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Study of the additional effect of Kampo medicine on conventional treatment for common cold symptoms in mild to moderate stage COVID-19 patients, A Multicenter Randomized Clinical Trial (IMJEDI study-R1)

Study of the additional effect of Kampo medicine on common cold symptoms in COVID-19 patients (IMJEDI study-R2)

160

The baseline characteristics of the patients included in the primary analysis were as follows. Kampo group Number of subjects, 70; Sex, Male 45 (64.3%) / Female 25 (35.7%); Age, 38.2 +- 13.01 years (mean +- SD); Control group Number of subjects, 73; Sex, Male 47 (64.4%) / Female 26 (35.6%); Age, 37.4 +-12.58 years (mean +- SD); Age, sex, risk factors, symptoms, and clinical staging of COVID-19 matched closely in both groups. Regarding age, there were only two patients over 65 years of age. There were few cases with co-morbidities (such as diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, respiratory disease, renal dysfunction, and cancer).

A total of 161 patients were enrolled, and after confirmation of eligibility, they were randomly assigned to the Kampo (n = 81) or control (n = 80) groups; 1 patient was misregistration. 80 patients in the Kampo group and 79 patients in the control group received interventions and were included in the safety analysis. In total, 70 patients in Kampo group and 73 patients in control group were included in the primary analysis due to their availability to collect analyzable symptom data.

Adverse events included epigastric discomfort (Kampo group, n = 1), gout (Kampo group, n = 1), and hand eczema (Kampo group, n = 1). All were not serious AEs.

1.Primary outcomes The Kaplan-Meier estimates for relief of at least one of the symptoms, including fever, cough, sputum, fatigue, and shortness of breath, are conducted. The median number of days until symptomatic relief in the control group (median, 3.0; 90% confidence interval [CI], 3.0-4.0) was similar to that in the Kampo group (median, 3.0; 90% CI, 2.0-4.0) and there were not significant differences between the two groups (p=0.4343 by log-rank test; hazard ratio, 1.02; 90% CI, 0.76-1.38). 2.Secondary outcomes (1)Symptom relief The Kaplan-Meier estimates for relief of each symptoms, including fever, cough, sputum, fatigue, and shortness of breath, are calculated. In the Kampo group, fever decreased relatively faster (median, 3.0; 95% CI, 2.0-4.0) than in the control group (median, 4.0; 95% CI, 3.0-5.0); however, there were no significant differences between the treatment groups (p=0.1563 by log-rank test; hazard ratio, 1.44; 95% CI, 0.77-2.70). There were no statistically significant differences between the treatment groups with regards to relief of other symptoms. Furthermore, we compared the two groups based on covariate-adjusted cumulative incidence of symptom relief wherein drop out due to primary disease worsening was treated as a competing risk. Age, severity, duration from onset to enrollment, vaccination, and each baseline symptom were included as adjusted covariates. The results showed that recovery of fever was significantly faster in the Kampo group than in the control group (HR, 1.76; 95% CI, 1.03-3.01; p=0.0385). In regard to relief of other symptoms, there were no significant difference between the treatment groups. (2) Disease progression to respiratory failure In all cases who received interventions, the number of patients that progressed to respiratory failure was 10 and 6 in the control and Kampo groups, respectively (risk difference, -0.05; 95% CI, -0.15-0.04; p = 0.2786). Additional assessment only on patients who were unvaccinated and in moderate stage I at the baseline was conducted. In this subgroup, the number of patients who progressed to severe respiratory failure in the Kampo group (n=3) was less than that in the control group (n=8) (risk difference, -0.13; 95% CI, -0.27-0.01; p = 0.0752). 3.Safety outcomes Numbness in the hands and feet, edema, skin rash and other allergic symptoms, and gastric discomfort were prespecified as events of interest, and the incidence of these events was monitored. Their incidence was less in the control group (n = 19) than in the Kampo group (n = 27); however, there were no significant differences between the groups.

Additional treatment with Kampo (KT and SSKKS) in mild to moderate COVID-19 patients was not verified in symptom relief, but after adjusting for patient background bias, days of fever were significantly shortened in Kampo treatment. Exacerbation to respiratory failure showed a trend of suppression with Kampo treatment. No significant adverse events were shown. The limitation of this study is the small sample size.

April. 13, 2023

Nov. 09, 2022

https://www.frontiersin.org/articles/10.3389/fphar.2022.1008946/full

No

Not applicable

https://jrct.niph.go.jp/latest-detail/jRCTs021200020

Takayama Takayama Shin

Tohoku University Hospital

1-1, Seiryo-machi, Aoba ward, Sendai, Miyagi

takayama@med.tohoku.ac.jp

Takayama Shin

Tohoku University Hospital

1-1, Seiryo-machi, Aoba ward, Sendai, Miyagi

+81-22-728-3036

takayama@med.tohoku.ac.jp

Complete

Aug. 25, 2020

Interventional

randomized controlled trial

open(masking not used)

no treatment control/standard of care control

parallel assignment

treatment purpose

(1) Disease name: COVID-19
(2) Clinical stage: Mild to moderate
Mild: Minor clinical symptoms and no abnormal findings on chest image
Moderate: Fever, respiratory tract symptoms, pneumonia image(ground glass shadows and infiltrated shadows) is recognized on the image, but no abnormality in breathing or oxygenation
(3)Have cold-like symptoms(Cough, sputum, malaise, shortness of breath, any of which is "NRS 2 points or more")
(4) Age: 20 years old or older (at the time of registration)
(5) Gender: Male, Female
(6) Communicable in Japanese
(7) Outpatient , Inpatient
(8) Written informed consent from the individual to participate in the study

(1) Difficulty to obtain informed consent because of dementia, mental illness, and mental symptoms
(2) Patients who are allergy to Kampo formulas and western medicine using in this study
(3) Pregnant and lactating patients
(4) Patients who may not be able to follow up
(5) Patients participating in clinical trials or other intervention studies
(6) Patients with hypokalemia or taking furosemide or taking steroids
(7) Those who have judged that the doctor in charge is not suitable for this study

Both

coronavirus disease 2019 (COVID-19)

In both groups, symptomatic treatment including antipyretic, antitussive, expectorant, antiemetic, and probiotic agents will be administered.
In the conventional treatment group, no treatment will be added.
In the additional Kampo treatment group, daily 7.5g of kakkonto and 7.5g of shosaikotokakikyosekko extract granule for ethical use (Tsumura & Co, Tokyo, Japan) before meal will be added for 14 days.

infectious disease, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19)

Kampo medicine, kakkonto, shosaikotokakikyosekko

coronavirus disease 2019

kakkonto, shosaikotokakikyosekko

Number of days ro improve fever (< 37.0 degrees Celsius ), cough, general malaise, dyspnea, diarrhea, and vomitting.

Severity outcome from enrollment to day 14

+81-22-718-0461

Aug. 04, 2020

none