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A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (Adaptive COVID-19 Treatment Trial (ACTT))

A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults

1114

Of the 1062 subjects randomized in this study, the mean age of the patients was 58.9+-15.0 years, and 64.4% were male. On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia among 73 trial sites and subsites. Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported; 250 (23.5%) were Hispanic or Latino. The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12). A total of 957 patients (90.1%) had the severe disease at enrollment; 285 patients (26.8%) met category 7 criteria on an eight-category ordinal scale of clinical condition, which was determined for the study, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment; all these patients discontinued the study before treatment.

Of the 1114 patients who were assessed for eligibility, 1062 underwent randomization; 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population); 159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent. Of those assigned to receive placebo, 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and 14 withdrew consent.

In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and 163 of 516 patients (31.6%) in the placebo group. There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients). No deaths were considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group; 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo. The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level. The incidence of these adverse events was generally similar in the remdesivir and placebo groups.

Primary Outcome Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days, rate ratio for recovery, 1.29, 95% confidence interval [CI], 1.12 to 1.49, P-value is less than 0.001) Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5, 95% CI, 1.2 to 1.9, adjusted for disease severity) Mortality Kaplan-Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55, 95% CI, 0.36 to 0.83), the estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73, 95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity, with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30, 95% CI, 0.14 to 0.64). Additional Secondary Outcomes Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days, hazard ratio, 1.27, 95% CI, 1.10 to 1.46). The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days), 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs. 21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]). For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]). Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27])

The data show that remdesivir was superior to placebo in shortening the recovery time in adults hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Although serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and 163 of 516 patients (31.6%) in the placebo group, no deaths were considered by the investigators to be related to treatment assignment.

July. 27, 2021

May. 22, 2020

https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

No

https://jrct.niph.go.jp/latest-detail/jRCT2031190264

Ohmagari Norio

Center Hospital of the National Center for Global Health and Medicine

1-21-1 Toyama, Shinjuku-ku, Tokyo Japan

nohmagari@hosp.ncgm.go.jp

Mikami Ayako

National Center for Global Health and Medicine

1-21-1 Toyama, Shinjuku-ku, Tokyo Japan

+81-3-3202-7181

amikami@hosp.ncgm.go.jp

Complete

Mar. 26, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1.Admitted to a hospital with symptoms suggestive of COVID-19 infection.
2.Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
3.Understands and agrees to comply with planned study procedures.
4.Agrees to the collection of oropharyngeal (OP) swabs.
5.Male or non-pregnant female adult =>18 years of age at time of enrollment.
6.Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen collected < 72 hours prior to randomization.
Note - 72 hours is not necessarily time from initial diagnosis. If => 72 hours since positive PCR, the PCR may be repeated to assess eligibility.
7.Illness of any duration, and at least one of the following:
-Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
-Clinical assessment (evidence of rales/crackles on exam) AND SpO2 <= 94% on room air, OR
-Requiring supplemental oxygen, OR
-Requiring mechanical ventilation.
8.Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29.
9.Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2.

1.ALT/AST > 5 times the upper limit of normal.
2.Estimated glomerular filtration rate (eGFR) < 50 or requiring dialysis.
3.Pregnancy or breast feeding.
4.Anticipated transfer to another hospital which is not a study site within 72 hours.
5.Allergy to any study medication.

Both

Novel Coronavirus Infectious Disease (COVID-19)

Dosing and Administration
Subjects will be randomized 1:1 to receive either active product or placebo. Initially, the trial will have 2 arms:
-Remdesivir will be administered as a 200 mg IV loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose for the duration of the hospitalization up to a 10 day total course. If a subject is no longer hospitalized, then infusions will no longer be given.
-A matching placebo will be given at an equal volume at the same schedule.

Any dose that is delayed, but still the same study day, may be given. Any dose that is missed (not given that calendar day) is not made up.

The overall objective of the study is to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19.
-The primary objective will be determined by a pilot study of the first 100 subjects.
-Subject clinical status (8-point ordinal scale) at Day 15 is the default primary endpoint.

1. Evaluate the clinical efficacy of different investigational therapeutics as compared to the control arm as assessed by:
(1) Clinical Severity
1) Ordinal scale:
Time to an improvement of one category and two categories from Day 1 using an ordinal scale.
-Subject clinical status using ordinal scale at Days 3, 5, 8, 11, 22, and 29.
-Mean change in the ordinal scale from Day 1 to Days 3, 5, 8, 11, 15, 22, and 29.
2)National Early Warning Score (NEWS):
-Time to discharge or to a NEWS of <= 2 and maintained for 24 hours, whichever occurs first.
-Change from Day 1 to Days 3, 5, 8, 11, 15, and 29 in NEWS.
3)Oxygenation:
-Oxygenation free days to Day 29.
-Incidence and duration of new oxygen use during the study.
4)Non-invasive ventilation/high flow oxygen:
-Non-invasive ventilation/high flow oxygen - free days to Day 29.
-Incidence and duration of new non-invasive ventilation or high flow oxygen use during the study.
5)Invasive Mechanical Ventilation / extracorporeal membrane oxygenation (ECMO):
-Ventilator / ECMO free days to Day 29.
-Incidence and duration of new mechanical ventilation or ECMO use during the study.
(2) Hospitalization
1)Duration of hospitalization.
(3) Mortality
1)14-day mortality
2)28-day mortality

2. Evaluate the safety of different investigational therapeutics as compared to the control arm as assessed by:
(1) Cumulative incidence of SAEs through Day 29.
(2) Cumulative incidence of Grade 3 and 4 clinical and/or laboratory AEs through Day 29.
(3) Discontinuation or temporary suspension of infusions (for any reason)
(4) Changes in WBC with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, AST, and PT over time (analysis of lab values in addition to AEs noted above).

+81-3-3202-7181

USA/KOREA