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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-2))

A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-2 Baricitinib / Remdesivir Vs. Remdesivir Trial)

1033

The mean age of the patients was 55.4 years, and 63.1% were male. Overall, 48.0% of the patients were White, 15.1% were Black, 9.8% were Asian, and 1.0% were American Indian or Alaska Native; 51.4% were Hispanic or Latino. 92.3% of patients were enrolled at sites in North America, 1.3% in Europe, and 6.5% in Asia among 67 trial sites in 8 countries.

Of 1067 patients assessed for eligibility, 1033 underwent randomization; 515 were assigned to the combination group (baricitinib plus remdesivir), and 518 to the control group (placebo plus remdesivir). The intention-to-treat population included 706 patients with moderate disease (ordinal score of 4 or 5 [not receiving ventilation]) and 327 with severe disease (ordinal score of 6 or 7 [receiving noninvasive or invasive ventilation]). Of those assigned to the combination group, 507 (98.4%) received treatment as assigned. Of those assigned to the control group, 509 (98.3%) received treatment as assigned. A total of 498 patients in the combination group and 495 in the control group completed the trial through day 29, recovered, or died.

Grade 3 or 4 adverse events occurred in 207 patients (40.7%) in the combination group and 238 (46.8%) in the control group. A total of 25 grade 3 or 4 adverse events were judged by the principal investigators to be related to combination treatment and 28 to control. The most common grade 3 or 4 adverse events occurring in at least 5% of all patients were hyperglycemia, anemia, decreased lymphocyte count, and acute kidney injury. The incidence of these adverse events was similar in the two treatment groups. The percentage of patients who were reported to have a serious or nonserious adverse event of venous thromboembolism was similar in the combination group and the control group (21 patients [4.1%] and 16 patients [3.1%], respectively; difference, 1.0 percentage points; 95% CI, -1.3 to 3.3). The patients receiving baricitinib plus remdesivir had a significantly lower incidence of adverse events, adverse events leading to discontinuation of the trial drug, serious adverse events, serious adverse events with a fatal outcome, and infection-related adverse events than patients who received remdesivir alone.

1. Primary Outcome Patients who received combination treatment with baricitinib plus remdesivir recovered a median of 1 day faster than patients who received remdesivir and placebo (median, 7 days vs. 8 days; rate ratio for recovery, 1.16; 95% confidence interval [CI], 1.01 to 1.32; P=0.03 by log-rank test stratified according to actual baseline severity). When analyzed according to the severity entered at the time of randomization (moderate vs. severe), the hazard ratio was 1.15 (95% CI, 1.00 to 1.31; P=0.047). The median time to recovery among patients receiving noninvasive ventilation or high-flow oxygen (baseline ordinal score of 6) was 10 days in the combination group and 18 days in the control group (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). Among patients with a baseline score of 4 (no oxygen) and 5 (supplemental oxygen), the rate ratio for recovery was 0.88 (95% CI, 0.63 to 1.23) and 1.17 (95% CI, 0.98 to 1.39), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 1.08 (95% CI, 0.59 to 1.97). The rate ratio for recovery among the 223 patients who received glucocorticoids for clinical indications during the trial was 1.06 (95% CI, 0.75 to 1.48). A sensitivity analysis with a random effect for hospital sites yielded similar results (conditional random-effects estimate of rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.33; restricted maximum likelihood-based random-effects estimate of variance, 0.0305). 2. Key Secondary Outcome The odds of improvement in clinical status at day 15 as assessed with the ordinal scale were greater in the combination group than in the control group (odds ratio for improvement, 1.3; 95% CI, 1.0 to 1.6). Patients with a baseline ordinal score of 6 who received combination treatment were most likely to have clinical improvement at day 15 (odds ratio, 2.2; 95% CI, 1.4 to 3.6. The odds of improvement in clinical status at day 15 as assessed with the ordinal scale were greater in the combination group than in the control group (odds ratio for improvement, 1.3; 95% CI, 1.0 to 1.6). Patients with a baseline ordinal score of 6 who received combination treatment were most likely to have clinical improvement at day 15 (odds ratio, 2.2; 95% CI, 1.4 to 3.6).

Combination treatment with the antiinflammatory drug baricitinib and the antiviral drug remdesivir was superior to remdesivir alone for the treatment of hospitalized patients with Covid-19 pneumonia. The beneficial effects of the combination treatment were seen both in the primary outcome, with a shorter time to recovery, and in the key secondary outcome, with a greater improvement in clinical status as assessed on the ordinal scale. The combination was associated with fewer serious adverse events.

Sept. 02, 2021

Dec. 11, 2020

https://www.nejm.org/doi/full/10.1056/NEJMoa2031994

No

https://jrct.niph.go.jp/latest-detail/jRCT2031200035

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

May. 20, 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 informed consent prior to initiation of any study procedures.
3.Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
4.Male or non-pregnant female adult =>18 years of age at time of enrollment.
5.Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen, as documented by either of the following
-PCR positive in sample collected < 72 hours prior to randomization OR
-PCR positive in sample collected => 72 hours prior to randomization, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking > 24 hours, etc.). AND progressive disease suggestive of ongoing SARS-CoV-2 infection.
6.Illness of any duration, and at least one of the following
-Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
-SpO2 <= 94% on room air, OR
-Requiring supplemental oxygen, OR
-Requiring mechanical ventilation.
7.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.
8.Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 through Day 29.

1. ALT or AST > 5 times the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening.
3. Neutropenia (absolute neutrophil count <1000 cells/microL) (<1.0 x 103/microL or <1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count <200 cells/microL) (<0.20 x 103/microL or <0.20 GI/L)
5. Pregnancy or breast feeding.
6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
7. Allergy to any study medication.
8. Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19.
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the current illness for which they are being enrolled.
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening
11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
13. Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with baricitinib is larger than the risk of COVID-19.
14. Received =>20 mg/day of prednisone or equivalent for =>14 consecutive days in the 4 weeks prior to screening.
15. Use of probenecid that cannot be discontinued at study enrollment.
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE).
20. Immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at increased risk for serious infections or other safety concerns given the study products.

Both

Novel Coronavirus Infectious Disease (COVID-19)

Dosing and Administration
All subjects will receive remdesivir as a 200 mg intravenous (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 subjects already received the loading dose as under the EUA or similar mechanism, then start at 100 mg/day. Any doses of remdesivir under an EUA (or similar mechanism) prior to enrollment will be counted, so the total duration of remdesivir (i.e. EUA + on this trial) is 10 days (i.e., a maximum of 10 total infusions). If one or two doses of remdesivir were administered (under EUA or similar mechanism) prior to study enrollment, this should be documented in eClinical as a concomitant medication given prior to Day 1.
For the baricitinib component, subjects will receive either active product or placebo as follows:
- Baricitinib will be administered as a 4 mg orally (po) (two 2mg tablets) or crushed for NG tube, daily for the duration of the hospitalization up to a 14-day total course.
- A placebo will be given as two tablets po or crushed for NG tube, daily for the duration of the hospitalization up to a 14-day total course.

-The overall objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to the control arm among hospitalized adults who have COVID-19.
-To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm.
-To evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 15

1.To 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 Day1(baseline) using an ordinal scale.
-Subject clinical status using ordinal scale at Days 3, 5, 8, 11, 15, 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 use up 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 use up 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 use up to Day 29.
-Incidence and duration of new mechanical ventilation or ECMO use during the study.(2) Hospitalization
1)Duration of hospitalization(days)
(3) Mortality
1)14-day mortality
2)28-day mortality

2. To 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 study product administrations (for any reason)
(4) Changes in white blood cell (WBC) count with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin time (PT) over time (analysis of lab values in addition to AEs noted above).

+81-3-3202-7181

May. 19, 2020

United States/Denmark/Korea/Mexico/Singapore/Spain/United Kingdom