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Casirivimab/imdevimab for COVID-19: real-time meta analysis of 15 studies
Covid Analysis, January 22, 2022, DRAFT
https://c19regn.com/meta.html
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 66% 15 39,275 Improvement, Studies, Patients Relative Risk With exclusions 66% 14 29,593 Mortality 48% 7 32,895 Ventilation 0% 2 9,326 ICU admission 67% 2 9,810 Hospitalization 49% 6 19,304 Progression 56% 3 680 Recovery 33% 5 8,277 Cases 80% 4 3,265 Viral clearance 55% 2 1,709 RCTs 61% 9 21,306 RCT mortality 20% 3 15,162 Peer-reviewed 80% 5 19,845 Prophylaxis 93% 3 3,061 Early 63% 9 23,276 Late 33% 3 12,938 Casirivimab/imdevimab for COVID-19 c19regn.com Jan 22, 2022 Favors casiri/imdevimab Favors control
Statistically significant improvements are seen for mortality, hospitalization, progression, recovery, cases, and viral clearance. 13 studies from 8 independent teams in 3 different countries show statistically significant improvements in isolation (6 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 66% [45‑80%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and better for peer-reviewed studies. Early treatment is more effective than late treatment.
Results are robust — in exclusion sensitivity analysis 10 of 15 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 66% 15 39,275 Improvement, Studies, Patients Relative Risk With exclusions 66% 14 29,593 Mortality 48% 7 32,895 Ventilation 0% 2 9,326 ICU admission 67% 2 9,810 Hospitalization 49% 6 19,304 Progression 56% 3 680 Recovery 33% 5 8,277 Cases 80% 4 3,265 Viral clearance 55% 2 1,709 RCTs 61% 9 21,306 RCT mortality 20% 3 15,162 Peer-reviewed 80% 5 19,845 Prophylaxis 93% 3 3,061 Early 63% 9 23,276 Late 33% 3 12,938 Casirivimab/imdevimab for COVID-19 c19regn.com Jan 22, 2022 Favors casiri/imdevimab Favors control
Efficacy is variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, VanBlargan]. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 33% of casirivimab/imdevimab studies show zero events in the treatment arm.
Multiple treatments are typically used in combination, and other treatments may be more effective.
Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 1563% [43‑76%]33% [-17‑61%]93% [79‑97%] 39,275 296
With exclusions 1462% [39‑76%]33% [-17‑61%]93% [79‑97%] 29,593 287
Peer-reviewed 580% [43‑93%] 19,845 104
Randomized Controlled TrialsRCTs 962% [39‑76%]19% [-17‑44%]93% [79‑97%] 21,306 177
Percentage improvement with casirivimab/imdevimab treatment
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.30-1.28] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 71% 0.29 [0.17-0.48] death/hosp. 18/1,355 62/1,341 Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 Webb 98% 0.02 [0.00-0.27] death 0/115 57/5,536 Cooper 77% 0.23 [0.03-1.65] death 1/1,148 33/8,534 Kakinoki 58% 0.42 [0.17-0.92] progression 13/55 22/53 Komagamine 77% 0.23 [0.01-4.63] ventilation 0/53 2/75 Suzuki (PSM) -200% 3.00 [0.12-73.3] death 1/222 0/222 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.09, I​2 = 22.5%, p < 0.0001 Early treatment 63% 0.37 [0.24-0.57] 35/5,231 183/18,045 63% improvement Horby (RCT) 6% 0.94 [0.86-1.03] death 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] death 59/804 45/393 McCreary (PSM) 93% 0.07 [0.01-0.51] death 1/652 29/1,304 Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 0.67 [0.39-1.17] 1,004/6,295 1,100/6,643 33% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 0.07 [0.03-0.21] 3/1,756 27/1,305 93% improvement All studies 66% 0.34 [0.20-0.55] 1,042/13,282 1,310/25,993 66% improvement 15 casirivimab/imdevimab COVID-19 studies c19regn.com Jan 22, 2022 Tau​2 = 0.43, I​2 = 80.2%, p < 0.0001 Effect extraction pre-specified, see appendix Favors casiri/imdevimab Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of casirivimab/imdevimab for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Variant Dependence
Efficacy is variant dependent, for example in vitro studies suggest that casirivimab/imdevimab is not effective for the omicron variant [Liu, Sheward, VanBlargan].
Results
Figure 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies. Table 1 summarizes the results by treatment stage.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 8 9 88.9% 63% improvement
RR 0.37 [0.24‑0.57]
p < 0.0001
Late treatment 3 3 100% 33% improvement
RR 0.67 [0.39‑1.17]
p = 0.16
Prophylaxis 3 3 100% 93% improvement
RR 0.07 [0.03‑0.21]
p < 0.0001
All studies 14 15 93.3% 66% improvement
RR 0.34 [0.20‑0.55]
p < 0.0001
Table 1. Results by treatment stage.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.30-1.28] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 71% 0.29 [0.17-0.48] death/hosp. 18/1,355 62/1,341 Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 Webb 98% 0.02 [0.00-0.27] death 0/115 57/5,536 Cooper 77% 0.23 [0.03-1.65] death 1/1,148 33/8,534 Kakinoki 58% 0.42 [0.17-0.92] progression 13/55 22/53 Komagamine 77% 0.23 [0.01-4.63] ventilation 0/53 2/75 Suzuki (PSM) -200% 3.00 [0.12-73.3] death 1/222 0/222 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.09, I​2 = 22.5%, p < 0.0001 Early treatment 63% 0.37 [0.24-0.57] 35/5,231 183/18,045 63% improvement Horby (RCT) 6% 0.94 [0.86-1.03] death 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] death 59/804 45/393 McCreary (PSM) 93% 0.07 [0.01-0.51] death 1/652 29/1,304 Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 0.67 [0.39-1.17] 1,004/6,295 1,100/6,643 33% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 0.07 [0.03-0.21] 3/1,756 27/1,305 93% improvement All studies 66% 0.34 [0.20-0.55] 1,042/13,282 1,310/25,993 66% improvement 15 casirivimab/imdevimab COVID-19 studies c19regn.com Jan 22, 2022 Tau​2 = 0.43, I​2 = 80.2%, p < 0.0001 Effect extraction pre-specified, see appendix Favors casiri/imdevimab Favors control
Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Weinreich (RCT) 50% 0.50 [0.09-2.72] 2/2,091 4/2,089 Improvement, RR [CI] Treatment Control Webb 98% 0.02 [0.00-0.27] 0/115 57/5,536 Cooper 77% 0.23 [0.03-1.65] 1/1,148 33/8,534 Suzuki (PSM) -200% 3.00 [0.12-73.3] 1/222 0/222 Tau​2 = 1.61, I​2 = 54.1%, p = 0.13 Early treatment 73% 0.27 [0.05-1.48] 4/3,576 94/16,381 73% improvement Horby (RCT) 6% 0.94 [0.86-1.03] 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] 59/804 45/393 McCreary (PSM) 93% 0.07 [0.01-0.51] 1/652 29/1,304 Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 0.67 [0.39-1.17] 1,004/6,295 1,100/6,643 33% improvement All studies 48% 0.52 [0.29-0.94] 1,008/9,871 1,194/23,024 48% improvement 7 casirivimab/imdevimab COVID-19 mortality results c19regn.com Jan 22, 2022 Tau​2 = 0.25, I​2 = 71.8%, p = 0.029 Favors casiri/imdevimab Favors control
Figure 4. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Komagamine 77% 0.23 [0.01-4.63] 0/53 2/75 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.34 Early treatment 77% 0.23 [0.01-4.63] 0/53 2/75 77% improvement Horby (RCT) 0% 1.00 [0.89-1.13] 479/4,556 487/4,642 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 1. Late treatment 0% 1.00 [0.89-1.13] 479/4,556 487/4,642 0% improvement All studies 0% 1.00 [0.89-1.12] 479/4,609 489/4,717 0% improvement 2 casirivimab/imdevimab COVID-19 mechanical ventilation results c19regn.com Jan 22, 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.97 Favors casiri/imdevimab Favors control
Figure 5. Random effects meta-analysis for ventilation.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Cooper 48% 0.52 [0.23-1.20] 6/1,148 85/8,534 Improvement, RR [CI] Treatment Control Komagamine 92% 0.08 [0.00-1.32] 0/53 7/75 Tau​2 = 0.70, I​2 = 37.9%, p = 0.18 Early treatment 67% 0.33 [0.07-1.65] 6/1,201 92/8,609 67% improvement All studies 67% 0.33 [0.07-1.65] 6/1,201 92/8,609 67% improvement 2 casirivimab/imdevimab COVID-19 ICU results c19regn.com Jan 22, 2022 Tau​2 = 0.70, I​2 = 37.9%, p = 0.18 Favors casiri/imdevimab Favors control
Figure 6. Random effects meta-analysis for ICU admission.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Webb 91% 0.09 [0.01-0.63] hosp. 1/115 538/5,536 Improvement, RR [CI] Treatment Control Cooper 52% 0.48 [0.35-0.64] hosp. 45/1,148 703/8,534 Komagamine 29% 0.71 [0.58-0.87] hosp. time 53 (n) 75 (n) O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.10, I​2 = 68.5%, p = 0.0052 Early treatment 48% 0.52 [0.32-0.82] 46/1,416 1,244/14,249 48% improvement McCreary (PSM) 48% 0.52 [0.33-0.82] hosp. 22/652 85/1,304 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.0053 Late treatment 48% 0.52 [0.33-0.82] 22/652 85/1,304 48% improvement Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.08 Prophylaxis 92% 0.08 [0.00-1.36] 0/841 6/842 92% improvement All studies 49% 0.51 [0.36-0.73] 68/2,909 1,335/16,395 49% improvement 6 casirivimab/imdevimab COVID-19 hospitalization results c19regn.com Jan 22, 2022 Tau​2 = 0.08, I​2 = 58.0%, p = 0.00026 Favors casiri/imdevimab Favors control
Figure 7. Random effects meta-analysis for hospitalization.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Kakinoki 58% 0.42 [0.17-0.92] 13/55 22/53 Improvement, RR [CI] Treatment Control Komagamine 68% 0.32 [0.13-0.68] 8/53 33/75 Suzuki (PSM) 45% 0.55 [0.31-0.96] 17/222 31/222 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Early treatment 56% 0.44 [0.31-0.62] 38/330 86/350 56% improvement All studies 56% 0.44 [0.31-0.62] 38/330 86/350 56% improvement 3 casirivimab/imdevimab COVID-19 progression results c19regn.com Jan 22, 2022 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Favors casiri/imdevimab Favors control
Figure 8. Random effects meta-analysis for progression.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.30-1.28] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 29% 0.71 [0.60-0.85] recov. time 1,355 (n) 1,341 (n) Weinreich (RCT) 29% 0.71 [0.58-0.87] recov. time 1,355 (n) 1,341 (n) Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Early treatment 29% 0.71 [0.63-0.81] 0/2,802 0/2,773 29% improvement Somersan.. (DB RCT) 29% 0.71 [0.53-0.96] no disch. 92/804 63/393 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.026 Late treatment 29% 0.71 [0.53-0.96] 92/804 63/393 29% improvement Regeneron (DB RCT) 62% 0.38 [0.23-0.61] recov. time 753 (n) 752 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.0001 Prophylaxis 62% 0.38 [0.23-0.61] 0/753 0/752 62% improvement All studies 33% 0.67 [0.57-0.79] 92/4,359 63/3,918 33% improvement 5 casirivimab/imdevimab COVID-19 recovery results c19regn.com Jan 22, 2022 Tau​2 = 0.01, I​2 = 37.0%, p < 0.0001 Favors casiri/imdevimab Favors control
Figure 9. Random effects meta-analysis for recovery.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ O'Brien (DB RCT) 33% 0.67 [0.43-0.98] symp. case 29/100 44/104 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.039 Early treatment 33% 0.67 [0.43-0.98] 29/100 44/104 33% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 81% 0.19 [0.12-0.30] cases 20/841 108/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.05, I​2 = 11.7%, p < 0.0001 Prophylaxis 85% 0.15 [0.09-0.26] 23/1,756 129/1,305 85% improvement All studies 80% 0.20 [0.07-0.61] 52/1,856 173/1,409 80% improvement 4 casirivimab/imdevimab COVID-19 case results c19regn.com Jan 22, 2022 Tau​2 = 0.89, I​2 = 88.3%, p = 0.0043 Favors casiri/imdevimab Favors control
Figure 10. Random effects meta-analysis for cases.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ O'Brien (DB RCT) 40% 0.60 [0.45-0.81] viral load 100 (n) 104 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.001 Early treatment 40% 0.60 [0.45-0.81] 0/100 0/104 40% improvement Regeneron (DB RCT) 69% 0.31 [0.17-0.55] viral time 753 (n) 752 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 69% 0.31 [0.17-0.55] 0/753 0/752 69% improvement All studies 55% 0.45 [0.24-0.87] 0/853 0/856 55% improvement 2 casirivimab/imdevimab COVID-19 viral clearance results c19regn.com Jan 22, 2022 Tau​2 = 0.17, I​2 = 74.9%, p = 0.017 Favors casiri/imdevimab Favors control
Figure 11. Random effects meta-analysis for viral clearance.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 Improvement, RR [CI] Treatment Control Webb 98% 0.02 [0.00-0.27] death 0/115 57/5,536 Cooper 77% 0.23 [0.03-1.65] death 1/1,148 33/8,534 Komagamine 77% 0.23 [0.01-4.63] ventilation 0/53 2/75 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.08, I​2 = 5.3%, p = 0.0027 Early treatment 80% 0.20 [0.07-0.57] 3/3,507 99/16,338 80% improvement All studies 80% 0.20 [0.07-0.57] 3/3,507 99/16,338 80% improvement 5 casirivimab/imdevimab COVID-19 peer reviewed trials c19regn.com Jan 22, 2022 Tau​2 = 0.08, I​2 = 5.3%, p = 0.0027 Effect extraction pre-specified, see appendix Favors casiri/imdevimab Favors control
Figure 12. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.
The studies excluded are as below. Figure 13 shows a forest plot for random effects meta-analysis of all studies after exclusions.
[Cooper], unadjusted results with no group details.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.30-1.28] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 71% 0.29 [0.17-0.48] death/hosp. 18/1,355 62/1,341 Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 Webb 98% 0.02 [0.00-0.27] death 0/115 57/5,536 Kakinoki 58% 0.42 [0.17-0.92] progression 13/55 22/53 Komagamine 77% 0.23 [0.01-4.63] ventilation 0/53 2/75 Suzuki (PSM) -200% 3.00 [0.12-73.3] death 1/222 0/222 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.12, I​2 = 30.5%, p < 0.0001 Early treatment 62% 0.38 [0.24-0.61] 34/4,083 150/9,511 62% improvement Horby (RCT) 6% 0.94 [0.86-1.03] death 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] death 59/804 45/393 McCreary (PSM) 93% 0.07 [0.01-0.51] death 1/652 29/1,304 Tau​2 = 0.15, I​2 = 80.8%, p = 0.16 Late treatment 33% 0.67 [0.39-1.17] 1,004/6,295 1,100/6,643 33% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 0.07 [0.03-0.21] 3/1,756 27/1,305 93% improvement All studies 66% 0.34 [0.21-0.56] 1,041/12,134 1,277/17,459 66% improvement 14 casirivimab/imdevimab COVID-19 studies after exclusions c19regn.com Jan 22, 2022 Tau​2 = 0.43, I​2 = 81.1%, p < 0.0001 Effect extraction pre-specified, see appendix Favors casiri/imdevimab Favors control
Figure 13. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Randomized Controlled Trials (RCTs)
Figure 14 shows the distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results. Figure 15 and 16 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 2 summarizes the results.
Figure 14. The distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Regeneron (RCT) 38% 0.62 [0.30-1.28] recov. time 92 (n) 91 (n) Improvement, RR [CI] Treatment Control Regeneron (RCT) 71% 0.29 [0.17-0.48] death/hosp. 18/1,355 62/1,341 Weinreich (RCT) 50% 0.50 [0.09-2.72] death 2/2,091 4/2,089 O'Brien (DB RCT) 85% 0.15 [0.01-2.78] hosp. 0/100 3/104 Tau​2 = 0.03, I​2 = 11.1%, p < 0.0001 Early treatment 62% 0.38 [0.24-0.61] 20/3,638 69/3,625 62% improvement Horby (RCT) 6% 0.94 [0.86-1.03] death 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] death 59/804 45/393 Tau​2 = 0.05, I​2 = 74.8%, p = 0.26 Late treatment 19% 0.81 [0.56-1.17] 1,003/5,643 1,071/5,339 19% improvement Regeneron (RCT) 94% 0.06 [0.00-1.10] symp. case 0/186 8/223 Improvement, RR [CI] Treatment Control Regeneron (DB RCT) 92% 0.08 [0.00-1.36] hosp. 0/841 6/842 Isa (DB RCT) 93% 0.07 [0.01-0.28] symp. case 3/729 13/240 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Prophylaxis 93% 0.07 [0.03-0.21] 3/1,756 27/1,305 93% improvement All studies 61% 0.39 [0.23-0.68] 1,026/11,037 1,167/10,269 61% improvement 9 casirivimab/imdevimab COVID-19 Randomized Controlled Trials c19regn.com Jan 22, 2022 Tau​2 = 0.38, I​2 = 83.1%, p = 0.00097 Effect extraction pre-specified, see appendix Favors casiri/imdevimab Favors control
Figure 15. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Weinreich (RCT) 50% 0.50 [0.09-2.72] 2/2,091 4/2,089 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.43 Early treatment 50% 0.50 [0.09-2.72] 2/2,091 4/2,089 50% improvement Horby (RCT) 6% 0.94 [0.86-1.03] 944/4,839 1,026/4,946 Improvement, RR [CI] Treatment Control Somersan.. (DB RCT) 36% 0.64 [0.44-0.93] 59/804 45/393 Tau​2 = 0.05, I​2 = 74.8%, p = 0.26 Late treatment 19% 0.81 [0.56-1.17] 1,003/5,643 1,071/5,339 19% improvement All studies 20% 0.80 [0.58-1.11] 1,005/7,734 1,075/7,428 20% improvement 3 casirivimab/imdevimab COVID-19 RCT mortality results c19regn.com Jan 22, 2022 Tau​2 = 0.04, I​2 = 55.2%, p = 0.19 Favors casiri/imdevimab Favors control
Figure 16. Random effects meta-analysis for RCT mortality results. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 9 9 100% 61% improvement
RR 0.39 [0.23‑0.68]
p = 0.00097
RCT mortality results 3 3 100% 20% improvement
RR 0.80 [0.58‑1.11]
p = 0.19
Table 2. Randomized Controlled Trial results.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
Treatment delay.
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours [McLean, Treanor]. Other medications might be beneficial for late stage complications, while early use may not be effective or may even be harmful. Figure 17 shows an example where efficacy declines as a function of treatment delay.
Figure 17. Effectiveness may depend critically on treatment delay.
Patient demographics.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in [López-Medina]).
Effect measured.
Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.
Variants.
There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics [Faria, Karita, Nonaka, Zavascki]. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective [Peacock, Willett].
Regimen.
Effectiveness may depend strongly on the dosage and treatment regimen.
Treatments.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though the treatment may be very effective when used earlier.
In general, by combining heterogeneous studies, as all meta analyses do, we run the risk of obscuring an effect by including studies where the treatment is less effective, not effective, or harmful.
When including studies where a treatment is less effective we expect the estimated effect size to be lower than that for the optimal case. We do not a priori expect that pooling all studies will create a positive result for an effective treatment. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations.
Discussion
Publication bias.
Publishing is often biased towards positive results. Trials with patented drugs may have a financial conflict of interest that results in positive studies being more likely to be published, or bias towards more positive results. For example with molnupiravir, several trials with negative results remain unpublished to date (NCT04575584, CTRI/2021/05/033864, and CTRI/2021/08/0354242). For casirivimab/imdevimab, there is currently not enough data to evaluate publication bias with high confidence.
One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
The median effect size for retrospective studies is 77% improvement, compared to 78% for prospective studies, consistent with a negative publication bias. 100% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 80% of prospective studies, consistent with a bias toward publishing positive results. Figure 18 shows a scatter plot of results for prospective and retrospective studies.
Figure 18. Prospective vs. retrospective studies.
Early/late vs. mild/moderate/severe.
Some analyses classify treatment based on early/late administration (as we do here), while others distinguish between mild/moderate/severe cases. We note that viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Conclusion
Casirivimab/imdevimab is an effective treatment for COVID-19. Statistically significant improvements are seen for mortality, hospitalization, progression, recovery, cases, and viral clearance. 13 studies from 8 independent teams in 3 different countries show statistically significant improvements in isolation (6 for the most serious outcome). Meta analysis using the most serious outcome reported shows 66% [45‑80%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and better for peer-reviewed studies. Early treatment is more effective than late treatment. Results are robust — in exclusion sensitivity analysis 10 of 15 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Efficacy is variant dependent. In Vitro studies suggest a lack of efficacy for omicron [Liu, Sheward, VanBlargan]. Monoclonal antibody use with variants can be associated with prolonged viral loads, clinical deterioration, and immune escape [Choudhary].
Study Notes
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 77% Improvement Relative Risk ICU admission 48% Hospitalization 52% c19regn.com/cooperr.html Favors casiri/imdevimab Favors control
[Cooper] Retrospective 2,879 patients and matched controls in the USA, showing significantly lower mortality and hospitalization with bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab. There was significantly lower hospitalization with casirivimab/imdevimab compared to bamlanivimab or bamlanivimab/etesevimab. PSM and multivariate analysis is only provided for all treatments combined.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 6% Improvement Relative Risk Mechanical ventilation 0% Mortality (b) 20% Mechanical ventilation (b) 12% c19regn.com/horbyr.html Favors casiri/imdevimab Favors control
[Horby] RCT 9,785 hospitalized patients in the UK showing lower mortality with casirivimab/imdevimab, with statistical significance reached for baseline seronegative patients.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Symptomatic case 93% Improvement Relative Risk Case 93% c19regn.com/isa.html Favors casiri/imdevimab Favors control
[Isa] RCT 969 patients, 729 treated with monthly subcutaneous casirivimab/imdevimab, showing significantly lower risk of COVID-19 with treatment. There were no grade 3 injection site reactions or hypersensitivity reactions. Slightly more TEAEs were reported with treatment (54.9% vs. 48.3%), due to grade 1-2 ISRs. Serious adverse events were rare and occurred with similar percentages for treatment and control groups. There were no deaths. NCT04519437.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Further treatment incl.. 58% Improvement Relative Risk