NCT04646109

Ivermectin for Severe COVID-19 Management

Completed Phase 3 Results posted Last updated 27 January 2021

What this trial tests

Phase 3 trial testing Ivermectin in COVID-19 in 66 participants. Completed in 2 September 2020.

Timeline

11 May 2020

Primary endpoint
2 September 2020

2 September 2020

Quick facts

Lead sponsor	Afyonkarahisar Health Sciences University
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	66
Start date	11 May 2020
Primary completion	2 September 2020
Estimated completion	2 September 2020
Sites	4 locations across Turkey (Türkiye)

Drugs / interventions tested

• Ivermectin (ivermectin) — full drug profile →

Conditions studied

• COVID-19 — all drugs for COVID-19 →

Sponsor

Afyonkarahisar Health Sciences University

Who can join

18 and older, any sex, with COVID-19. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Gender Distribution of the Patients Primary · At the first day of the study

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

Male

Group	Value	95% CI
Control Group	19
Study Group	21

Female

Group	Value	95% CI
Control Group	11
Study Group	9

Age Distribution of the Patients Primary · At the first day of the study

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

Group	Value	95% CI
Control Group	66.23	± 13.31
Study Group	58.17	± 11.52

Percentage of Patients With Accompanying Diseases Primary · 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

Diabetes Mellitus

Group	Value	95% CI
Control Group	10
Study Group	9

Hypertension

Group	Value	95% CI
Control Group	12
Study Group	15

Coronary artery disease

Group	Value	95% CI
Control Group	8
Study Group	5

Cardiac failure

Group	Value	95% CI
Control Group	1
Study Group	0

Chronic obstructive pulmonary disease

Group	Value	95% CI
Control Group	3
Study Group	6

Malignancy

Group	Value	95% CI
Control Group	1
Study Group	0

Immunodeficiency

Group	Value	95% CI
Control Group	1
Study Group	0

Percentage of Patients With Baseline Clinical Symptoms Primary · 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

Fever

Group	Value	95% CI
Control Group	13
Study Group	15

Cough

Group	Value	95% CI
Control Group	14
Study Group	16

Sore throat

Group	Value	95% CI
Control Group	1
Study Group	3

dyspnea

Group	Value	95% CI
Control Group	19
Study Group	23

Headache

Group	Value	95% CI
Control Group	2
Study Group	5

Weakness

Group	Value	95% CI
Control Group	11
Study Group	13

Myalgia

Group	Value	95% CI
Control Group	7
Study Group	9

Diarrhea

Group	Value	95% CI
Control Group	0
Study Group	1

Body Temperature Means of the Patients Primary · 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.

Group	Value	95% CI
Control Group	36.8	± 0.8
Study Group	36.9	± 0.7

Heart Rate Means of the Patients Primary · 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.

Group	Value	95% CI
Control Group	92	± 18
Study Group	88	± 12

Respiratory Rate Means of the Patients Primary · 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.

Group	Value	95% CI
Control Group	24.7	± 0.7
Study Group	24	± 5

Systolic and Diastolic Pressure Means of the Patients Primary · 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.

Systolic pressure

Group	Value	95% CI
Control Group	124.61	± 15.37
Study Group	124.39	± 15.60

Diastolic pressure

Group	Value	95% CI
Control Group	73.43	± 8.47
Study Group	75.64	± 9.79

Number of Participants With Clinical Response Primary · 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.

Group	Value	95% CI
Control Group	11
Study Group	14

Changes in Oxygen Saturation (SpO2) Values Primary · 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).

Baseline

Group	Value	95% CI
Control Group	89.67	± 5.09
Study Group	89.93	± 6.51

TD1

Group	Value	95% CI
Control Group	90.50	± 7.47
Study Group	92.85	± 4.86

TD3

Group	Value	95% CI
Control Group	91.90	± 4.97
Study Group	93.07	± 4.12

TD5

Group	Value	95% CI
Control Group	93.00	± 3.25
Study Group	93.52	± 4.36

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

Baseline

Group	Value	95% CI
Control Group	197.44	± 102.31
Study Group	158.83	± 88.15

TD1

Group	Value	95% CI
Control Group	181.83	± 99.62
Study Group	147.31	± 74.15

TD3

Group	Value	95% CI
Control Group	174.77	± 94.74
Study Group	147.74	± 83.30

TD5

Group	Value	95% CI
Control Group	180.13	± 95.43
Study Group	178.94	± 98.21

Changes in Serum Lymphocyte Counts Primary · 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).

Baseline

Group	Value	95% CI
Control Group	1010	± 438
Study Group	932	± 483

TD1

Group	Value	95% CI
Control Group	1034	± 450
Study Group	928	± 607

TD3

Group	Value	95% CI
Control Group	977	± 575
Study Group	1021	± 648

TD5

Group	Value	95% CI
Control Group	968	± 477
Study Group	1273	± 822

Adverse events — posted to ClinicalTrials.gov

Time frame: From the beginning of the study to the end of the 10th day. Reporting threshold: 1%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Control Group

Serious: 0/30 (0%)

Deaths: 9/30

Study Group

Serious: 0/30 (0%)

Deaths: 6/30

Participants With Mutations

Serious: 5/6 (83%)

Deaths: 0/6

Serious adverse events (1 terms)

Reaction	System	Control Group	Study Group	Participants With Mutations
Encephalopathy	Nervous system disorders	—	—	—

Other adverse events (2 terms — click to expand)

Reaction	System	Control Group	Study Group	Participants With Mutations
Nausea and vomiting	Gastrointestinal disorders	—	—	—
Increase in liver function tests	Gastrointestinal disorders	—	—	—

Most-reported serious reactions: Encephalopathy.

Data from ClinicalTrials.gov NCT04646109 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
2. Ivermectin for preventing and treating COVID-19.
   Popp M, Stegemann M, Metzendorf MI, Gould S, et al · · 2021 · cited 102× · PMID 34318930 · DOI 10.1002/14651858.cd015017.pub2
3. The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.
   Ning Q, Wu D, Wang X, Xi D, et al · · 2022 · cited 64× · PMID 35197452 · DOI 10.1038/s41392-022-00907-1
4. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients.
   Okumuş N, Demirtürk N, Çetinkaya RA, Güner R, et al · · 2021 · cited 56× · PMID 33947344 · DOI 10.1186/s12879-021-06104-9
5. Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype.
   Marcolino MS, Meira KC, Guimarães NS, Motta PP, et al · · 2022 · cited 28× · PMID 35870876 · DOI 10.1186/s12879-022-07589-8
6. Efficacy and safety of ivermectin for the treatment of COVID-19: a systematic review and meta-analysis.
   Deng J, Zhou F, Ali S, Heybati K, et al · · 2021 · cited 28× · PMID 34570241 · DOI 10.1093/qjmed/hcab247
7. The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis.
   Kow CS, Merchant HA, Mustafa ZU, Hasan SS. · · 2021 · cited 26× · PMID 33779964 · DOI 10.1007/s43440-021-00245-z
8. Ivermectin and mortality in patients with COVID-19: A systematic review, meta-analysis, and meta-regression of randomized controlled trials.
   Zein AFMZ, Sulistiyana CS, Raffaelo WM, Pranata R. · · 2021 · cited 23× · PMID 34237554 · DOI 10.1016/j.dsx.2021.102186