaluated in study and control groups
Measured: Through study completion, an average of 3 months
Changes in Oxygen Saturation (SpO2) Values
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).
Measured: From 6th to the end of 10th day
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
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).
Measured: From 6th to the end of 10th day
Changes in Serum Lymphocyte Counts
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).
Measured: From 6th to the end of 10th day
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
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).
Measured: From 6th to the end of 10th day
Changes in Serum Ferritin Levels
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).
Measured: From 6th to the end of 10th day
Changes in Serum D-dimer Levels
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).
Measured: From 6th to the end of 10th day
Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity
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.
Measured: At the end of 10th day
Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Adverse effects of ivermectin and drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the study group and and the number of participants were noted.
Adverse effects of drugs other than ivermectin (Hydroxychloroquine, favipiravir, azithromycin) were evaluated in the patients in the control group and and the number of participants were noted.
Measured: From the 6th day of study to the 10th day of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Nov 2020
- Study start11 May 2020
- Primary completion2 Sep 2020
- Study completion2 Sep 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 group
- Masking
- None (open label)
- Enrolment
- 66 participants (actual)
Sponsor and investigators
- Lead sponsor
- Afyonkarahisar Health Sciences University
- Sponsor type
- University, hospital or other
- Collaborators
- NeuTec Pharma
- Responsible party
- Principal investigator, Nurullah Okumuş, Afyonkarahisar Health Sciences University
- Investigators
- Nurullah Okumuş, Prof. Dr., Study chair, Afyonkarahisar Health Science University, Afyonkarahisar, TurkeyNeşe Demirtürk, A. Prof. Dr., Study director, Afyonkarahisar Health Science University, Afyonkarahisar, TurkeyRıza A. Çetinkaya, Prof. Dr., Study director, Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, TurkeyRahmet Güner, Prof. Dr., Study director, Yıldırım Beyazıt University, Ankara City Hospital, Ankara, Turkeyİsmail Y. Avcı, Study director, Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04646109
- Sponsor's protocol ID
- IVMC_03
- Status last verified
- Jan 2021
- First submitted
- 15 Nov 2020
- Last updated
- 27 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
PubMed 32109013Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020 Jun;53(3):436-443. doi: 10.1016/j.jmii.2020.03.034. Epub 2020 Apr 4.
PubMed 32307245Croci R, Bottaro E, Chan KW, Watanabe S, Pezzullo M, Mastrangelo E, Nastruzzi C. Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin. Int J Biomater. 2016;2016:8043983. doi: 10.1155/2016/8043983. Epub 2016 May 8.
PubMed 27242902Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo). 2020 Sep;73(9):593-602. doi: 10.1038/s41429-020-0336-z. Epub 2020 Jun 12.
PubMed 32533071Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.
PubMed 32251768
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effectiveness and Safety of Ivermectin as add-on Therapy in Severe COVID-19 Management
- ClinicalTrials.gov ID
- NCT04646109
- Acronym / sponsor ID
- IVMC_03
- Conditions
- COVID-19
- Keywords
- Ivermectin, SARS-CoV-2, Treatment
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 66 participants (actual)
- Lead sponsor
- Afyonkarahisar Health Sciences UniversityUniversity, hospital or other
- Collaborators
- NeuTec Pharma
- Study start
- 11 May 2020 (actual)
- Primary completion
- 2 Sep 2020 (actual)
- Study completion
- 2 Sep 2020 (actual)
- First posted
- 27 Nov 2020 (actual)
- Results
- Posted 27 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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 group
| Arm | Type | Receives |
|---|---|---|
| Control Group | No intervention | –Patients who were hospitalised with a pre-diagnosis of severe COVID-19 pneumonia and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the control and study group, respectively. Hydroxychloroquine, favipiravir and azithromycin (HFA) standard treatment protocol were given to the control group as recommended in the "COVID-19 (SARS-CoV-2 Infection) Guide" prepared by the Republic of Turkey Ministry of Health. |
| Study Group | Experimental | Drug: IvermectinIn 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Patients who were hospitalised with a pre-diagnosis of "severe COVID-19 pneumonia" and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively.
- Patients with at least one of the criteria below were accepted as patients with severe COVID-19 pneumonia;
- Presence of tachypnea ≥ 30/minute, SpO2 level < 90% in room air, PaO2/FiO2 <300 in oxygen receiving patient
- Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities)
- Mechanical ventilation requirement
Key exclusion criteria (5 listed)
- Patients with the following characteristics were excluded from the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IvermectinAlso: Hydroxychloroquine, favipiravir and azithromycinIvermectin 5mg/5ml solution was manufactured by NEUTEC™ Pharmaceutical Company-Turkey, under "Good Manufacturing Practices" (GMP) certification conditions. | Drug | Study Group |
Primary outcome
Gender Distribution of the Patients
Time frame: At the first day of the study
The gender of patients (Male/female) in both groups were recorded at the time of inclusion.
Age Distribution of the Patients
Time frame: At the first day of the study
The age of the patients (years) in both groups were recorded at the time of inclusion.
Percentage of Patients With Accompanying Diseases
Time frame: 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
Percentage of Patients With Baseline Clinical Symptoms
Time frame: 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
Body Temperature Means of the Patients
Time frame: 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.
Heart Rate Means of the Patients
Time frame: 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.
Respiratory Rate Means of the Patients
Time frame: 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.
Systolic and Diastolic Pressure Means of the Patients
Time frame: 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.
Number of Participants With Clinical Response
Time frame: 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.
Changes in Oxygen Saturation (SpO2) Values
Time frame: 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).
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
Time frame: 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).
Changes in Serum Lymphocyte Counts
Time frame: 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).
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
Time frame: 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).
Changes in Serum Ferritin Levels
Time frame: 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).
Changes in Serum D-dimer Levels
Time frame: 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).
Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism
Time frame: 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.
Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Time frame: 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.
10 secondary outcomes
Number of Participants With Clinical Response
Time frame: 10 days (5 days ivermectin therapy plus 5 days follow-up)
Mortality
Time frame: Through study completion, an average of 3 months
Changes in Oxygen Saturation (SpO2) Values
Time frame: From 6th to the end of 10th day
Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
Time frame: From 6th to the end of 10th day
Changes in Serum Lymphocyte Counts
Time frame: From 6th to the end of 10th day
Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
Time frame: From 6th to the end of 10th day
Changes in Serum Ferritin Levels
Time frame: From 6th to the end of 10th day
Changes in Serum D-dimer Levels
Time frame: From 6th to the end of 10th day
Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity
Time frame: At the end of 10th day
Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Time frame: From the 6th day of study to the 10th day of study
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 32109013Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
- Background: PubMed 32307245Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020 Jun;53(3):436-443. doi: 10.1016/j.jmii.2020.03.034. Epub 2020 Apr 4.
- Background: PubMed 27242902Croci R, Bottaro E, Chan KW, Watanabe S, Pezzullo M, Mastrangelo E, Nastruzzi C. Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin. Int J Biomater. 2016;2016:8043983. doi: 10.1155/2016/8043983. Epub 2016 May 8.
- Background: PubMed 32533071Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo). 2020 Sep;73(9):593-602. doi: 10.1038/s41429-020-0336-z. Epub 2020 Jun 12.
- Background: PubMed 32251768Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.
- World Health Organization (WHO) Coronavirus Disease (COVID-19) DashboardLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nurullah Okumuş, Prof. Dr. study chair
Afyonkarahisar Health Science University, Afyonkarahisar, Turkey
Neşe Demirtürk, A. Prof. Dr. study director
Afyonkarahisar Health Science University, Afyonkarahisar, Turkey
Rıza A. Çetinkaya, Prof. Dr. study director
Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ivermectin in people with COVID-19, run by Afyonkarahisar Health Sciences University at 4 sites in Turkey (Türkiye).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Turkey (Türkiye). Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Gender Distribution of the Patients (time frame: At the first day of the study). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04646109, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2021.