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A Phase III Confirmatory Study of K-237-Multi-regional, Multi-center, Placebo Controlled, Randomized, Double Blind, Parallel Group Controlled Trial in Patients with mild COVID-19

A Phase III Confirmatory Study of K-237

1063

In FAS, there was no difference in any of these items between the K-237 and placebo groups. K-237 group (n=502) [Age (years): Mean (SD)] 35.5 (12.4) [Gender: n (%)] Male: 283 (56.4), Female: 219 (43.6) [Region: n (%)] Japan: 455 (90.6), Thailand: 47 (9.4) [Oxygen Saturation (%) at Baseline: Mean (SD)] 97.420 (0.864) [PCR Test Result at Baseline: n (%)] Positive: 431 (85.9), Negative: 71 (14.1) [SARS-CoV-2 Vaccination Status: n (%)] No: 75 (14.9), Yes: 427 (85.1) [Duration of COVID-19 Symptom Onset (days), Day1: Mean (SD)] 3.1 (1.4) [Duration of COVID-19 Symptom Onset (days), Day1: n (%)] <=3 days: 286 (57.0), 3 days <: 216 (43.0) Placebo group (n=527) [Age (years): Mean (SD)] 35.9 (12.0) [Gender: n (%)] Male: 292 (55.4), Female: 235 (44.6) [Region: n (%)] Japan: 478 (90.7), Thailand: 49 (9.3) [Oxygen Saturation (%) at Baseline: Mean (SD)] 97.404 (0.864) [PCR Test Result at Baseline: n (%)] Positive: 436 (82.9), Negative: 90 (17.1) [SARS-CoV-2 Vaccination Status: n (%)] No: 86 (16.3), Yes: 441 (83.7) [Duration of COVID-19 Symptom Onset (days), Day1: Mean (SD)] 3.2 (1.4) [Duration of COVID-19 Symptom Onset (days), Day1: n (%)] <=3 days: 275 (52.2), 3 days <: 252 (47.8)

[Informed Consent Obtained] 1063 participants [Randomization] 1030 participants (K-237 group: 502, Placebo group: 528) [Start of Administration] 1029 participants (K-237 group: 502, Placebo group: 527) [Completion of Treatment Period] 1023 participants (K-237 group: 499, Placebo group: 524) [Completion of Follow-up Period] 1017 participants (K-237 group: 495, Placebo group: 522) [Withdrawal During Treatment and Follow-up Periods] 12 participants (K-237 group: 7, Placebo group: 5) [Full Analysis Set (FAS)] 1029 participants (K-237 group: 502, Placebo group: 527) [Safety Analysis Set] 1029 participants (K-237 group: 502, Placebo group: 527)

The incidence of adverse events was 14.1% (71/502 participants) in the K-237 group and 14.2% (75/527 participants) in the placebo group. The incidence of adverse drug reactions was 6.2% (31/502 participants) in the K-237 group and 7.0% (37/527 participants) in the placebo group. No statistically significant differences in the incidence of adverse events and adverse drug reactions were observed between the K-237 group and placebo group (p = 0.968 and p = 0.585, respectively, by the chi-square test). Severe adverse events or adverse drug reactions were observed in neither of these groups. Moderate adverse events included 22 events in 15 participants (3.0%) in the K-237 group and 11 events in 9 participants (1.7%) in the placebo group, while moderate adverse drug reactions included 1 event in 1 participant (0.2%) in the K-237 group and 2 events in 2 participants (0.4%) in the placebo group. Neither of the groups had adverse events and adverse drug reactions with the outcome reported as "recovered/resolved with sequelae, fatal, unknown". Not recovered/not resolved adverse events included 7 events in 7 participants (1.4%) in the K-237 group and 18 events in 17 participants (3.2%) in the placebo group, while not recovered/not resolved adverse drug reactions included 3 events in 3 participants (0.6%) in the K-237 group and 11 events in 11 participants (2.1%) in the placebo group. All other adverse events and adverse drug reactions recovered/resolved or were being recovered/resolved. Serious adverse events included 3 events in 3 participants, 2 events (COVID-19 pneumonia and COVID-19) in 2 participants of the K-237 group and 1 event (urticaria) in 1 participant in the placebo group. The investigators decided that only urticaria was causally related to the investigational product. Among the serious adverse events, 2 events in 2 participants in the K-237 group were "serious adverse events related COVID-19", its incidence was 0.4% (2/502 participants) in the K-237 group and 0.0% (0/527 participants) in the placebo group, demonstrating no statistically significant differences between the K-237 and placebo groups (p = 0.147 by the chi-square test). No serious adverse events related COVID-19 were reported. Adverse events leading to study discontinuation included 5 events in 5 participants, 4 events (3 events of COVID-19 and 1 event of COVID-19 pneumonia) in 4 participants of the K-237 group and 1 event (COVID-19) in 1 participant in the placebo group. The investigators decided that none of the events was causally related to the investigational product. The incidence of adverse event of special interest related to "visual disturbance" was 0.2% in the K-237 group (1/502 participants, photophobia) and 0.0% in the placebo group (0/527 participants). No changes of clinical concern were observed in any of items of the laboratory and physiological tests.

The primary efficacy endpoint was the time at which clinical symptoms (fever, myalgia, sore throat, diarrhea, nausea, vomiting, cough, and shortness of breath) first showed an improving trend by 168 hours after investigational product administration. A total of 347/502 (69.1%) and 371/527 (70.4%) participants in the K-237 and placebo groups, respectively, showed an improving trend, with a 50% event time of 97.075 hours (95% CI: 91.550-113.600) and 95.733 hours (95% CI: 88.750-111.433), respectively. No statistically significant difference in efficacy was detected between the two (stratified log-rank test, p = 0.61). Using a stratified Cox proportional hazards model, the hazard ratio of the placebo group compared to that of the K-237 group was 1.04 (95% CI: 0.90-1.21). The prespecified subgroup analysis by participant background similarly showed no efficacy of K-237. No noteworthy results were found in the secondary endpoints.

K-237 0.3 to 0.4 mg/kg was orally administered once daily for 3 days to patients with mild COVID-19 to evaluate the effect of K-237 on clinical symptoms, but the superiority of K-237 to placebo could not be verified. Meanwhile, there was no statistically significant difference in the incidence of adverse events and adverse drug reactions between the K-237 group and the placebo group, which verified the safety of K-237 in this study.

Jan. 01, 2024

https://doi.org/10.1016/j.jiac.2023.12.012

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210316

Tanigawa Ryohei

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

ctrdinfo@kowa.co.jp

- Contact for clinical trial information

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

+81-3-3279-7857

ctrdinfo@kowa.co.jp

Complete

Oct. 22, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

Patients who meet all of the following criteria will be eligible for this study.
(1) Males and females who are 12 years of age or older at the time of obtaining consent
(2) Patients who are confirmed positive for SARS-CoV-2 by antigen test or RT-PCR test using specimens (nasopharynx, nasal cavity, oropharynx, or saliva) collected within 120 hours prior to obtaining consent.
(3) Patients who have fevers (>= 37.5 degrees Celsius) and/or at least one of the following symptoms of Score 2 or higher at a screening test:Myalgia, sore throat, diarrhea, nausea, vomiting, cough, and shortness of breath.
(4) Patients with a room air oxygen saturation (SpO2) of 96% or higher at the time of the screening test.

Subjects who meet any one of the following criteria will be excluded from this study.
(1) Patients who have had symptoms caused by COVID-19 for more than 6 days on the day of initiation of investigational drug administration (Day 1) with the day of onset of symptoms as Day 0.
(2) Patients who need to receive concomitant therapy or administration of prohibited drugs during the study period
(3) Patients who have taken or received drugs that have or may have antiviral activity against SARS-CoV-2 within 2 weeks prior to the start of study drug administration
(4) Patients with suspected complications of infectious diseases other than COVID-19
(5) Persons whose weight at the time of the screening test falls into the following categories (The first decimal place of the weight shall be rounded off.)
1) Those who are 18 years of age or older at the time of consent and weigh less than 25 kg or more than 127 kg
2) Those who are between 12 and 18 years of age and weigh less than 40 kg or 127 kg or more at the time of obtaining consent.
(6) Patients undergoing dialysis treatment
(7) Patients wno have severe liver dysfunction (hepatic dysfunction, hepatic fibrosis, etc.)
(8) Patients wno have complications of poorly controlled hypertension (systolic blood pressure (SBP) of 180 mmHg or more or diastolic blood pressure (DBP) of 110 mmHg or more)
(9) Patients requiring oxygen therapy
(10) Patients wno have complications of methemoglobinemia or other diseases that may cause measurement errors in the pulse oximeter

Both

COVID-19

K-237 0.3-0.4mg/kg group: oral doses once daily
Placebo group: oral doses once daily

Time from the start of study drug administration to 168 hours before the clinical symptoms started to improve

Sept. 17, 2021

Thailand