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A placebo-controlled, randomized, double-blind study in COvid-19
patients with iveRmectin; An inVEstigator iniTiaTEd trial (CORVETTE-01)

double-blind study in COvid-19 patients with iveRmectin (CORVETTE-01)

248

In the full analysis set (106 patients in the ivermectin group and 106 patients in the placebo group), 73 (68.9%) patients were males in the ivermectin group, and 66 (62.3%) were in the placebo group, respectively. 89 (84.0%) patients in the ivermectin group were younger than 65 years, 17 (16.0%) were older than 65 years, and 91 (85.8%) and 15 (14.2%) were in the placebo group, respectively.Drug allergy: 7 (6.6%) patients in the ivermectin group had drug allergies, while 99 (93.4%) had no drug allergies. In the placebo group, 4 (3.8%) and 102 (96.2%), respectively. Smoking history: 33 (31.1%) patients of the ivermectin group were "currently smoking," 22 (20.8%) were "past smoking," and 51 (48.1%) had "no smoking history." In the placebo group, 28 (26.4%), 28 (26.4%), and 50 (47.2%) were, respectively. Complications: 77 (72.6%) patients in the ivermectin group had complications, and 29 (27.4%) had no complications. The placebo group had 68 (64.2%) and 38 (35.8%), respectively. Medical history: 42 (39.6%) patients in the ivermectin group had a medical history, and 64 (60.4%) had no medical history. In the placebo group, 41 (38.7%) and 65 (61.3%), respectively. Chronic obstructive pulmonary disease: 2 (1.9%) patients in the ivermectin group had chronic obstructive pulmonary disease, and 104 (98.1%) had no chronic obstructive pulmonary disease. The placebo group had 2 (1.9%) and 104 (98.1%), respectively. Diabetes: 14 (13.2%) patients in the ivermectin group had diabetes, and 92 (86.8%) had no diabetes. In the placebo group, 15 (14.2%) and 91 (85.8%), respectively. Pneumonia: 78 (73.6%) patients in the ivermectin group had pneumonia, and 28 (26.4%) had no pneumonia. The placebo group had 77 (72.6%) and 29 (27.4%), respectively.

Of the 257 patients who signed informed consent, 248 were evaluated for eligibility, excluding those who withdrew consent before eligibility determination. Of the eligible patients, 221 were randomized, excluding those who did not meet the eligibility criteria or were excluded before allocation due to withdrawal or other reasons. As a result, 112 patients were randomized to ivermectin and 109 patients to placebo. Of the randomized patients, 87 patients completed observation and 25 patients discontinued in the ivermectin group, and 90 and 19 patients in the placebo group, respectively. The safety analysis set included 107 patients in the ivermectin group and 107 in the placebo group, excluding seven untreated patients. The Full Analysis Set (FAS) included 106 patients in the ivermectin group and 106 patients in the placebo group, excluding two patients who took prohibited concomitant medications within one month before the study drug administration.

Adverse events occurred in 29/107 (27.1%) patients in the ivermectin group and 28/107 (26.2%) in the placebo group. Of the adverse events, Grade 3 or higher by severity (CTCAE Grade) were one Grade 3 in the ivermectin group, one Grade 3 and one Grade 4 in the placebo group. Related adverse events (Grade 3 or above) were one Grade 3 in the ivermectin group, one Grade 3 and one Grade 4 in the placebo group. There was one serious adverse event in each of the ivermectin and placebo groups, and one related serious adverse event in the placebo group. There were no adverse events in either group that led to discontinuation of the trial. The main adverse events (two or more) occurring in this trial were insomnia 5/107 (4.7%), constipation 4/107 (3.7%), diarrhoea 3/107 (2.8%), back pain 3/107 (2.8%) and joint pain 2/107 (1.9%) in the ivermectin group, constipation 5/107 (4.7%), Hepatic function abnormal 2/107 (1.9 %), neck pain 2/107 (1.9 %), back pain 2/107 (1.9 %), insomnia 2/107 (1.9 %), eczema 2/107 (1.9 %) and rash 2/107 (1.9 %) in the placebo group, of which Grade 3 or higher adverse events "organ classifications" were. 1 case of increased blood creatine phosphokinase in "Laboratory tests" in the ivermectin group and 2 cases of Hepatic function abnormal in "Hepatobiliary disorders" in the placebo group.Related adverse events were 2/107 (1.9%) cases of diarrhoea, 1/107 (0.9%) cases of Hepatic function abnormal, 1/107 (0.9%) cases of Liver disorder, 1/107 (0.9%) cases of rash and 1/107 (0.9%) cases of increased blood creatine phosphokinase in the ivermectin group; liver function abnormalities 2/107 (1.9%), soft stool 1/107 (0.9%), myalgia 1/107 (0.9%), rash 1/107 (0.9%), increased aspartate aminotransferase 1/107 (0.9%) and increased alanine aminotransferase 1/107 (0.9%) in the placebo group. Of these, related adverse events of Grade 3 or higher "organ classifications" were 1 case of increased creatine phosphokinase in blood "Laboratory tests" in the ivermectin group and 2 cases of Hepatic function abnormal in "Hepatobiliary disorders" in the placebo group. No adverse events leading to death occurred in this study. Other serious adverse events were observed in one patient in the ivermectin group (acute abdomen Grade 2) and one patient in the placebo group (Hepatic function abnormal Grade 4).The "acute abdomen" was ruled out as being related to the study drug, and the patient recovered after treatment with other drugs."Hepatic function abnormal", which was judged to be an adverse event of undeniable relevance, also became mild after treatment with other drugs. No other significant adverse events, including adverse events that led to discontinuation of the study, occurred in this study. Abnormal laboratory values judged to be adverse events in the 'organ classifications' were one case of hyponatraemia (Grade 2) in the ivermectin group under 'metabolic and nutritional disorders' and one case of increased creatine phosphokinase in blood (Grade 3) under 'laboratory tests', while in the placebo group there was one case of hypoglycaemia (Grade 1) under 'metabolic and nutritional disorders' and one case of increased gamma-glutamyltransferase (Grade 2), one case of increased aspartate aminotransferase (Grade 1), one case of increased alanine aminotransferase (Grade 1) and one case of increased creatinine in blood (Grade 1) in the "Laboratory tests". No significant laboratory abnormalities leading to discontinuation of the study drug or discontinuation of the study were observed. The measured vital signs (blood pressure [systolic/diastolic] and pulse rate) (both median) at each assessment time point were 123.0/79.0 mmHg and 80.0/min in the ivermectin group at the eligibility test (day of randomisation) and 115.0/76.0 mmHg, 73.0/min on Day 7, 121.0/76.0 mmHg, 78.0/min on Day 15 (at discontinuation) and 119.5/76.0 mmHg, 79.5/min, 114.0/73.5 mmHg, 72.5/min, 119.5/71 .5 mmHg, 79.0/min in the placebo group respectively. There were no clinically relevant changes in vital signs in the ivermectin or placebo groups. Changes in findings with more than half of the findings being present in either the ivermectin or placebo group at the eligibility test (day of randomisation, hereafter at start) are: 'cough' was 72.9% at start and 25.2% at Day 15 in the ivermectin group, 81.3% at start and 24.3% at Day 15 in the placebo group. 'Phlegm' was 48.6% at start and 16.8% at Day 15 in the ivermectin group, 52.3% at start and 16.8% at Day 15 in the placebo group. Headache was 54.2% at start and 3.7% at Day 15 in the placebo group, 59.8% at start and 4.7% at Day 15 in the placebo group. Subjective symptoms decreased over time from the start of treatment in both the ivermectin and placebo groups, and there was no significant difference in subjective symptoms at Day 15.

Time to negative COVID-19 PCR test (SARS-CoV-2 nucleic acid detection) (primary endpoint) The median time to negative PCR test was 14 days (95% CI 13, 16 days) in the ivermectin group and 14 days (95% CI 12, 16 days) in the placebo group. The stratified log-rank test with stratification factors in randomization had a p=0.7849, and the stratified generalized Wilcoxon test had a p=0.8863. The point estimate of the adjusted hazard ratio for the ivermectin group versus the placebo group by stratified Cox regression model was 0.96 (95% CI: 0.70, 1.32). The median (minimum, maximum) number of days that rescue therapy was initiated was 5 (2, 8) days in the ivermectin group and 4 (2, 7) days in the placebo group. When the cut-off date for rescue treatment was defined as 45 days, the median time to negative PCR test was 14 days (95% CI 13-16 days) in the ivermectin group and 14 days (95% CI 12-16 days) in the placebo group. The stratified log-rank test with stratification factors in randomization had a p=0.9551. The point estimate of the adjusted hazard ratio for the ivermectin group versus the placebo group using a stratified Cox regression model was 1.01 (95% CI 0.74, 1.37). The incidence rate of patients with a change in disease status (Secondary endpoint) From the eligibility test (at enrollment) to Day 15, the number (%) of patients with symptom change as assessed by a 7-point ordinal scale was 19 (17.9%) in the ivermectin group (95% CI: 11.2, 26.6%) and 23 (21.7%) in the placebo group (95% CI: 14.3, 30.8%). The CMH test with stratification factors in randomization had a p=0.4617. The odds ratio of the ivermectin group to the placebo group was OR=0.77 (95%CI: 0.38, 1.54). The proportion of patients with pneumonia (Secondary endpoint) The number (%) of patients of pneumonia without pneumonia on eligibility testing was 7/28 (25.0%) patients (95% CI: 10.7, 44.9%) in the ivermectin group and 9/29 (31.0%) (95% CI: 15.3, 50.8%) in the placebo group. The CMH test with stratification factors in randomization had a p=0.4689. The odds ratio of the ivermectin group to the placebo group was OR=0.65 (95%CI: 0.20, 2.09). The proportion of patients who required oxygen (Secondary endpoint) 22 (20.8%) patients in the ivermectin group (95% CI: 13.5, 29.7%) and 19 (17.9%) in the placebo group (95% CI: 11.2, 26.6%) required oxygen inhalation. The CMH test with stratification factors in randomization had a p=0.6516. The odds ratio of the ivermectin group to the placebo group was OR=1.18 (95%CI: 0.58, 2.43). The proportion of patients who required ventilatory management and the number of days of ventilatory management (Secondary endpoint) There were no patients that corresponded to the FAS, and the results of the analysis were not valid. Body temperature (Secondary endpoint) The median temperatures at the time of eligibility testing (the day of randomization) and the median maximum temperatures on Days 1 to 7 and Day 15 were 36.9, 37.5, 37.1, 37.0, 36.9, 36.9, 36.7, 36.6, and 36.6 in the ivermectin group and 36.7, 37.5, 37.1, 37.0, 36.9, 36.7, 36.6 and 36.6 in the placebo group. The proportion of negative SARS-CoV-2 PCR by Day 15 (Secondary endpoint) The number (%) of patients with negative PCR was 59 (55.7%) (95% CI: 45.7, 65.3%) in the ivermectin group and 60 (56.6%) (95% CI: 46.6, 66.2%) in the placebo group. The CMH test with stratification factors in randomization had a p=0.9120. The odds ratio of the ivermectin group to the placebo group was OR=0.97 (95% CI: 0.56, 1.68). All-cause mortality by the end of the follow-up period (Secondary endpoint) There were no patients that corresponded to the FAS, and the results of the analysis were not valid. The proportion of patients who started rescue therapy by Day 15 and the number of days (Secondary endpoint) The number (%) of patients who started rescue therapy by Day 15 was 15 (14.2%) patients (95% CI: 8.1, 22.3%) in the ivermectin group and 14 (13.2%) (95% CI: 7.4, 21.2%) in the placebo group. The results of the CMH test with stratification factors in randomization had a p=0.9418. The odds ratio of the ivermectin versus placebo group was OR=0.97 (95%CI: 0.43, 2.19). The median (minimum, maximum) number of days that rescue therapy was initiated was 5 (2, 8) days in the ivermectin group and 4 (2, 7) days in the placebo group. Proportion and number of days of severe arteriovenous thrombosis (ex. cerebral infarction, pulmonary thrombus) (secondary endpoint) Serious arteriovenous thrombosis occurred in 0 patients in the ivermectin group and one in the placebo group after Day 7. The CMH test was not validated due to the insufficient number of patients. Number of days required for normalization of oxygen saturation (Secondary endpoint) The number of patients requiring oxygen inhalation was 22 in the ivermectin group and 19 in the placebo group. The median (minimum, maximum) number of days required for normalization of oxygen saturation (SpO2 more than 95% for 24 hours) from the start of oxygen inhalation was one day (1, 7 days) in 8 patients in the ivermectin group. The placebo group had 11 patients and two days (1 and 12 days), respectively. A two-sample Wilcoxon test of the number of days required for normalization of oxygen saturation between groups showed a p-value of 0.236. Number of patients whose clinical condition improved from the eligibility test (at enrollment) to Day 15 (secondary endpoint) The number of patients who improved by at least one step from clinical status (ordinal scale) 3) and 4) from the eligibility test (at enrollment) to Day 15 (incidence rate%) was 15 (14.2%) in the ivermectin group and 18 (17.0%) (95%CI: 10.4, 25.5%) in the placebo group. The CMH test with stratification factors in randomization had a p-value=0.6077. The odds ratio of the ivermectin group to the placebo group was OR=0.81 (95%CI: 0.36, 1.80).

The time to negative COVID-19 PCR test (SARS-CoV-2 nucleic acid detection) was not shortened versus the placebo group. In addition, there was no statistically significant interaction of allocation adjustment factors on the effect of treatment with ivermectin. Regarding safety, there was no significant difference in the number and severity of adverse events (CTCAE Grade) between the ivermectin and placebo groups.

June. 24, 2023

May. 23, 2023

https://www.frontiersin.org/articles/10.3389/fmed.2023.1139046/full

No

https://jrct.niph.go.jp/latest-detail/jRCT2031200120

Yamaoka Kunihiro

Kitasato University Hospital

1-15-1 Kitasato, Minami-ku, Sagamihara-city, Kanagawa

yamaoka@med.kitasato-u.ac.jp

Nonaka Miwa

Kitasato University Hospital

5-9-1 Shirokane, Minato-ku, Tokyo

+81-3-5791-6398

ivm-iit@insti.kitasato-u.ac.jp

Complete

Sept. 16, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1) A person who has been diagnosed with COVID-19 (including asymptomatic) by the COVID-19 PCR test (SARS-CoV-2 nucleic acid detection) within 3 days before the qualification test.
2) A person with oxygen saturation (SpO2) in the room air of 95% or more.
3) A person who are 20 years or older at the time of obtaining consent.
4) A person who weigh 40 kg or more at the time of qualification test.
5) A person who understands the content of this clinical trial and can obtain written consent to participate in the clinical trial.

1) A woman who is in lactation period or who may be pregnant, or those who do not agree to prevent pregnancy by medically appropriate means for up to 7 days after study drug administration.
Medically appropriate contraception means that using a combination of two or more of the following: not having sexual intercourse, taking surgical sterilization such as vasectomy or intrauterine device, taking oral contraceptive, using condom.
2) A person who has severe liver damage (AST or ALT at the time of qualification test is more than 3 times the upper limit of institutional standard and total bilirubin is more than twice the upper limit of institutional standard value), renal disorder (eGFR of eligibility test value 30 mL/min/1.73m2 or less).
3) A person with hypersensitivity to ivermectin.
4) A person with a history of severe drug allergies such as Stevens-Johnson syndrome, toxic epidermal necrolysis.
5) A person who has received the prohibited medication within the past month (within the past 6 months for biologics), or those who need to use the prohibited medication during the clinical trial period.
6) Those who are scheduled to receive SARS-CoV-2 vaccination from the date of consent to the end of the follow-up period.
7) A person who are currently participating in other clinical trials or who have participated in other clinical trials within 30 days before obtaining consent.
8) In addition, a person who is determined to be unsuitable as a subject of this clinical trial by the principal investigator."

Both

COVID-19

ivermectin group Ivermectin approximately 200microgram per kg administered as a single oral dose on day 1 (fasting state)
placebo group placebo without ivermectin as an ingredient, single oral administration on day 1 (fasting state)
on day 1 subjects take the study drug (3 mg tablet of ivermectin) or the control drug (ivermectin placebo tablet) at the dose of the study drug taken once per body weight of the subject.

Period until the COVID-19 PCR test (SARS-CoV-2 nucleic acid detection) becomes negative

1) Occurrence rate of cases in which the condition changed between Day1 and Day15 (evaluation by 7-point ordinal scale)
Ordinal scale;
1 No pneumonia, no restrictions on activities of daily living (PS0)
2 No pneumonia, limited daily activities (PS1 or higher)
3 With pneumonia, no oxygen inhalation
4 With pneumonia and oxygen inhalation
5 With non-invasive assisted ventilation or high-flow oxygen inhalation therapy
6 With artificial respiration management (including ECMO use)
7 Death"
Definition of change in medical condition; The following change in clinical condition is defined as change in medical condition.
(1) Change from 1 by two or more steps
(2) Change from 2 or 3 by one or more steps

Definition of pneumonia: A chest X-ray film or chest CT shows a shadow, and there is no obvious cause other than pneumonia such as heart failure.

Criteria for restricting activities of daily living; 0 is not restricted to activities of daily living and 1 or more is restricted to activities of daily living according to the following criteria."
"Table 11.2 ECOG (Eastern Cooperative Oncology Group) Performance Status (PS)

GRADE ECOG PERFORMANCE STATUS
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5 Dead
Source: Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 1982. 5(6): p. 649-55.

Evaluator: The Principle investigator or sub-investigator in each facility will be the evaluator.
In order to unify the evaluation criteria, the evaluation method will be unified at the startup meeting."
2) Percentage of pneumonia on Day 15 and survival follow-up period
3) Percentage requiring oxygen inhalation
4) Percentage and number of days requiring artificial respiration management
5) Changes in body temperature up to Day 15
6) Negative rate of SARS-CoV-2 PCR up to Day15
7) All deaths until the end of the follow-up period
8) Percentage and number of days rescue treatment started up to Day 15
9) Percentage and number of days of severe arteriovenous thrombosis such as cerebral infarction and pulmonary thrombosis
10) Adverse events [Safety evaluation items: subjective findings (patient findings at the time of examination), vital signs (blood pressure, pulse rate, body temperature), adverse events observed in clinical laboratory values]
11) Number of days required for normalization of oxygen saturation in indoor air (SpO2>=95% lasting 24 hours) when oxygen inhalation was required
12) The number of cases in which clinical status (sequential scale) 3, 4 on Day 1 improved by more than one stage on Day 15"

+81-3-5791-6177

Aug. 14, 2020

none