Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial
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Design
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Ongoing, multipart, phase 2/3, randomized, double-blind, placebo-controlled, single-infusion study
N=592
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Objective
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To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) viral load in mild to moderate COVID-19
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Study Groups
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Part I:
- Bamlanivimab (n=317)
- 700 mg (n=104)
- 2,800 mg (n=109)
- 7,000 mg (n=104)
- Placebo (n=161)
Part II
- Bamlanivimab and etesevimab (n=114)
- Placebo (n=161)
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Inclusion Criteria
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Age ≥18 years, positive SARS-CoV2- infection, 1 or more mild to moderate symptoms, presented within 3 days of their first positive test result
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Exclusion Criteria
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SpO2 ≤93% on room air, mechanial ventilation, vasopressor within 24 hours of randomization, serious concomitant systemic diseases, previous use of monoclonal antibody for SARS-CoV2
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Methods
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Part I of the trial consisted of bamlanivimab monotherapy or placeb followed by Part II with combination therapy of bamlanivimab and etesevimab or placebo.
Treatment was administered within 3 days of first positive SARS-CoV2 test. Doses for bamlanivam included 700 mg, 2,800 mg, and 7,000 mg. Doses for combination therapy with bamlanivimab and etesevimab were both 2,800 mg. All doses were administered as a single, 1 hour intravenous infusion.
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Duration
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Part I: June 17 to August 21, 2020
Part II: August 22 to September 3, 2020
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Outcome Measures
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Primary endpoint: change in SARS-CoV-2 log viral load at day 11 ± 4 days
Secondary endpoints:
- viral load (viral clearance at days 7, 11, 15, and 22; viral load area under the curve [AUC] at day 29)
- symptoms (total symptom score, time to symptom improvement, time to symptom resolution at days 7, 11, 15, and 22)
- COVID-19–related hospitalization, emergency department visit, or death at day 29
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Baseline Characteristics
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Bamlanivimab
700 mg (n=101)
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Bamlanivimab
2,800 mg (n=107)
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Bamlanivimab
7,000 mg (n=101)
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Bamlanivimab and etesevimab
(n=112)
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Placebo
(n=156)
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Age, years (IQR)
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39 (31-58) |
45 (31-56) |
46 (34-55) |
44 (30-60) |
46 (35-57) |
Female
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63 (62.4%) |
51 (47.7%) |
58 (57.4%) |
58 (51.8%) |
85 (54.5%) |
White
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90 (89.1%) |
90 (86.5%) |
89 (89.0%) |
105 (94.6%) |
133 (88.1%) |
BMI, kg/m2 (IQR)
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28.8 (25.1-35.4) |
30.4 (25.6-34.0) |
27.8 (24.7-32.3) |
27.2 (22.9-33.0) |
29.2 (25.9-34.2) |
Risk factors for severe COVID-19*
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74 (73.3%) |
78 (72.9%) |
63 (62.4% ) |
67 (59.8%) |
105 (67.3%) |
COVID-19 severity
Mild
Moderate
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83 (82.2%)
18 (17.8%)
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79 (73.8%)
28 (26.2%)
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70 (69.3%)
31 (30.7%)
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92 (82.1%)
20 (17.9%)
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125 (80.1%)
31 (19.9%)
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Duration of symptoms, days (IQR)
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5 (3-6)
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4 (3-6)
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4 (2-7)
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4 (3-5)
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4 (3-6)
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IQR=interquartile range; BMI=body mass index
*Risk factors include: age ≥55 years; BMI of ≥30; a medical history of diabetes, chronic kidney disease, cardiovascular disease, chronic respiratory disease, or immunosuppressive disease; or receiving immunosuppressive treatment
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Results
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Bamlanivimab
700 mg (n=101)
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Bamlanivimab
2,800 mg (n=107)
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Bamlanivimab
7,000 mg (n=101)
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Bamlanivimab and etesevimab
(n=112)
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Placebo
(n=156)
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Change in Log Viral Load at day 11
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-3.72 |
-4.08 |
-3.49 |
-4.37* |
-3.80 |
Viral load AUC at day 29
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70.17 |
63.74* |
71.53 |
61.69* |
74.45 |
Viral clearance
Day 7
Day 11
Day 15
Day 22
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10 (9.9%)
13 (12.9%)
25 (24.8%)
41 (40.6%)
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12 (11.2%)
21 (19.6%)
30 (28.0%)
43 (40.2%)
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8 (7.9%)
14 (13.9%)
25 (24.8%)
37 (36.6%)
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14 (12.8%)
30 (27.5%)
36 (33.0%)
40 (36.7%)
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16 (10.5%)
27 (17.8%)
34 (22.4%)
56 (36.8%)
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COVID-19–related hospitalization or emergency department visit at day 29
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1 (1.0%)
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2 (1.9%)
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2 (2.0%)
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1 (0.9%)*
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9 (5.8%)
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Total symptom score
Day 7
Day 11
Day 15
Day 22
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1.90 ± 2.49
1.06 ± 1.58*
1.00 ± 2.25
0.46 ± 1.16
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2.07 ± 2.93
1.59 ± 2.24
1.20 ± 2.03
0.74 ± 1.67
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2.22 ± 2.97
1.56 ± 2.61
1.00 ± 2.07
0.71 ± 1.54
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2.14 ± 2.98
1.28 ± 2.48*
1.04 ± 2.43
0.76 ± 2.00
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2.43 ± 2.67
1.88 ± 2.50
1.24 ± 2.05
0.77 ± 1.67
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Symptom improvement
Day 7
Day 11
Day 15
Day 22
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47 (46.5%)
60 (59.4%)*
63 (62.4%)
70 (69.3%)
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37 (34.6%)
48 (44.9%)
63 (58.9%)
69 (64.5%)
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46 (45.5%)
59 (58.4%)*
69 (68.3%)*
71 (70.3%)
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50 (45.9%)
58 (53.2%)
69 (63.3%)
78 (71.6%)
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62 (40.8%)
66 (43.4%)
83 (54.6%)
96 (63.2%)
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Symptom resolution
Day 7
Day 11
Day 15
Day 22
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37 (36.6%)
51 (50.5%)*
56 (55.4%)
68 (67.3%)
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33 (30.8%)
43 (40.2%)
59 (55.1%)
63 (58.9%)
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34 (33.7%)
44 (43.6%)
60 (59.4%)*
62 (61.4%)
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38 (34.9%)
50 (45.9%)
63 (57.8%)
75 (68.8%)
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48 (31.6%)
56 (36.8%)
70 (46.1%)
88 (57.9%)
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AUC=area under the curve
*significant difference vs placebo with at least p<0.05
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Adverse Events
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Common Adverse Events:
Nausea (3 [3%] vs 4 [3.7%] vs 5 [5.0%] vs 4 [3.6%] vs 6 [3.8%]);
Diarrhea (1 [1.0%] vs 2 [1.9%] vs 6 [5.9%] vs 1 [0.9%] vs 7 [4.5%])
Dizziness (3 [3%] vs 3 [2.8%] vs 3 [3.0%] vs 1 [0.9%] vs 3 [1.9%])
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Serious Adverse Events:
Urinary tract infection: bamlanivimab and etesevimab combination 1 [0.9%]
Upper abdominal pain: placebo 1 [0.6%]
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Study Author Conclusions
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Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy
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InpharmD Researcher Critique
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Only a single dose of bamlanivimab and etesevimab 2,800 mg was used in the study. It is difficult to assess the efficacy of treatment using the primary endpoint of viral load at day 11 as the body's natural immune response during this stage may have been the predominant factor in reducing viral load. Instead, a more clinical endpoint (e.g., symptom resolution) should have been chosen at an earlier time point (e.g., day 3 or day 7 post-treatment).
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