<table><caption>Table S15: Baseline characteristics of survivors with and without WHODAS scores</caption><thead><tr><th>Characteristic</th><th>WHODAS score available<br>N=720</th><th>Missing WHODAS score<br>N=1867</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>59 (51 - 67)</td><td>57 (48 - 64)</td></tr><tr><td>Male sex, n (%)</td><td>482 (66.9)</td><td>1230 (65.9)</td></tr><tr><td>Female sex, n (%)</td><td>238 (33.1)</td><td>637 (34.1)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>37/391 (9.5)</td><td>195/1527 (12.8)</td></tr><tr><td>Black</td><td>19/391 (4.9)</td><td>72/1527 (4.7)</td></tr><tr><td>Mixed</td><td>5/391 (1.3)</td><td>35/1527 (2.3)</td></tr><tr><td>Other <sup>a</sup></td><td>17/391 (4.4)</td><td>84/1527 (5.5)</td></tr><tr><td>White</td><td>313/391 (80.1)</td><td>1141/1527 (74.7)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>604/713 (84.7)</td><td>1623/1862 (87.2)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.8 (27.1 - 35.9) [N=671]</td><td>31.4 (27.2 - 36.8) [N=1712]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>11 (8-17) [N=695]</td><td>12 (8-18) [N=1834]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>210/720 (29.2)</td><td>496/1867 (26.6)</td></tr><tr><td>Respiratory disease</td><td>163/720 (22.6)</td><td>384/1867 (20.6)</td></tr><tr><td>Asthma/COPD</td><td>137/720 (19.0)</td><td>332/1867 (17.8)</td></tr><tr><td>Other</td><td>37/720 (5.1)</td><td>70/1867 (3.8)</td></tr><tr><td>Kidney disease</td><td>40/672 (6.0)</td><td>100/1726 (5.8)</td></tr><tr><td>Severe cardiovascular disease</td><td>39/706 (5.5)</td><td>113/1832 (6.2)</td></tr><tr><td>Immunosuppressive disease</td><td>24/720 (3.3)</td><td>33/1867 (1.8)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>29/720 (4.0)</td><td>46/1867 (2.5)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.5 (0.9 - 3.0)</td><td>1.6 (0.9 -3.0)</td></tr><tr><td>From ICU admission, hours</td><td>16.1 (8.4 - 21.8)</td><td>16.5 (8.9 - 22.1)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>1 (0.1)</td><td>3 (0.2)</td></tr><tr><td>High flow nasal cannula</td><td>298 (41.4)</td><td>483 (25.9)</td></tr><tr><td>Non-invasive ventilation only</td><td>214 (29.7)</td><td>728 (39.0)</td></tr><tr><td>Invasive mechanical ventilation</td><td>207 (28.8)</td><td>653 (35.0)</td></tr><tr><td>ECMO, n/N (%)</td><td>0/711 (0.0)</td><td>1/1845 (0.1)</td></tr><tr><td>Vasopressor support, n (%)</td><td>134 (18.6)</td><td>352 (18.9)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>121 (91 - 165) [N=657]</td><td>121 (93 - 163) [N=1779]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>117 (69 - 182) [N=480]</td><td>119 (64 - 189) [N=1481]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.7 - 1.0) [N=698]</td><td>0.8 (0.7 - 1.0) [N=1845]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.8) [N=631]</td><td>1.2 (1.0 - 1.7) [N=1723]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>257 (201 - 326) [N=699]</td><td>251 (194 - 321) [N=1842]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.7) [N=634]</td><td>0.5 (0.4 - 0.8) [N=1779]</td></tr></tbody></table>

Percentages may not sum to 100 because of rounding. SD denotes standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; ECMO, extracorporeal membrane oxygenation.

<sup>a</sup>Self-reported via fixed categories. Data collection was not approved in Asia, Canada, and continental Europe. "Other" includes "other ethnic group" and those who declined to respond or were not asked by registration personnel.

<sup>b</sup>SARS-CoV2 infection was confirmed by respiratory tract polymerase chain reaction test.

<sup>c</sup>Measures the severity of illness based on age, medical history, and physiological variables. Scores range from 0 to 71; higher numbers represent greater risk of death. The median score of 12 is typical for patients with COVID-19 admitted to intensive care units (ICUs).
<sup>d</sup>Kidney disease was determined from the most recent stable serum creatinine level prior to this hospital admission, except in patients who were receiving dialysis. Abnormal kidney function was defined as a creatinine level of 130 µmol/L or greater (1.5mg/dL) for males or 100 µmol/L or greater (1.1 mg/dL) for females not previously receiving dialysis. Cardiovascular disease was defined as New York Heart Association class IV symptoms. Immunosuppression was defined by the receipt of recent chemotherapy, radiation, high-dose or long-term steroid treatment, or presence of immunosuppressive disease.

<sup>e</sup>Laboratory results available when captured for clinical care. Although specific laboratory cut-offs may vary, ranges for the following variables are generally considered normal: $P_3O_2/FiO_2$ ratio ≥400; creatinine <1.2 mg/dL; platelets ≥150 x10<sup>9</sup>/L; and bilirubin <1.2 mg/dL.
Table S16: Day 180 EQ-5D-5L results

<table><thead><tr><th rowspan="3"></th><th colspan="12">EQ-5D-5L domain n/N (%)</th></tr><tr><th colspan="2">Mobility</th><th colspan="2">Self Care</th><th colspan="2">Usual Activities</th><th colspan="2">Pain/Discomfort</th><th colspan="2">Anxiety/Depression</th></tr><tr><th>No Problems</th><th>Problems <sup>a</sup></th><th>No Problems</th><th>Problems <sup>a</sup></th><th>No Problems</th><th>Problems <sup>a</sup></th><th>No Problems</th><th>Problems <sup>a</sup></th><th>No Problems</th><th>Problems <sup>a</sup></th></tr></thead><tbody><tr><td colspan="11"><strong>Immune Modulation Domain</strong></td></tr><tr><td>Tocilizumab</td><td>106/231<br>(45.9)</td><td>125/231<br>(54.1)</td><td>164/234<br>(70.1)</td><td>70/234<br>(29.9)</td><td>90/235<br>(38.3)</td><td>145/235<br>(61.7)</td><td>92/233<br>(39.5)</td><td>141/233<br>(60.5)</td><td>131/234<br>(56.0)</td><td>103/234<br>(44.0)</td></tr><tr><td>Sarilumab</td><td>22/75<br>(29.3)</td><td>53/75<br>(70.7)</td><td>44/76<br>(57.9)</td><td>32/76<br>(42.1)</td><td>24/76<br>(31.6)</td><td>52/76<br>(68.4)</td><td>27/76<br>(35.5)</td><td>49/76<br>(64.5)</td><td>30/76<br>(39.5)</td><td>46/76<br>(60.5)</td></tr><tr><td>Anakinra</td><td>40/80<br>(50.0)</td><td>40/80<br>(50.0)</td><td>61/80<br>(76.3)</td><td>19/80<br>(23.8)</td><td>32/78<br>(41.0)</td><td>46/78<br>(59.0)</td><td>33/80<br>(41.3)</td><td>47/80<br>(58.8)</td><td>46/80<br>(57.5)</td><td>34/80<br>(42.5)</td></tr><tr><td>Control</td><td>31/93<br>(33.3)</td><td>62/93<br>(66.7)</td><td>59/97<br>(60.8)</td><td>38/97<br>(39.2)</td><td>31/97<br>(32.0)</td><td>66/97<br>(68.0)</td><td>38/97<br>(39.2)</td><td>59/97<br>(60.8)</td><td>45/96<br>(46.9)</td><td>51/96<br>(53.1)</td></tr><tr><td colspan="11"><strong>Immunoglobulin Domain</strong></td></tr><tr><td>Convalescent plasma</td><td>83/218<br>(38.1)</td><td>135/218<br>(61.9)</td><td>139/217<br>(64.1)</td><td>78/217<br>(35.9)</td><td>79/218<br>(36.2)</td><td>139/218<br>(63.8)</td><td>77/218<br>(35.3)</td><td>141/218<br>(64.7)</td><td>100/217<br>(46.1)</td><td>117/217<br>(53.9)</td></tr><tr><td>Control</td><td>64/176<br>(36.4)</td><td>112/176<br>(63.6)</td><td>113/177<br>(63.8)</td><td>64/177<br>(36.2)</td><td>58/177<br>(32.8)</td><td>119/177<br>(67.2)</td><td>63/176<br>(35.8)</td><td>113/176<br>(64.2)</td><td>79/176<br>(44.9)</td><td>97/176<br>(55.1)</td></tr><tr><td colspan="11"><strong>Antiplatelet Domain</strong></td></tr><tr><td>Aspirin</td><td>27/83<br>(32.5)</td><td>56/83<br>(67.5)</td><td>55/84<br>(65.5)</td><td>29/84<br>(34.5)</td><td>32/84<br>(38.1)</td><td>52/84<br>(61.9)</td><td>39/84<br>(46.4)</td><td>45/84<br>(53.6)</td><td>36/83<br>(43.4)</td><td>47/83<br>(56.6)</td></tr><tr><td>P2Y12 inhibitor</td><td>41/82<br>(50.0)</td><td>41/82<br>(50.0)</td><td>63/83<br>(75.9)</td><td>20/83<br>(24.1)</td><td>35/82<br>(42.7)</td><td>47/82<br>(57.3)</td><td>33/83<br>(39.8)</td><td>50/83<br>(60.2)</td><td>45/83<br>(54.2)</td><td>38/83<br>(45.8)</td></tr><tr><td>Control</td><td>31/95<br>(32.6)</td><td>64/95<br>(67.4)</td><td>63/95<br>(66.3)</td><td>32/95<br>(33.7)</td><td>36/95<br>(37.9)</td><td>59/95<br>(62.1)</td><td>28/95<br>(29.5)</td><td>67/95<br>(70.5)</td><td>42/95<br>(44.2)</td><td>53/95<br>(55.8)</td></tr><tr><td colspan="11"><strong>Anticoagulation Domain</strong></td></tr><tr><td>Therapeutic<br>anticoagulation</td><td>53/118<br>(44.9)</td><td>65/118<br>(55.1)</td><td>79/120<br>(65.8)</td><td>41/120<br>(34.2)</td><td>51/120<br>(42.5)</td><td>69/120<br>(57.5)</td><td>49/119<br>(41.2)</td><td>70/119<br>(58.8)</td><td>62/119<br>(52.1)</td><td>57/119<br>(47.9)</td></tr><tr><td>Thromboprophylaxis</td><td>51/124<br>(41.1)</td><td>73/124<br>(58.9)</td><td>87/125<br>(69.6)</td><td>38/125<br>(30.4)</td><td>51/125<br>(40.8)</td><td>74/125<br>(59.2)</td><td>50/125<br>(40.0)</td><td>75/125<br>(60.0)</td><td>61/125<br>(48.8)</td><td>64/125<br>(51.2)</td></tr><tr><td colspan="11"><strong>Antiviral Domain</strong></td></tr><tr><td>Lopinavir-ritonavir</td><td>29/76<br>(38.2)</td><td>47/76<br>(61.8)</td><td>47/81<br>(58.0)</td><td>34/81<br>(42.0)</td><td>32/82<br>(39.0)</td><td>50/82<br>(61.0)</td><td>29/82<br>(35.4)</td><td>53/82<br>(64.6)</td><td>35/81<br>(43.2)</td><td>46/81<br>(56.8)</td></tr><tr><td>Hydroxychloroquine</td><td>1/1<br>(100)</td><td>0/1 (0.0)</td><td>1/1<br>(100)</td><td>0/1 (0.0)</td><td>1/1<br>(100)</td><td>0/1 (0.0)</td><td>1/1<br>(100)</td><td>0/1 (0.0)</td><td>1/1<br>(100)</td><td>0/1 (0.0)</td></tr><tr><td>Combination antiviral<br>therapy</td><td>1/2<br>(50.0)</td><td>1/2<br>(50.0)</td><td>2/2<br>(100)</td><td>0/2 (0.0)</td><td>1/2<br>(50.0)</td><td>1/2<br>(50.0)</td><td>0/2 (0.0)</td><td>2/2<br>(100)</td><td>0/2 (0.0)</td><td>2/2<br>(100)</td></tr><tr><td>Control</td><td>48/102<br>(47.1)</td><td>54/102<br>(52.9)</td><td>68/103<br>(66.0)</td><td>35/103<br>(34.0)</td><td>45/103<br>(43.7)</td><td>58/103<br>(56.3)</td><td>50/103<br>(48.5)</td><td>53/103<br>(51.5)</td><td>56/102<br>(54.9)</td><td>46/102<br>(45.1)</td></tr><tr><td colspan="11"><strong>Corticosteroid Domain</strong></td></tr><tr><td>Fixed dose<br>corticosteroids</td><td>16/27<br>(59.3)</td><td>11/27<br>(40.7)</td><td>23/27<br>(85.2)</td><td>4/27<br>(14.8)</td><td>17/27<br>(63.0)</td><td>10/27<br>(37.0)</td><td>14/27<br>(51.9)</td><td>13/27<br>(48.2)</td><td>17/27<br>(63.0)</td><td>10/27<br>(37.0)</td></tr><tr><td>Shock-dependent<br>corticosteroids</td><td>19/35<br>(54.3)</td><td>16/35<br>(45.7)</td><td>29/36<br>(80.6)</td><td>7/36<br>(19.4)</td><td>21/36<br>(58.3)</td><td>15/36<br>(41.7)</td><td>15/36<br>(41.7)</td><td>21/36<br>(58.3)</td><td>26/35<br>(74.3)</td><td>9/35<br>(25.7)</td></tr><tr><td>Control</td><td>10/21<br>(47.6)</td><td>11/21<br>(52.4)</td><td>14/21<br>(66.7)</td><td>7/21<br>(33.3)</td><td>9/21<br>(42.9)</td><td>12/21<br>(57.1)</td><td>14/21<br>(66.7)</td><td>7/21<br>(33.3)</td><td>12/21<br>(57.1)</td><td>9/21<br>(42.9)</td></tr></tbody></table>

<footnote>a Patients reporting problems includes patients reporting mild problems, moderate problems, severe problems or extreme problems</footnote>
<table><caption>Table S17: Day 180 EQ VAS results</caption><thead><tr><th rowspan="2"></th><th rowspan="2">n</th><th colspan="2">EQ VAS</th></tr><tr><th>Mean (SD)</th><th>Median (IQR)</th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Tocilizumab</td><td>235</td><td>69.1 (22.6)</td><td>75 (50 – 86)</td></tr><tr><td>Sarilumab</td><td>76</td><td>63.4 (25.5)</td><td>70 (50 – 81)</td></tr><tr><td>Anakinra</td><td>75</td><td>70.9 (21.3)</td><td>75 (70 – 80)</td></tr><tr><td>Control</td><td>97</td><td>68.5 (20.7)</td><td>75 (60 – 85)</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>218</td><td>65.0 (23.7)</td><td>70 (50 – 82)</td></tr><tr><td>Control</td><td>177</td><td>65.4 (23.0)</td><td>70 (50 – 80)</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Aspirin</td><td>84</td><td>65.7 (22.3)</td><td>70 (50 – 85)</td></tr><tr><td>P2Y12 inhibitor</td><td>83</td><td>71.3 (20.1)</td><td>75 (50 – 90)</td></tr><tr><td>Control</td><td>96</td><td>66.1 (21.0)</td><td>70 (50 – 80)</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>119</td><td>71.8 (20.0)</td><td>78 (60 – 85)</td></tr><tr><td>Thromboprophylaxis</td><td>124</td><td>68.6 (20.6)</td><td>75 (50 – 80)</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>82</td><td>67.7 (23.1)</td><td>73 (50 – 90)</td></tr><tr><td>Hydroxychloroquine</td><td>1</td><td>NA</td><td>70 (70 – 70)</td></tr><tr><td>Combination antiviral therapy</td><td>2</td><td>NA</td><td>100 (100 – 100)</td></tr><tr><td>Control</td><td>103</td><td>72.2 (20.8)</td><td>75 (60 – 90)</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>27</td><td>76.9 (17.4)</td><td>80 (70 – 90)</td></tr><tr><td>Shock-dependent corticosteroids</td><td>36</td><td>74.0 (22.2)</td><td>80 (70 – 90)</td></tr><tr><td>Control</td><td>21</td><td>69.0 (22.5)</td><td>75 (60 – 85)</td></tr></tbody></table>

SD denotes standard deviation; IQR, interquartile range
Table S18: Day 180 Disability Categories

<table><thead><tr><th rowspan="2"></th><th colspan="5">WHODAS category n/N (%)</th></tr><tr><th>No Disability</th><th>Mild Disability</th><th>Moderate Disability</th><th>Severe Disability</th><th>Complete Disability</th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tocilizumab</td><td>49/159 (30.8)</td><td>46/159 (28.9)</td><td>38/159 (23.9)</td><td>25/159 (15.7)</td><td>1/159 (0.6)</td></tr><tr><td>Sarilumab</td><td>12/44 (27.3)</td><td>14/44 (31.8)</td><td>8/44 (18.2)</td><td>10/44 (22.7)</td><td>0/44 (0.0)</td></tr><tr><td>Anakinra</td><td>19/58 (32.8)</td><td>17/58 (29.3)</td><td>14/58 (24.1)</td><td>8/58 (13.8)</td><td>0/58 (0.0)</td></tr><tr><td>Control</td><td>12/58 (20.7)</td><td>18/58 (31.0)</td><td>17/58 (29.3)</td><td>9/58 (15.5)</td><td>2/58 (3.4)</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>40/152 (26.3)</td><td>48/152 (31.6)</td><td>35/152 (23.0)</td><td>25/152 (16.4)</td><td>4/152 (2.6)</td></tr><tr><td>Control</td><td>29/115 (25.2)</td><td>47/115 (40.9)</td><td>20/115 (17.4)</td><td>19/115 (16.5)</td><td>0/115 (0.0)</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Aspirin</td><td>15/60 (25.0)</td><td>18/60 (30.0)</td><td>15/60 (25.0)</td><td>12/60 (20.0)</td><td>0/60 (0.0)</td></tr><tr><td>P2Y12 inhibitor</td><td>22/62 (35.5)</td><td>24/62 (38.7)</td><td>9/62 (14.5)</td><td>7/62 (11.3)</td><td>0/62 (0.0)</td></tr><tr><td>Control</td><td>19/70 (27.1)</td><td>23/70 (32.9)</td><td>16/70 (22.9)</td><td>11/70 (15.7)</td><td>1/70 (1.4)</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>27/82 (32.9)</td><td>28/82 (34.1)</td><td>19/82 (23.2)</td><td>7/82 (8.5)</td><td>1/82 (1.2)</td></tr><tr><td>Thromboprophylaxis</td><td>27/92 (29.3)</td><td>34/92 (37)</td><td>20/92 (21.7)</td><td>10/92 (10.9)</td><td>1/92 (1.1)</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>18/61 (29.5)</td><td>12/61 (19.7)</td><td>19/61 (31.1)</td><td>11/61 (18.0)</td><td>1/61 (1.6)</td></tr><tr><td>Hydroxychloroquine</td><td>1/1 (100)</td><td>0/1 (0.0)</td><td>0/1 (0.0)</td><td>0/1 (0.0)</td><td>0/1 (0.0)</td></tr><tr><td>Combination antiviral therapy</td><td>0/2 (0.0)</td><td>2/2 (100)</td><td>0/2 (0.0)</td><td>0/2 (0.0)</td><td>0/2 (0.0)</td></tr><tr><td>Control</td><td>28/74 (37.8)</td><td>17/74 (23.0)</td><td>18/74 (24.3)</td><td>11/74 (14.9)</td><td>0/74 (0.0)</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>12/24 (50.0)</td><td>6/24 (25.0)</td><td>4/24 (16.7)</td><td>2/24 (8.3)</td><td>0/24 (0.0)</td></tr><tr><td>Shock-dependent corticosteroids</td><td>13/31 (41.9)</td><td>12/31 (38.7)</td><td>5/31 (16.1)</td><td>1/31 (3.2)</td><td>0/31 (0.0)</td></tr><tr><td>Control</td><td>6/19 (31.6)</td><td>6/19 (31.6)</td><td>3/19 (15.8)</td><td>4/19 (21.1)</td><td>0/19 (0.0)</td></tr></tbody></table>
<table><caption>Table S19: Day 180 Disability</caption><thead><tr><th></th><th>N (survivors at day 180)</th><th>WHODAS score, median (IQR) [N]</th><th>Adjusted Odds Ratio<sup>a</sup> (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>812</td><td>14.6 (3.2-36.4) [N=203]</td><td>0.67 (0.39 to 1.15)</td><td>92.6%</td></tr><tr><td>Anakinra</td><td>187</td><td>16.7 (2.1-35.4) [N=58]</td><td>0.62 (0.30 to 1.26)</td><td>90.8%</td></tr><tr><td>Control</td><td>210</td><td>21.8 (8.3-30.8) [N=58]</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>574</td><td>17.4 (4.2-41.1) [N=152]</td><td>1.14 (0.72 to 1.77)</td><td>28.6%</td></tr><tr><td>Control</td><td>466</td><td>12.5 (4.4-31.2) [N=115]</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>597</td><td>12.5 (2.1-30.8) [N=122]</td><td>0.78 (0.46 to 1.33)</td><td>81.6%</td></tr><tr><td>Control</td><td>298</td><td>14.6 (4.2-38.5) [N=70]</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>238</td><td>10.4 (2.1-31.2) [N=82]</td><td>1.07 (0.61 to 1.86)</td><td>41.2%</td></tr><tr><td>Thromboprophylaxis</td><td>271</td><td>13.6 (4.2-29.3) [N=92]</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>145</td><td>25 (4.2-38.6) [N=61]</td><td>1.56 (0.84 to 2.93)</td><td>8.3%</td></tr><tr><td>Hydroxychloroquine</td><td>25</td><td>0 (0-0) [N=1]</td><td>NA</td><td>NA</td></tr><tr><td>Combination antiviral therapy</td><td>13</td><td>15.1 (13.2-16.9) [N=2]</td><td>NA</td><td>NA</td></tr><tr><td>Control</td><td>204</td><td>12.5 (0-28.4) [N=74]</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>74</td><td>5.2 (2.1-20.3) [N=24]</td><td>0.75 (0.29 to 2.00)</td><td>72.3%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>98</td><td>8.3 (2.1-19.8) [N=31]</td><td>0.85 (0.35 to 2.07)</td><td>63.9%</td></tr><tr><td>Control</td><td>52</td><td>10.4 (3.2-32.3) [N=19]</td><td>1 (referent)</td><td>-</td></tr></tbody></table>

IQR denotes interquartile range; CrI, credible interval.

<footnote>a Odds ratio parameters are for the analysis of WHODAS disability category. An OR<1 indicates reduced disability.</footnote>

<footnote>b The probability of superiority is computed from the posterior distribution of a Bayesian mixture model.</footnote>
<table><caption>Table S20: Sensitivity Analysis of EQ-5D-5L utility score without imputation</caption><thead><tr><th></th><th>Adjusted Mean Difference<br>(95% CrI)</th><th>Probability of Superiority<br>of Intervention (%)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td></tr><tr><td>IL-6 Receptor Antagonists</td><td>0.04 (-0.03 to 0.12)</td><td>87.2%</td></tr><tr><td>Anakinra</td><td>0.07 (-0.03 to 0.18)</td><td>92.2%</td></tr><tr><td>Control</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>-0.03 (-0.09 to 0.03)</td><td>18.4%</td></tr><tr><td>Control</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>0.08 (0.00 to 0.16)</td><td>98.0%</td></tr><tr><td>Control</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>0.01 (-0.07 to 0.09)</td><td>60.6%</td></tr><tr><td>Thromboprophylaxis</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>-0.10 (-0.19 to -0.01)</td><td>1.3%</td></tr><tr><td>Hydroxychloroquine</td><td>NA</td><td>NA</td></tr><tr><td>Combination antiviral therapy</td><td>NA</td><td>NA</td></tr><tr><td>Control</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>-0.01 (-0.17 to 0.16)</td><td>46.3%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>-0.02 (-0.17 to 0.14)</td><td>42.5%</td></tr><tr><td>Control</td><td>0 (referent)</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote>a The probability of superiority is computed from the posterior distribution of a Bayesian mixture model.</footnote>
<table><caption>Table S21: Sensitivity Analysis of WHODAS disability category without imputation</caption><thead><tr><th></th><th>Adjusted Odds Ratio<sup>a</sup><br>(95% CrI)</th><th>Probability of Superiority<br>of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td></tr><tr><td>IL-6 Receptor Antagonists</td><td>0.69 (0.40 to 1.19)</td><td>91.1%</td></tr><tr><td>Anakinra</td><td>0.62 (0.30 to 1.26)</td><td>90.5%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>1.14 (0.72 to 1.78)</td><td>27.9%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>0.78 (0.45 to 1.35)</td><td>81.2%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>1.05 (0.60 to 1.83)</td><td>43.0%</td></tr><tr><td>Thromboprophylaxis</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>1.56 (0.84 to 2.93)</td><td>8.2%</td></tr><tr><td>Hydroxychloroquine</td><td>NA</td><td>NA</td></tr><tr><td>Combination antiviral therapy</td><td>NA</td><td>NA</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>0.77 (0.29 to 2.03)</td><td>69.4%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>0.88 (0.35 to 2.18)</td><td>60.9%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote>a Odds ratio parameters are for the analysis of WHODAS disability category. An OR<1 indicates reduced disability.</footnote>

<footnote>b The probability of superiority is computed from the posterior distribution of a Bayesian mixture model.</footnote>
<table><caption>Table S22: Day 180 mortality in patients mechanically ventilated at baseline</caption><thead><tr><th></th><th>N</th><th>Day 180 mortality<sup>a</sup>, n/N (%)</th><th>Hazard Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>b</sup></th><th>Probability of Futility of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>467</td><td>188/437 (43.0)</td><td>0.70 (0.51 to 1.00)</td><td>97.5%</td><td>15.9%</td></tr><tr><td>Anakinra</td><td>137</td><td>70/128 (54.7)</td><td>0.93 (0.62 to 1.41)</td><td>63.9%</td><td>69.1%</td></tr><tr><td>Control</td><td>123</td><td>58/115 (50.4)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>357</td><td>159/333 (47.8)</td><td>0.93 (0.74 to 1.17)</td><td>72.5%</td><td>83.8%</td></tr><tr><td>Control</td><td>291</td><td>145/276 (52.5)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>373</td><td>126/317 (39.7)</td><td>0.93 (0.70 to 1.28)</td><td>69.2%</td><td>77.0%</td></tr><tr><td>Control</td><td>194</td><td>62/155 (40.0)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>147</td><td>69/132 (52.3)</td><td>1.30 (0.91 to 1.84)</td><td>7.0%</td><td>99.4%</td></tr><tr><td>Thromboprophylaxis</td><td>166</td><td>63/148 (42.6)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>73</td><td>36/70 (51.4)</td><td>1.20 (0.79 to 1.78)</td><td>20.0%</td><td>96.0%</td></tr><tr><td>Hydroxychloroquine</td><td>26</td><td>7/19 (36.8)</td><td>1.10 (0.59 to 1.96)</td><td>37.7%</td><td>82.0%</td></tr><tr><td>Combination antiviral therapy</td><td>13</td><td>7/12 (58.3)</td><td>1.31 (0.63 to 2.70)</td><td>23.0%</td><td>89.2%</td></tr><tr><td>Control</td><td>114</td><td>46/102 (45.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>87</td><td>20/67 (29.9)</td><td>1.08 (0.58 to 2.03)</td><td>40.7%</td><td>78.9%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>74</td><td>21/72 (29.2)</td><td>1.04 (0.55 to 2.02)</td><td>44.5%</td><td>75.6%</td></tr><tr><td>Control</td><td>53</td><td>10/41 (24.4)</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote><sup>a</sup>Due to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status.</footnote>

<footnote><sup>b</sup>The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
<table><caption>Table S23: Day 180 mortality in patients not mechanically ventilated at baseline</caption><thead><tr><th></th><th>N</th><th>Day 180 mortality<sup>a</sup>, n/N (%)</th><th>Hazard Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>b</sup></th><th>Probability of Futility of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>966</td><td>248/811 (30.6)</td><td>0.76 (0.59 to 0.98)</td><td>98.2%</td><td>22.4%</td></tr><tr><td>Anakinra</td><td>234</td><td>68/197 (34.5)</td><td>0.93 (0.67 to 1.28)</td><td>67.8%</td><td>72.7%</td></tr><tr><td>Control</td><td>283</td><td>82/235 (34.9)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>721</td><td>211/611 (34.5)</td><td>1.03 (0.86 to 1.24)</td><td>37.0%</td><td>98.8%</td></tr><tr><td>Control</td><td>620</td><td>179/514 (34.8)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>646</td><td>148/554 (26.7)</td><td>0.80 (0.62 to 1.05)</td><td>94.7%</td><td>38.3%</td></tr><tr><td>Control</td><td>333</td><td>81/286 (28.3)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>352</td><td>96/271 (35.4)</td><td>1.12 (0.86 to 1.46)</td><td>19.7%</td><td>98.6%</td></tr><tr><td>Thromboprophylaxis</td><td>345</td><td>84/270 (31.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>183</td><td>45/156 (28.9)</td><td>1.02 (0.74 to 1.41)</td><td>45.0%</td><td>89.0%</td></tr><tr><td>Hydroxychloroquine</td><td>24</td><td>9/22 (40.9)</td><td>1.85 (1.01 to 3.28)</td><td>2.3%</td><td>99.3%</td></tr><tr><td>Combination antiviral therapy</td><td>14</td><td>6/14 (42.9)</td><td>1.89 (0.93 to 3.70)</td><td>3.8%</td><td>98.7%</td></tr><tr><td>Control</td><td>248</td><td>61/209 (29.2)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>50</td><td>14/42 (33.3)</td><td>0.93 (0.48 to 1.74)</td><td>60.1%</td><td>63.0%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>73</td><td>18/65 (27.7)</td><td>0.94 (0.49 to 1.70)</td><td>57.7%</td><td>65.3%</td></tr><tr><td>Control</td><td>48</td><td>17/38 (44.7)</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote>a Due to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status.</footnote>

<footnote>b The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
<table><caption>Table S24: Day 180 mortality in immune deficient patients<sup>a</sup></caption><thead><tr><th></th><th>N</th><th>Day 180 mortality<sup>b</sup>, n/N (%)</th><th>Hazard Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>c</sup></th><th>Probability of Futility of Intervention (%)<sup>c</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>36</td><td>16/31 (51.6)</td><td>0.94 (0.43 to 2.19)</td><td>55.8%</td><td>61.4%</td></tr><tr><td>Anakinra</td><td>6</td><td>3/5 (60.0)</td><td>1.38 (0.41 to 4.13)</td><td>29.5%</td><td>79.5%</td></tr><tr><td>Control</td><td>18</td><td>8/17 (47.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>67</td><td>30/64 (46.9)</td><td>0.67 (0.41 to 1.13)</td><td>93.4%</td><td>20.3%</td></tr><tr><td>Control</td><td>61</td><td>33/53 (62.3)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>43</td><td>28/41 (68.3)</td><td>1.63 (0.82 to 3.42)</td><td>7.6%</td><td>97.3%</td></tr><tr><td>Control</td><td>23</td><td>11/22 (50.0)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>31</td><td>20/28 (71.4)</td><td>2.33 (1.11 to 5.20)</td><td>1.2%</td><td>99.7%</td></tr><tr><td>Thromboprophylaxis</td><td>25</td><td>8/24 (33.3)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>15</td><td>7/15 (46.7)</td><td>1.05 (0.43 to 2.46)</td><td>45.7%</td><td>69.5%</td></tr><tr><td>Hydroxychloroquine</td><td>2</td><td>2/2 (100)</td><td>3.17 (0.75 to 12.30)</td><td>5.8%</td><td>96.7%</td></tr><tr><td>Combination antiviral therapy</td><td>1</td><td>1/1 (100)</td><td>3.29 (0.63 to 17.15)</td><td>8.3%</td><td>94.7%</td></tr><tr><td>Control</td><td>24</td><td>13/22 (59.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>12</td><td>3/10 (30.0)</td><td>0.55 (0.15 to 1.89)</td><td>83.4%</td><td>25.2%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>12</td><td>5/12 (41.7)</td><td>0.91 (0.26 to 3.25)</td><td>55.4%</td><td>55.9%</td></tr><tr><td>Control</td><td>6</td><td>3/5 (60.0)</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote><sup>a</sup>Immune deficient patients include the combination of patients receiving immunosuppressive therapy prior to this hospital admission (including chemotherapy within 4 weeks of admission, radiation, high-dose or long-term steroid treatment) and immunosuppressive disease (including acquired immunodeficiency syndrome, acute leukemia, lymphoma, metastatic cancer, myeloma, or any other disease that is sufficiently advanced to suppress resistance to infection but excluding malignancy which has been in remission for 5 years or more)</footnote>

<footnote><sup>b</sup>Due to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status.</footnote>

<footnote><sup>c</sup>The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
<table><caption>Table S25: Day 180 mortality in non-immune deficient patients</caption><thead><tr><th></th><th>N</th><th>Day 180 mortality<sup>a</sup>, n/N (%)</th><th>Hazard Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>b</sup></th><th>Probability of Futility of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>1395</td><td>420/1217 (34.5)</td><td>0.72 (0.59 to 0.90)</td><td>99.9%</td><td>9.4%</td></tr><tr><td>Anakinra</td><td>365</td><td>135/320 (42.2)</td><td>0.92 (0.71 to 1.20)</td><td>71.0%</td><td>78.3%</td></tr><tr><td>Control</td><td>388</td><td>132/333 (39.6)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>1011</td><td>340/880 (38.6)</td><td>1.02 (0.88 to 1.18)</td><td>41.6%</td><td>99.5%</td></tr><tr><td>Control</td><td>850</td><td>291/737 (39.5)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>976</td><td>246/830 (29.6)</td><td>0.82 (0.67 to 1.00)</td><td>97.5%</td><td>41.7%</td></tr><tr><td>Control</td><td>504</td><td>132/419 (31.5)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>467</td><td>145/375 (38.7)</td><td>1.08 (0.86 to 1.34)</td><td>26.2%</td><td>98.8%</td></tr><tr><td>Thromboprophylaxis</td><td>486</td><td>139/394 (35.3)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>241</td><td>74/211 (35.1)</td><td>1.08 (0.83 to 1.40)</td><td>29.1%</td><td>97.1%</td></tr><tr><td>Hydroxychloroquine</td><td>48</td><td>14/39 (35.9)</td><td>1.46 (0.94 to 2.29)</td><td>4.7%</td><td>99.3%</td></tr><tr><td>Combination antiviral therapy</td><td>25</td><td>12/25 (48.0)</td><td>1.58 (0.94 to 2.71)</td><td>4.6%</td><td>99.1%</td></tr><tr><td>Control</td><td>338</td><td>94/289 (32.5)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>125</td><td>31/99 (31.3)</td><td>0.98 (0.61 to 1.56)</td><td>54.1%</td><td>73.9%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>135</td><td>34/125 (27.2)</td><td>0.95 (0.59 to 1.52)</td><td>58.7%</td><td>69.5%</td></tr><tr><td>Control</td><td>95</td><td>24/74 (32.4)</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote>ªDue to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status.</footnote>

<footnote>ᵇThe probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
### 3. Supplemental Results Figures

<figure><img src="image_9.png" /><figcaption>Figure S1: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population</figcaption></figure>
<figure><img src="image_10.png" /><figcaption>Figure S2: Forest plot of Day 180 mortality hazard ratios in sensitivity analyses</figcaption></figure>
<figure><img src="image_11.png" /><figcaption>Figure S3: Fitted Kaplan-Meier curves for mortality through Day 180 with proportional hazard ratios, adjusting for covariates.</figcaption></figure>

Shaded area represents the 95% credible interval of the fitted survival curves.
<figure><img src="image_12.png" /><figcaption>Figure S4: Fitted Kaplan-Meier curves for mortality through Day 180 with time-varying hazards, adjusting for covariates.</figcaption></figure>

Shaded area represents the 95% credible interval of the fitted survival curves.
<figure><img src="image_13.png" /><figcaption>Figure S5: Association between OSFD odds ratios and the reciprocal of day 180 mortality hazard ratios</figcaption></figure>

Each point represents the posterior median for an intervention. The solid line segments display the 50% CrI for each intervention on the respective endpoint. The horizontal/vertical dashed lines represent no effect on each outcome. The diagonal dashed reference line is provided as a visual reference to assess the association between treatment effects.

<figure><img src="image_14.png" /><figcaption>Figure S6: Forest plot of Day 90 mortality odds ratios in unblinded ITT population</figcaption></figure>
<figure><img src="image_15.png" /><figcaption>Figure S8: Forest plot of the odds ratio on WHODAS disability category in survivors in unblinded ITT analysis</figcaption></figure>

<figure><img src="image_16.png" /></figure>
<figure><img src="image_17.png" /><figcaption>Figure S9: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing mechanical ventilation status at baseline</figcaption></figure>
<figure><img src="image_18.png" /><figcaption>Figure S10: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing immune deficient status at baseline</figcaption></figure>
# 4. Model Evaluation Report

# REMAP-CAP Long Term Outcomes Model Evaluation Report

Prepared by the ITSC Analysis Committee

November 17, 2022

## 4.1 Overview

This report describes sensitivity analyses and model evaluation of the primary model for the Long-Term Outcomes analysis of REMAP-CAP. The primary analysis model is a Bayesian piecewise exponential model of Day 180 mortality that estimates proportional hazard ratios for each intervention. The primary analysis model adjusts for baseline covariates including age, sex, site nested within country, and time period of enrollment. The full model specification is detailed in the Long-Term Outcomes SAP. This report evaluates specific assumptions made in the primary analysis model.

### 4.1.1 Proportional hazards assumption

We evaluate the proportional hazards assumption in two ways:

1. First, for each domain, we perform a hypothesis test of the proportional hazards assumption for a Cox regression based on the Schoenfeld weighted residuals versus transformed time. For each intervention within each domain, we report the p-value of the hypothesis test, where a p-value <0.05 would indicate a statistically significantly deviation from proportionality for an intervention.

2. Second, we fit a Bayesian piecewise exponential model with a non-proportional hazard ratio. This sensitivity analysis is identical to the primary analysis except for estimating time-varying hazard ratios for each intervention. Time-varying hazards and hazard ratios are estimated for each 15-day period up to day 90 and then the 90-day period up to day 180 (corresponding to the original intervals used for the hazard rates in the primary analysis). Fitted survival curves are displayed to provide a visual inspection of whether the proportional hazards assumptions hold.
### 5.1.1.1 Hypothesis tests of proportional hazards

For each domain, we fit a Cox model and assess the proportional hazards assumption of each intervention using the R function `cox.zph`. This function performs a hypothesis test of whether the hazard ratio for that intervention is proportional. For all interventions, the p-value exceeds 0.05 and we fail to detect a violation of proportional hazards.

<table><caption>Table S5.1: Results of hypothesis test of proportional hazards for each intervention</caption><thead><tr><td>Intervention</td><td>Chi-square test statistic</td><td>Degrees of freedom</td><td>p-value</td></tr></thead><tbody><tr><td>Interferon-beta-1a</td><td>2.916</td><td>1</td><td>0.088</td></tr><tr><td>Anakinra</td><td>2.837</td><td>1</td><td>0.092</td></tr><tr><td>IL-6 receptor antagonists</td><td>2.319</td><td>1</td><td>0.128</td></tr><tr><td>Fixed dose steroids</td><td>0.269</td><td>1</td><td>0.604</td></tr><tr><td>Shock-dependent steroids</td><td>0.675</td><td>1</td><td>0.411</td></tr><tr><td>Lopinavir-ritonavir</td><td>1.629</td><td>1</td><td>0.202</td></tr><tr><td>Hydroxychloroquine</td><td>0.030</td><td>1</td><td>0.862</td></tr><tr><td>Combination antiviral therapy</td><td>0.092</td><td>1</td><td>0.762</td></tr><tr><td>Convalescent plasma</td><td>0.906</td><td>1</td><td>0.341</td></tr><tr><td>Delayed convalescent plasma</td><td>1.418</td><td>1</td><td>0.234</td></tr><tr><td>Therapeutic anticoagulation</td><td>0.758</td><td>1</td><td>0.384</td></tr><tr><td>Antiplatelet</td><td>0.025</td><td>1</td><td>0.875</td></tr></tbody></table>

### 5.1.1.2 Visualization of proportional hazards assumptions

Next, we perform a sensitivity analysis of the primary analysis where we allow hazard ratio to differ over time. In this analysis, time-varying hazards and hazard ratios are estimated for each 15-day period up to day 90 and then the 90-day period up to day 180 (corresponding to the original intervals used for the hazard rates in the primary analysis). As an example, we display the estimated hazard ratios for the pooled IL-6ra intervention from the immune modulation domain. In this figure (S5.1), we plot the IL-6ra hazard ratio and 95% credible interval for each interval; the hazard ratio from the primary analysis model (assumed constant over time) is displayed as a horizontal dashed line with blue shading representing the 95% credible interval. Because most events are observed in earlier time periods, the 95% credible intervals are narrower in earlier periods compared to the later periods. In general, it appears that the time-varying hazard ratios are relatively constant over time and consistent with the proportional hazard ratio.
<figure><img src="image_19.png" /><figcaption>Figure S5.1: Estimated hazard ratios from time-varying sensitivity model for pooled IL-6ra</figcaption></figure>

As a diagnostic visualization tool of the proportional odds assumption, we provide estimated mortality curves for each intervention based on the primary model and the time-varying hazard sensitivity analysis. We display a set of estimated mortality curves from each model. The first set of figures (S5.2) summarizes the fitted mortality curves for each intervention under the pre-specified primary analysis model assuming a proportional hazards ratio. The second figure (S5.3) displays the fitted mortality curves from the model with time-varying hazard ratios. In the primary analysis, the assumption of a constant hazard ratio implies that the difference between the estimated mortality curves must increase proportionally over time. This means that, given proportional hazards, the estimated mortality curves cannot cross or separate and then come back together. In the time-varying hazard ratio model, the hazard ratio is allowed to vary by time interval. If the estimated hazard ratio varied over time, the curves would reveal this through non-proportional behavior where the curves cross or the distance between curves is not proportional over time. In general, the estimated mortality curves from the sensitivity analysis appear to be largely proportional. There are some minor deviations from proportionality observed. For example, Lopinavir-ritonavir and Control cross at approximately 20 days and the Steroid arms appear to have higher mortality than Control until approximately day 30. However, despite these minor deviations, the overall takeaways about the effect of interventions appear to hold when the proportionality assumption is removed.
<figure><img src="image_20.png" /><figcaption>Figure S5.2: Fitted survival curves from primary analysis model</figcaption></figure>
<figure><img src="image_21.png" /><figcaption>Figure S5.3: Fitted survival curves from sensitivity analysis with time-varying hazard ratios</figcaption></figure>

## 4.2 Prior distributions / Piecewise constant hazards

In this section, we evaluate the impact of two assumptions made in the primary model: 1) the prior distributions specified in the primary analysis model, and 2) the parametric assumption that survival times are piecewise exponential. To address both of these assumptions, we have performed frequentist Cox models with similar covariate adjustments to the primary analysis. These Cox models are fit within the frequentist framework, so no prior distributions are specified, and the results will be similar to a Bayesian model with non-informative prior distributions. Additionally, the Cox model makes no assumption on the underlying distribution of survival times, so this analysis will evaluate robustness of the results to the assumption of piecewise constant hazards in the primary model.

The Cox model summarized in this section adjusts for the same covariates as the Bayesian analysis. For site and time effects, we have incorporated each as a random intercept term in the model which is similar to
the hierarchical prior that is pre-specified in the primary model. In Table S5.2 below, we present the hazard ratios and 95% credible/confidence intervals for each intervention for the primary analysis (column 1) and the Cox model sensitivity analysis (column 2). We also compare the hazard ratios for each intervention in a forest plot.

The hazard ratios and uncertainty intervals from the Cox model are very similar to the primary analysis results. Removing the prior distributions and incorporating a more flexible model of time did not appear to impact the resulting hazard ratio for each intervention. The largest difference across the two models is the hazard ratio estimated for the combination antiviral intervention which is 1.61 (0.97 to 2.67) in the primary analysis and 2.94 (1.10 to 7.90) in the Cox model. The Bayesian analysis incorporates a prior distribution on the interaction term for lopinavir-ritonavir and hydroxychloroquine that 1) pulls the interaction term towards zero and 2) borrows information from the lopinavir-ritonavir and hydroxychloroquine interventions when estimating the combination effect. The Bayesian model structure results in an estimated hazard ratio that is smaller and less variable than the Cox model estimate. However, the overall conclusion of the two models is the same in that it appears that combination antiviral therapy is harmful.
<table><caption>Table S5.2: Comparison of results from primary analysis and equivalent frequentist Cox model</caption><thead><tr><td>Intervention</td><td>Primary analysis hazard ratio (95% CrI)</td><td>Frequentist Cox model hazard ratio (95% CI)</td></tr></thead><tbody><tr><td>Pooled IL-6ra</td><td>0.74 (0.61, 0.90)</td><td>0.75 (0.61, 0.92)</td></tr><tr><td>Pooled antiplatelet</td><td>0.85 (0.71, 1.03)</td><td>0.82 (0.67, 0.99)</td></tr><tr><td>Fixed duration hydrocortisone</td><td>0.93 (0.61, 1.47)</td><td>0.96 (0.60, 1.53)</td></tr><tr><td>Anakinra</td><td>0.96 (0.75, 1.23)</td><td>0.95 (0.74, 1.23)</td></tr><tr><td>Shock-dependent hydrocortisone</td><td>0.96 (0.61, 1.50)</td><td>0.97 (0.61, 1.56)</td></tr><tr><td>Convalescent plasma</td><td>0.99 (0.86, 1.14)</td><td>0.99 (0.86, 1.14)</td></tr><tr><td>Lopinavir/ritonavir</td><td>1.06 (0.82, 1.38)</td><td>1.00 (0.76, 1.32)</td></tr><tr><td>Therapeutic anticoagulation</td><td>1.13 (0.93, 1.42)</td><td>1.12 (0.90, 1.39)</td></tr><tr><td>Hydroxychloroquine</td><td>1.51 (0.98, 2.29)</td><td>1.46 (0.85, 2.51)</td></tr><tr><td>Antiviral combination therapy</td><td>1.61 (0.97, 2.67)</td><td>2.95 (1.10, 7.90)</td></tr></tbody></table>

<figure><img src="image_22.png" /><figcaption>Figure S5.4: Forest plot of Day 180 mortality hazard ratios estimated from the primary analysis and frequentist Cox model.</figcaption></figure>