Introduction
Methods
Study design
Participant recruitment and baseline assessment
Patient State | Descriptor | Scale |
---|---|---|
Uninfected | No clinical and virological evidence of infection | 1 |
Ambulatory | No limitation of activities | 2 |
Limitation of activities | 3 | |
Hospitalised mild disease | Hospitalised, no oxygen therapy | 4 |
Oxygen by mask or nasal prong | 5 | |
Hospitalised severe disease | Non-invasive ventilation or high-flow oxygen | 6 |
Intubation and mechanical ventilation | 7 | |
Ventilation + additional organ support -pressors, ECMO, RRT | 8 | |
Dead | Death | 9 |
Randomisation and intervention
Follow up
Outcome variables
Sample size calculation
Statistical analysis
Results
Patient population
Baseline variables | Total population# (n = 882) | Group A (Atorvastatin) (n = 221) | Group B (Aspirin) (n = 221) | Group C (Both) (n = 221) | Group D (None) (n = 219) |
---|---|---|---|---|---|
Age (years) | 52 (46–59) | 51 (45–59) | 53 (46–60) | 52 (46–57) | 52 (46–60) |
Sex–Male | 650 (74) | 166 (75) | 160 (72) | 163 (74) | 161 (74) |
Number of days since symptom onset | 6 (4–8) | 6 (3–8) | 6 (4–8) | 6 (4–9) | 5 (4–8) |
Comorbidities | |||||
Diabetes | 244 (28) | 65 (29) | 57 (26) | 69 (31) | 53 (24) |
Hypertension | 252 (29) | 66 (30) | 65 (29) | 62 (28) | 59 (27) |
Coronary artery disease | 10 (1) | 2 (1) | 2 (1) | 4 (2) | 2 (1) |
Liver dysfunction | 5 (1) | 2 (1) | 2 (1) | 1 (0) | 0 (0) |
Chronic kidney disease | 21 (2) | 5 (2) | 5 (2) | 4 (2) | 7 (3) |
Symptoms | |||||
Fever | 572 (65) | 149 (67) | 136 (62) | 147 (67) | 140 (64) |
Cough | 496 (56) | 122 (55) | 119 (54) | 127 (58) | 128 (58) |
Shortness of breath | 256 (29) | 58 (26) | 66 (30) | 76 (34) | 56 (26) |
Desaturation | 82 (9) | 16 (7) | 18 (8) | 28 (13) | 20 (9) |
Body ache | 94 (11) | 29 (13) | 22 (10) | 21 (10) | 22 (10) |
G I symptoms | 85 (10) | 20 (9) | 24 (11) | 21 (10) | 20 (9) |
Loss of smell | 31 (4) | 7 (3) | 7 (3) | 6 (3) | 11 (5) |
Loss of taste | 49 (6) | 11 (5) | 12 (6) | 13 (6) | 13 (6) |
Treatment received | |||||
Hydroxychloroquine | 87 (10) | 29 (13) | 18 (8) | 19 (9) | 21 (10) |
Azithromycin | 103 (12) | 31 (14) | 23 (10) | 26 (12) | 23 (11) |
Remdesivir | 182 (21) | 39 (18) | 51 (23) | 51 (23) | 41 (19) |
Favipiravir | 38 (4) | 11 (5) | 10 (5) | 7 (3) | 10 (5) |
Doxycycline | 177 (20) | 48 (22) | 48 (22) | 36 (16) | 45 (21) |
Anticoagulation | 247 (28) | 66 (30) | 64 (29) | 63 (29) | 54 (25) |
Plasma therapy | 2 (0) | 0 (0) | 0 (0) | 1 (0) | 1 (1) |
Tocilizumab | 5 (1) | 1 (0) | 1 (0) | 2 (1) | 1 (1) |
Steroid | 241 (27) | 58 (26) | 65 (29) | 58 (26) | 60 (27) |
Baseline ordinal scale | |||||
3 | 724 (82) | 181 (82) | 182 (82) | 178 (81) | 183 (84) |
4 | 133 (15) | 33 (15) | 33 (15) | 37 (17) | 30 (14) |
5 | 25 (3) | 7 (3) | 6 (3) | 6 (3) | 6 (3) |
Blood investigations | |||||
Hemoglobin (g/dL) | 13 (11.7–14.3) | 13.1 (11.8–14.3) | 12.9 (11.7–14.4) | 13.1 (12–14.3) | 12.9 (11.6–14.2) |
TLC (/μL) | 5905 (4540 -7 710) | 5670 (4530–7510) | 5920 (4600–7670) | 5890 (4480–7860) | 6020 (4600–8000) |
Platelet (× 103 /μL) | 200 (149–258) | 203 (156–262) | 210 (151–261) | 196 (149–254) | 187 (141–262) |
Urea (mg/dL) | 27 (21.4–36.4) | 25.7 (21–36.4) | 25.7 (21.4–36) | 27.00 (21–36.4) | 28.50 (22–38.5) |
Creatinine (mg/dL) | 0.8 (0.7–0.9) | 0.8 (0.7–0.9) | 0.8 (0.7–0.9) | 0.8 (0.7–0.9) | 0.8 (0.7–0.9) |
Total Bilirubin (mg/dL) | 0.5 (0.4–0.7) | 0.5 (0.4–0.7) | 0.5 (0.4–0.7) | 0.5 (0.4–0.7) | 0.5 (0.4–0.8) |
SGOT (IU/L) | 38 (28.4–55) | 37 (27.7–53) | 41 (29–56) | 38 (29–54.2) | 36 (29–54) |
SGPT (IU/L) | 39 (25.5–60) | 38 (24–57.2) | 39.9 (27–61) | 39 (26.5–59) | 39 (25–60) |
ALP (IU) | 83 (67–108) | 80 (65–110) | 83 (20–109) | 85 (67–108) | 85 (69–104) |
Ferritin (ng/mL) | 220.6 (106–506) | 202 (97.9–436) | 249.85 (121–493.9) | 225.5 (109–538.4) | 220.5 (105.9–571.3) |
D-Dimer (ng/mL) | 153 (84–271) | 138 (84–244) | 159 (83–256) | 152 (87–299) | 168 (85–284) |
PT (sec) | 12.2 (11.5–13) | 12.3 (11.5–13.1) | 12.3 (11.6–13.2) | 12.1 (11.45–12.9) | 12.1 (11.5–13) |
INR | 1.1 (1–1.1) | 1.1 (1–1.1) | 1.1 (1–1.1) | 1.1 (1–1.11) | 1 (1–1.1) |
CRP (mg/dl) | 1.4 (0.3–5.8) | 1.4 (0.3–5.3) | 1.5 (0.3–7) | 1.2 (0.3–6.3) | 1.2 (0.3–4.9) |
IL-6 (pg/mL) | 6 (1.8–22) | 6.8 (2–25.4) | 5.5 (1.8–22) | 7.9 (2–28.6) | 5.2 (1.4–14.7) |
Trop I (ng/mL) | 0.005 (0.001–0.008) | 0.006 (0.001–0.007) | 0.004 (0.001–0.008) | 0.005 (0.001–0.008) | 0.005 (0.001–0.008) |
CPK (IU/L) | 96 (57–170) | 92.50 (56–190) | 98 (53–176) | 97 (62–154) | 97.50 (54–162) |
Primary outcome
Outcome variables | Group A (Atorvastatin) | Group B (Aspirin) | Group C (Both) | Group D (None) | P Value | |
---|---|---|---|---|---|---|
Primary outcome (Progression to WHO ordinal score ≥ 6) | ||||||
Modified ITT (N = 882) | n/N (%) | 7/221 (3.2) | 3/221 (1.4) | 8/221 (3.6) | 7/219 (3.2) | 0.46 a |
HR (95% CI), P | 0.98 (0.34–2.79), 0.97 | 0.40 (0.10–1.54), 0.18 | 1.00 (0.36–2.77), 0.99 | 1 | ||
True ITT (N = 900) | n/N (%) | 7/224 (3.1) | 3/225 (1.3) | 8/225 (3.6) | 7/226 (3.1) | 0.45 a |
HR (95% CI), P | 0.86 (0.30–2.47), 0.78 | 0.37 (0.09–1.43), 0.15 | 0.81 (0.28–2.29), 0.68 | 1 | ||
Per protocol (N = 716) | n/N (%) | 3/167 (1.8) | 3/162 (1.8) | 6/168 (3.6) | 7/219 (3.2) | 0.67a |
HR (95% CI), P | 0.56 (0.14–2.16), 0.40 | 0.50 (0.13–1.96), 0.32 | 1.06 (0.36–3.16), 0.92 | 1 | ||
As per treatment received(N = 878) | n/N (%) | 3/179 (1.7) | 3/166 (1.8) | 6/173 (3.5) | 13/360 (3.6) | 0.52a |
HR (95% CI), P | 0.45 (0.13–1.57), 0.21 | 0.46 (0.13–1.62), 0.23 | 0.95 (0.36–2.47), 0.89 | 1 | ||
Other clinical outcomes | ||||||
Death | ||||||
Modified ITT | 7/221 (3.2) | 3/221 (1.4) | 8/221 (3.6) | 7/219 (3.2) | 0.46a | |
True ITT | 7/224 (3.1) | 3/225 (1.3) | 8/225 (3.6) | 7/226 (3.1) | 0.46 a | |
Per protocol | 3/167 (1.8) | 3/162 (1.8) | 6/168 (3.6) | 7/219 (3.2) | 0.67a | |
As per treatment received | 3/179 (1.7) | 3/166 (1.8) | 6/173 (3.5) | 13/360 (3.6) | 0.52a | |
Mechanical ventilation | ||||||
Modified ITT | 7/221 (3.1) | 3/221 (1.3) | 8/221 (3.6) | 6/219 (2.7) | 0.48a | |
True ITT | 7/224 (3.1) | 3/225 (1.3) | 8/225 (3.6) | 6/226 (2.7) | 0.47 a | |
Per protocol | 3/167 (1.8) | 3/162 (1.8) | 6/168 (3.6) | 6/219 (2.7) | 0.72a | |
As per treatment received | 3/179 (1.7) | 3/166 (1.8) | 6/173 (3.5) | 12/360 (3.3) | 0.59a | |
Shock | ||||||
Modified ITT | 5/221 (2.2) | 1/221 (0.4) | 6/221 (2.7) | 6/219 (2.7) | 0.19a | |
True ITT | 5/224 (2.2) | 1/225 (0.4) | 6/225 (2.7) | 6/226 (2.7) | 0.20 a | |
Per protocol | 2/167 (1.2) | 1/162 (0.6) | 5/168 (3) | 6/219 (2.7) | 0.32a | |
As per treatment received | 2/179 (1.1) | 1/166 (0.6) | 5/173 (2.9) | 10/360 (2.8) | 0.27a | |
Clinical deteriorationb | ||||||
Modified ITT | 27/221 (12.2) | 26/221 (11.7) | 20/221 (9.0) | 22/219 (10.0) | 0.68 | |
True ITT | 27/224 (12.1) | 26/225 (11.6) | 21/225 (9.3) | 22/226 (9.7) | 0.74 | |
Per protocol | 17/167 (10.2) | 14/162 (8.6) | 15/168 (8.9) | 22/219 (10) | 0.95 | |
As per treatment received | 19/179 (10.6) | 14/166 (8.4) | 15/173 (8.7) | 46/360 (12.8) | 0.35 | |
Hospital admission duration (days)γ | ||||||
Modified ITT | 9 (8–11) | 9 (8–11) | 9 (8–12) | 9 (8–11) | 0.85 | |
True ITT | 9 (8–12) | 9 (8–11) | 9 (8–12) | 9 (7–11) | 0.65 | |
Per protocol | 9 (8–11) | 9 (8–11) | 9 (8–11) | 9 (8–11) | 0.69 | |
As per treatment received | 9 (8–11) | 9 (8–11) | 9 (8–11) | 9 (7–12) | 0.54 |
Secondary outcome
Variables | Group A (Atorvastatin) | Group B (Aspirin) | Group C (Both) | Group D (None) | P Value |
---|---|---|---|---|---|
CRP (mg/dl) | |||||
Pre | 1.05 (0.25–3.65) | 1.36 (0.20–6.72) | 0.95 (0.18–4.74) | 1.05 (0.23–4.48) | |
Post | 0.59 (0.13–1.60) | 0.60 (0.16–1.77) | 0.49 (0.09–1.59) | 0.61 (0.13–2.34) | |
Percentage (%) change | |||||
Per protocol | − 49.71 (− 81.98–3.50) | − 53.81 (− 84.73–9.09) | − 54.77 (− 82.76–29.22) | − 44.73 (− 81.22–14.09) | 0.89 |
As per treatment received | − 51.56 (− 82.14–4.85) | − 54.84 (− 84.73–8.10) | − 55.41 (− 83.59–28.60) | − 62.59 (− 84.77–4.12) | 0.86 |
IL-6 (pg/mL) | |||||
Pre | 4.95 (1.35–17.45) | 5 (1.3–20.6) | 6.15 (1.2–27.0) | 4.9 (1.2–13) | |
Post | 2.7 (0.75–8.7) | 2.8 (0.8–9.6) | 2.25 (0.7–6.4) | 3.3 (1.2–10.9) | |
Percentage (%) change | |||||
Per protocol | − 27.83 (− 78.91–98.21) | − 40.42 (− 79.86–71.42) | − 53.46 (− 84.29–23.21) | 0 (− 66.79–142.46) | 0.007 |
As per treatment received | − 27.83 (− 79.71–98.21) | − 40.42 (− 79.86–71.42) | − 51.54 (− 83.08–23.21) | − 16.66 (− 72–120) | 0.08 |
Trop I (ng/mL) | |||||
Pre | 0.006 (0.001–0.007) | 0.005 (0.001–0.01) | 0.006 (0.001–0.01) | 0.005 (0.001–0.007) | |
Post | 0.004 (0.001–0.006) | 0.005 (0.001–0.008) | 0.004 (0.001–0.006) | 0.003 (0.001–0.006) | |
Percentage (%) change | |||||
Per protocol | − 11.98 (− 83.33–40) | 0 (− 83.33–50) | − 33.33 (− 83.33–0) | 0 (− 83.33–50) | 0.55 |
As per treatment received | − 16.66 (− 83.33–40) | 0 (− 83.33–40) | − 34.52 (− 83.33–0) | − 24.03 (− 83.33–50) | 0.64 |