Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19 (ACTT-2)
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Design
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Randomized, multicenter, adaptive, double-blind, placebo-controlled trial
N=1,033
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Objective
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To evaluate whether the combination of baricitinib plus remdesivir was superior to remdesivir alone
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Study Groups
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Baracitinib + remdesivir (n=515)
Placebo + remdesivir (n=518)
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Inclusion Criteria
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18 years of age or older; laboratory-confirmed SARS-CoV-2 infection (via polymerase chain reaction [PCR]) within 72 hours of randomization or >72 hours if unable to collect sample plus progressive disease suggestive of COVID-19; radiographic infiltrates by imaging, peripheral oxygen saturation (SpO2) ≤94% on room air, or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
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Exclusion Criteria
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Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of the normal (ULN); impaired renal function (estimated glomerular filtration [eGFR] < 30 mL/min) or receiving hemodialysis or hemofiltration; allergy to study drugs; pregnancy or breast-feeding; anticipated discharge from the hospital or transfer within 72 hours of enrollment; neutropenia (<1,000/µL); lymphopenia (<200/µL); received similar or confounding medications (e.g. tyrosine kinase inhibitors, monoclonal antibodies targeting cytokines or B-cells, immunosuppressants) up to 4 weeks before screening; history of venous thromboembolism (VTE) in the past 12 weeks or any recurrent VTE
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Methods
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Participants were randomized 1:1 to receive either remdesivir and baricitinib or remdesivir and placebo. All patients also received standard supportive care at the trial site hospital.
All patients received remdesivir 200 mg on day 1, followed by 100 mg daily for 10 days or until hospital discharge or death. Baricitinib 4 mg daily (PO [two 2-mg tablets] or through a nasogastric tube) or placebo was given for 14 days or until hospital discharge. Patients with an eGFR < 60 mL/min received baricitinib at a dose of 2 mg once daily.
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Duration
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Enrollment: May 8 to July 1, 2020
Follow-up: 29 days
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Outcome Measures
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Primary: time to recovery through 28 days (defined as achieving category 1, 2, or 3 on the eight-category ordinal scale)
- 1: Not hospitalized, no limitations on activities
- 2: Not hospitalized, limitation on activities and/or requiring home oxygen
- 3: Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care
- 4: Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care
- 5: Hospitalized, requiring supplemental oxygen
- 6: Hospitalized, on non-invasive ventilation or high flow oxygen devices
- 7: Hospitalized, on mechanical ventilation or ECMO
- 8: Death
Secondary: clinical status at day 15 (based on the eight-category ordinal scale), mortality, time to discharge, days receiving supplemental oxygen
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Baseline Characteristics
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Baracitinib + remdesivir (n=515)
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Placebo + remdesivir (n=518)
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Age, years
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55.0±15.4 |
55.8±16.0 |
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Male
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319 (61.9%) |
333 (64.3%) |
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White |
251 (48.7%) |
245 (47.3%) |
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Body mass index, kg/m2 |
32.2±8.2 |
32.3±8.4 |
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Time from symptom onset to randomization, days (interquartile range) |
8 (5-10) |
8 (5-11) |
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Duration of symptoms >10 days before enrollment |
120 (23.3%) |
133 (25.7%) |
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Post-randomization corticosteroid use |
56 (10.9%) |
67 (12.9%) |
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Clinical status (category) on 8-point ordinal scale
4: not requiring oxygen
5: requiring oxygen
6: requiring non-invasive ventilation
7: requiring mechanical ventilation
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70 (13.6%)
288 (55.9%)
103 (20.0%)
54 (10.5%)
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72 (13.9%)
276 (53.3%)
113 (21.8%)
57 (11.0%)
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Patients presenting as category 6 or 7 were considered to have severe COVID-19 (30.5% vs 32.8%).
IQR=interquartile range
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Results
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Baracitinib + remdesivir (n=515)
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Placebo + remdesivir (n=518)
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Rate ratio (95% CI)
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P-value
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Time to recovery, days (IQR)
Patients recovered (category of 1, 2, or 3)
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7 (6-8)
433 (84.1%)
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8 (7-9)
406 (78.4%)
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1.16 (1.01 to 1.32)
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0.03 |
Mortality
By day 14
By day 28
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8 (1.6%)
24 (4.7%)
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15 (6.9%)
37 (7.1%)
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Hazard ratio (95% CI)
0.54 (0.23 to 1.28)
0.65 (0.39 to 1.09)
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Not significant |
Time to one-category improvement, days (IQR) |
6 (5-7) |
8 (7-9) |
1.21 (1.06 to 1.39) |
N/A |
Time to two-category improvement, days (IQR) |
12 (12-13) |
13 (not evaluable) |
1.20 (1.05 to 1.38) |
N/A |
Duration of hospitalization, days (IQR)
With imputation of data for those who died*
Among patients who did not die
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10 (4 to 27)
9 (4 to 23)
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12 (4 to 28)
10 (4 to 28)
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Difference (95% CI)
−2.0 (−5.2 to 1.2)
−1.0 (−3.5 to 1.5)
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N/A |
A subgroup analysis showed no significant difference in time to recovery between the groups in patients with a baseline clinical status of 4, 5, or 7. Patients with a baseline status of 6 (on non-invasive ventilation or high flow oxygen) improved significantly when baricitinib was added (10 days vs 18 days; RR 1.51; 95% CI 1.10 to 2.08).
The odds of improvement in clinical status at day 15 were greater with baricitinib than with remdesivir alone (odds ratio [OR] 1.3; 95% CI 1.0 to 1.6). Patients with a baseline ordinal score of 6 who received baricitinib were most likely to have clinical improvement at day 15 (OR 2.2; 95% C, 1.4 to 3.6).
*The duration for patients who died was imputed as 28 days.
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Adverse Events
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Any grade 3 or 4 adverse events (40.7% vs 46.8%):
Hyperglycemia (4.9% vs 7.9%), anemia (4.9% vs 6.5%), decreased lymphocyte count (2.2% vs 4.7%), acute kidney injury (3.9% vs 7.1%)
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Serious adverse events (16.0% vs 21.0%):
Acute respiratory failure (3.6% vs 2.6%), acute kidney injury (1.0% vs 2.2%), pulmonary embolism (1.0% vs 0.4%), respiratory failure (5.1% vs 7.3%)
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Study Author Conclusions
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Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation. The combination was associated with fewer serious adverse events.
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InpharmD Researcher Critique
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Although the primary endpoint of this study was statistically significant, the clinical benefit of time to recovery by 1 day is debated. This significant result is exclusive to hospitalized patients on non-invasive ventilation or high flow oxygen devices, which made up 20% of patients. Additionally, more patients in the remdesivir only group (26% vs 23%) received treatment after 10 days of symptoms, which could be the cutoff when treatment makes no difference.
The authors conclude that adding baricitinib is "superior" to remdesivir alone, but this study was not designed to detect statistical superiority between the treatments. Nor was this study powered to detect a difference in mortality. Additionally, the statistical analyses were not adjusted for multiple comparisons.
The mortality status by day 28 was unknown for 142 persons (13% with baricitinib; 14.5% with placebo); however, the authors estimate the incidence of death post-discharge is low.
While both groups received standard of care (per their hospital protocols), concomitant mediations/therapies given were not reported. This study concluded enrollment around 2 weeks after the results of the RECOVERY trial were released, which showed a mortality benefit with dexamethasone use. While the incidence of corticosteroid use after randomization was similar (no significant difference), the extent of their confounding or any comparison to baricitinib cannot be determined.
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