Figures
- FIGURE 1
Primary Endpoint: Cumulative Incidence Function of Sustained Clinical Improvement or Live Discharge (FAS).
- FIGURE 2
Forest Plot Subgroup analyses for Primary Endpoint: Time to Sustained Clinical Improvement or Discharge (FAS).
- FIGURE 3
Bar Chart of Daily Clinical Status (FAS).
Tables
- TABLE 1
Subject Disposition & Baseline Information (FAS/SS)
Full Analysis Set=Safety Set Statistic AZITHRO + SOC SOC Total Total Number of Patients N 119 64 183 Demographics Age [y] Mean (SD) 63 (15) 59 (15) 62 (15) Female n/N (%) 40/119 (33.61%) 30/ 64 (46.88%) 70/183 (38.25%) Ethnicity - Caucasian n/N (%) 104/119 (87.39%) 55/64 (85.94%) 159/183 (86.89%) - North African and Middle East n/N (%) 11/119 (9.24%) 5/64 (7.69%) 16/183 (8.74%) - Black or sub-Sahara (Africa) n/N (%) 3/119 (2.52%) 1/64 (1.56%) 4/183 (2.19%) - Other n/N (%) 1/119 (0.84%) 3/64 (4.68%) 4/183 (2.19%) Medical History Diabetes Mellitus n/N (%) 22/119 (18.49%) 9/ 64 (14.06%) 31/183 (16.94%) Arterial Hypertension n/N (%) 55/119 (46.22%) 27/ 64 (42.19%) 82/183 (44.81%) Arrhythmia n/N (%) 19/119 (15.97%) 12/ 64 (18.75%) 31/183 (16.94%) Smoking Status Active n/N (%) 5/110 (4.55%) 4/55 (7.27%) 9/165 (5.45%) Former n/N (%) 37/110 (33.64%) 20/55 (36.36%) 57/165 (34.55%) Never n/N (%) 68/110 (61.82%) 31/55 (56.36%) 99/165 (60.00%) Chronic Pulmonary Disease* n/N (%) 4/119 (3.36%) 2/ 63 (3.17%) 6/182 (3.30%) COPD n/N (%) 7/119 (5.88%) 8/ 64 (12.50%) 15/183 (8.20%) Asthma n/N (%) 10/119 (8.40%) 5/ 64 (7.81%) 15/183 (8.20%) Heart Failure n/N (%) 8/119 (6.72%) 3/ 64 (4.69%) 11/183 (6.01%) Ischemic Heart Disease n/N (%) 10/119 (8.40%) 8/ 64 (12.50%) 18/183 (9.84%) Chronic Kidney Disease n/N (%) 10/119 (8.40%) 6/ 64 (9.38%) 16/183 (8.74%) Respiratory status at first presentation Signs of Respiratory Distress at First Presentation (i.e. Oxygen Saturation <93%, PaO2/FiO2 <300 mmHg, respiratory rate >30/min) n/N (%) 57/119 (47.90%) 33/ 61 (54.10%) 90/180 (50.00%) Respiratory Support within First 2 Hours - Oxygen Support (oxygen mask or nasal prongs) n/N (%) 89/119 (74.79%) 46/ 63 (73.02%) 135/182 (74.18%) - High-Flow Oxygen Support or non-invasive ventilation n/N (%) 5/119 (4.20%) 4/ 64 (6.25%) 9/183 (4.92%) - Mechanical Ventilation n/N (%) 0/119 (0.00%) 3/ 64 (4.69%) 3/183 (1.64%) - ECMO n/N (%) 1/119 (0.84%) 0/ 64 (0.00%) 1/183 (0.55%) Clinical Status at Baseline 3. Hosp., not requiring supplemental oxygen n/N (%) 22/119 (18.49%) 14/64 (21.88%) 36/183 (19.67%) 4. Hosp., requiring supplemental oxygen n/N (%) 88/119 (73.95%) 43/64 (67.19%) 131/183 (71.58%) 5. Hosp., on non-invasive ventilation n/N (%) 9/119 (7.56%) 5/64 (7.81%) 14/183 (7.65%) 6. Hosp., on inv. MV or ECMO n/N (%) 0/119 (0.00%) 2/64 (3.13%) 2/183 (1.09%) 7. Death n/N (%) 0/119 (0.00%) 0/64 (0.00%) 0/183 (0.00%) Laboratory Parameters at Baseline CRP [mg/L] Ref. ≤ 5 Median (Q1; Q3) 73.8 (35.2; 125.8) 59.5 (23.5; 93.3) 68.0 (33.1; 119.2) WBC [109/L] Ref. 4.0–10.0 Median (Q1; Q3) 6.0 (4.2; 8.0) 5.6 (4.1; 8.0) 5.8 (4.2; 8.0) Lymphocytes [109/L] Ref. 1.2–3.6 Median (Q1; Q3) 1.0 (0.7; 1.4) 1.0 (0.7; 1.3) 1.0 (0.7; 1.4) Neutrophils [109/L] Ref. 2.5–7.8 Median (Q1; Q3) 4.4 (2.9; 6.5) 4.5 (3.4; 6.7) 4.5 (3.0; 6.6) Ferritin [µg/L] Ref. 30–400 Median (Q1; Q3) 722.5 (408.0; 1057.0) 748.0 (529.0; 1420.0) 736.0 (492.0; 1259.0) D-Dimer [µg/L] Ref. ≤ 500 Median (Q1; Q3) 743.0 (466.0; 1174.0) 670.0 (378.0; 958.0) 723.5 (455.5; 1160.0) Fibrinogen [g/L] Ref. 2.0–3.93 Median (Q1; Q3) 7.7 (5.6; 560.0) 139.2 (4.5; 547.0) 9.3 (5.3; 547.0) eGFR [mL/min] Ref. ≥ 60 Median (Q1; Q3) 82.0 (64.0; 90.0) 88.0 (74.0; 90.0) 85.0 (65.0; 90.0) ECG at Baseline QTc [MS] (Fridericia Formula) [n] Mean (SD) [111] 418.9 (25.3) [57] 416.5 (28.6) [168] 418.1 (26.4) Symptom onset Time from Symptom Onset to Randomisation [days] Median (Q1; Q3) 7 (4; 10) 7 (5; 10) 7 (5; 10) Abbreviations: Ref: reference value, CRP: C-reactive protein, WBC: white blood cell count.
- TABLE 2
Trial Primary and Secondary Endpoints – Full Analysis Set (FAS)
Full Analysis Set (n=183) Statistic Estimate (95% CI) Treatment Effect Estimate (95% CI) p value AZITHRO SOC Primary outcome Incidence of clinical improvement or live discharge Subdistribution HR* 1.023 (0.758; 1.379) 0.8839 - at 15 days CIF# (%) 78.2% (69.5%; 84.6%) 81.3% (69.0%; 89.0%) - at 29 days CIF# (%) 86.6% (78.9%; 91.6%) 89.1% (77.8%; 94.8%) Time to sustained clinical improvement or live discharge Median (Days) 6 (6; 8) 8 (6; 10) Secondary Outcomes (compared to FAS, total n-values may be lower than n=119 for AZITHRO and n=64 for SOC due to missing values**) Clinical status at day 15 n/N (%) Common OR of having lower clinical status at day 15$ 0.83 (0.47; 1.53) 0.5776 1. Not hosp., no limitations 14/97 (14.58%) 11/53 (20.75%) 2. Not hosp., limitations 50/97 (51.55%) 28/53 (52.83%) 3. Hosp., no suppl. oxygen 7/97 (7.22%) 2/53 (3.77%) 4. Hosp., requiring oxygen 10/97 (10.31%) 4/53 (7.55%) 5. Hosp., NIV 5/97 (5.15%) 3/53 (5.66%) 6. Hospitalised, MV or ECMO 7/97 (7.22%) 4/53 (7.55%) 7. Death 4/97 (4.12%) 1/53 (1.89%) Cumulative clinical status up to day 15 Geometric meanΣ 42.61 (39.66; 45.77) 42.60 (38.64; 46.98) Treatment ratio∫ 1.00 (0.90; 1.12) 0.9508 All-cause mortality - 15-days KM (%) 3.4% (1.3%; 8.7%) 1.6% (0.2%; 10.6%) Hazard Ratio◊ 1.799 (0.201; 16.09) 0.5996 - 29-days KM (%) 7.6% (4.0%; 14.0%) 6.5% (2.5%; 16.3%) Hazard Ratio◊ 1.109 (0.339; 3.628) 0.8666 ICU (29 days) - Incidence (all patients) CIF# (%) 26.1% (18.5%; 34.2%) 23.4% (13.9%; 34.4%) Subdistribution HR* 1.066 (0.572; 1.985) 0.8412 - Duration of ICU stay (ICU admitted patients) Median (days) 11 (7; 18) 17 (3; 28) Subdistribution HR for live discharge from ICU* 1.293 (0.661; 2.529) 0.4534 Mechanical ventilation (29 days) - Incidence (all patients) CIF# (%) 12.0% (6.9%; 18.6%) 15.6% (8.0%; 25.6%) Subdistribution HR* 0.738 (0.313; 1.741) 0.4838 - Duration of MV (MV patients) Median (Days) 13 (NC; NC) 19 (NC; NC) Subdistribution HR for live weaning from MV* 0.897 (0.263; 3.034) 0.8609 Supplemental oxygen (29 days) - Incidence (all patients) CIF# (%) 83.2% (75.1%; 88.9%) 79.7% (67.4%; 87.8%) Subdistribution HR* 0.998 (0.837; 1.191) 0.7811 - Duration of supplemental oxygen (patients with supplemental oxygen) Median (Days) 6 (5; 8) 7 (5;11) Subdistribution HR for live weaning from oxygen* 1.042 (0.737; 1.479) 0.9465 Hospital stay (29 days) Subdistribution HR for live hospital discharge* - Occurrence of live hospital discharge CIF# (%) 85.8% (78.0%; 91.0%) 84.4% (72.5%; 91.4%) 1.064 (0.780; 1.451) 0.6954 - Duration of hospital stay (Days) Median (Days) 7 (6; 8) 8 (6; 9) Safety Outcome Combined cardiac endpoint (hs-Troponin >0.5 ng/ml and/or ventricular arrhythmia requiring intervention and/or sudden cardiac death) n/N (%) 24/119 (20.17%) 12/64 (18.75%) Odds Ratio¥ 1.40 (0.61; 3.19) 0.4265 Exploratory Outcomes Normal CT at 5–7 weeks n/N (%) 25/75 (33.33%) 12/40 (30.00%) Odds Ratio‡ 1.56 (0.64;3.79) 0.3233 DLCO (% predicted) Estimated meanΩ (%) 66.49 (59.96; 73.02) 67.00 (57.91; 76.09) Treatment difference### 0.22 (−11.1; 11.51) 0.9695 6-min walking test Estimated meanΩ (meters) 496.5 (465.0; 528.0) 456.3 (413.2; 499.3) Treatment difference### 32.51 (−21.2; 86.25) 0.2383 Abbreviations: NIV: non-invasive ventilation, MV: mechanical ventilation, ECMO: extracorporeal membrane oxygenation.
#Event rates were estimated as cumulative incidence functions (CIF), taking into account the competing risk of death.
*Score>1 favours azithromycin. Hazard ratio was obtained using a Fine & Gray model for competing risk data including treatment, study site and study period as factors.
$Score>1 favours azithromycin. Odds ratio was obtained from a multinomial logistic regression with factors for treatment, disease severity and Clinical Status on Day 0.
ΣGeometric mean was obtained using a general linear model including treatment as factor.
∫Score>1 favours SOC. Treatment ratio was calculated as the ratio of geometric means, obtained using a general linear model including treatment, study site, study period and clinical status on Day 0 as factors. (Notes: Data were log-transformed prior to statistical analysis).
†Score>1 favours SOC. Hazard ratio was obtained using a Fine & Gray model for competing risk data including treatment, study site and study period as factors.
◊Score>1 favours SOC. Hazard ratio was obtained using Log-Rank test after event rates were estimated using Kaplan-Meier methodology.
‡Score>1 favours azithromycin. Odds ratios were obtained using logistic regression including treatment, study site and study period as factors in the model.
¥Score>1 favours SOC. Odds ratios were obtained using logistic regression including treatment, study site and study period as factors in the model.
ΩObtained using a general linear model including treatment as factor.
ΔScore>1 favours SOC. Hazard ratio was obtained using a Fine & Gray model for competing risk data including treatment, study site and study period as factors
###Higher score (> 0) favours azithromycin. Obtained using a general linear model including treatment, study site and period as factors.
**Missing data are accounted for by multiple imputation.
