Clinical trial NCT04646109: Ivermectin for Severe COVID-19 Management
Official title: The Effectiveness and Safety of Ivermectin as add-on Therapy in Severe COVID-19 Management
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Ivermectin
SARS-CoV-2
Treatment
Lead sponsor: Afyonkarahisar Health Sciences University
Sponsor class: OTHER
Collaborators: name: NeuTec Pharma
First posted: 2020-11-27
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients who were hospitalised with a pre-diagnosis of severe COVID-19 pneumonia and thereafter diagnosis of COVID-19 was also confirmed microbiologically with polymerase chain reaction (PCR) positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively. Single numbered patients were accepted as study group and double numbered patients as control group
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

* Patients who were hospitalised with a pre-diagnosis of "severe COVID-19 pneumonia" and thereafter diagnosis of COVID-19 was also confirmed microbiologically with PCR positivity in respiratory tract samples were included into the study. They were randomized to the study and control group, respectively.

Patients with at least one of the criteria below were accepted as patients with severe COVID-19 pneumonia;

1. Presence of tachypnea ≥ 30/minute, SpO2 level \< 90% in room air, PaO2/FiO2 \<300 in oxygen receiving patient
2. Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities)
3. Mechanical ventilation requirement
4. Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score \>2

Exclusion Criteria:

* Patients with the following characteristics were excluded from the study.

  1. Pediatric patients; \<18 years of old
  2. Patients with chronic liver or kidney disease
  3. Pregnant women
  4. Patients with known ivermectin allergy

Primary outcomes:
measure: Gender Distribution of the Patients
timeFrame: At the first day of the study
measure: Age Distribution of the Patients
timeFrame: At the first day of the study
measure: Percentage of Patients With Accompanying Diseases
timeFrame: At the first day of the study
measure: Percentage of Patients With Baseline Clinical Symptoms
timeFrame: At the first day of the study
measure: Body Temperature Means of the Patients
timeFrame: At the first day of the study
measure: Heart Rate Means of the Patients
timeFrame: At the first day of the study
measure: Respiratory Rate Means of the Patients
timeFrame: At the first day of the study
measure: Systolic and Diastolic Pressure Means of the Patients
timeFrame: At the first day of the study
measure: Number of Participants With Clinical Response
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in Oxygen Saturation (SpO2) Values
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in Serum Lymphocyte Counts
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in Serum Ferritin Levels
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Changes in Serum D-dimer Levels
timeFrame: From starting to the end of ivermectin therapy (0 to the end of 5th day)
measure: Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism
timeFrame: At the first day of ivermectin therapy (1st day)
measure: Treatment-Related Adverse Events as Assessed by CTCAE v4.0
timeFrame: At the first 5 days of study
Secondary outcomes:
measure: Number of Participants With Clinical Response
timeFrame: 10 days (5 days ivermectin therapy plus 5 days follow-up)
measure: Mortality
timeFrame: Through study completion, an average of 3 months
measure: Changes in Oxygen Saturation (SpO2) Values
timeFrame: From 6th to the end of 10th day
measure: Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2)
timeFrame: From 6th to the end of 10th day
measure: Changes in Serum Lymphocyte Counts
timeFrame: From 6th to the end of 10th day
measure: Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNL/L)
timeFrame: From 6th to the end of 10th day
measure: Changes in Serum Ferritin Levels
timeFrame: From 6th to the end of 10th day
measure: Changes in Serum D-dimer Levels
timeFrame: From 6th to the end of 10th day
measure: Rate of COVID-19 Polymerase Chain Reaction (PCR) Test Negativity
timeFrame: At the end of 10th day
measure: Treatment-Related Adverse Events as Assessed by CTCAE v4.0
timeFrame: From the 6th day of study to the 10th day of study
Other outcomes:
Locations:
city: Afyonkarahisar
country: Turkey
facility: Afyonkarahisar Health Science University
city: Ankara
country: Turkey
facility: Gulhane Faculty of Medicine, University of Health Sciences
city: Ankara
country: Turkey
facility: Yıldırım Beyazıt University, Ankara City Hospital
city: İstanbul
country: Turkey
facility: Haydarpasa Sultan Abdulhamid Han Training and Research Hospital
Study officials:
affiliation: Afyonkarahisar Health Science University, Afyonkarahisar, Turkey
name: Nurullah Okumuş, Prof. Dr.
role: STUDY_CHAIR
affiliation: Afyonkarahisar Health Science University, Afyonkarahisar, Turkey
name: Neşe Demirtürk, A. Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Haydarpasa Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey
name: Rıza A. Çetinkaya, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Yıldırım Beyazıt University, Ankara City Hospital, Ankara, Turkey
name: Rahmet Güner, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey
name: İsmail Y. Avcı
role: STUDY_DIRECTOR
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