Background
Methods
Study design and participants
Participants
Ethical considerations
Randomisation and masking
Procedures
Outcomes
Statistical analysis
Role of the funding source
Results
Participant flow and recruitment
Baseline characteristics
All (n = 275) | Baricitinib (n = 139) | Placebo (n = 136) | |
---|---|---|---|
Age (years), median (IQR) | 60 (49–69) | 59 (49–68) | 60 (50–70) |
n/N (%) | |||
< 60 | 137/275 (49.8) | 70/139 (50.4) | 67/136 (49.3) |
≥ 60 | 138/275 (50.2) | 69/139 (49.6) | 69/136 (50.7) |
Gender, n/N (%) | |||
Male | 211/275 (76.7) | 112/139 (80.6) | 99/136 (72.8) |
Female | 64/275 (23.3) | 27/139 (19.4) | 37/136 (27.2) |
Country, n/N (%) | |||
Austria | 6/275 (2.2) | 2/139 (1.4) | 4/136 (2.9) |
Belgium | 8/275 (2.9) | 2/139 (1.4) | 6/136 (4.4) |
France | 89/275 (32.4) | 48/139 (34.5) | 41/136 (30.1) |
Ireland | 9/275 (3.3) | 5/139 (3.6) | 4/136 (2.9) |
Italy | 24/275 (8.7) | 12/139 (8.6) | 12/136 (8.8) |
Luxembourg | 1/275 (0.4) | 1/139 (0.7) | 0/136 (0.0) |
Norway | 123/275 (44.7) | 61/139 (43.9) | 62/136 (45.6) |
Portugal | 3/275 (1.1) | 2/139 (1.4) | 1/136 (0.7) |
Spain | 12/275 (4.4) | 6/139 (4.3) | 6/136 (4.4) |
Comorbidities, n/N (%) | |||
Obesity (BMI ≥ 30 kg/m2) | 99/257 (38.5) | 53/127 (41.7) | 46/130 (35.4) |
Diabetes | 61/274 (22.3) | 36/139 (25.9) | 25/135 (18.5) |
Hypertension | 85/274 (31.0) | 44/139 (31.7) | 41/135 (30.4) |
Chronic obstructive pulmonary disease | 14/274 (5.1) | 9/139 (6.5) | 5/135 (3.7) |
Chronic cardiac disease | 52/274 (19.0) | 24/139 (17.3) | 28/135 (20.7) |
Chronic kidney disease | 11/274 (4.0) | 6/139 (4.3) | 5/135 (3.7) |
Chronic liver disease | 5/274 (1.8) | 3/139 (2.2) | 2/135 (1.5) |
Cancer | 10/274 (3.6) | 4/139 (2.9) | 6/135 (4.4) |
Autoimmune disease | 12/274 (4.4) | 3/139 (2.2) | 9/135 (6.7) |
Immunodeficiency | 4/274 (1.5) | 2/139 (1.4) | 2/135 (1.5) |
Any comorbidities, n/N (%) | 199/275 (72.4) | 107/139 (77.0) | 92/136 (67.6) |
Days from first confirmed SARS-CoV-2 PCR to randomisation, median (IQR) | 6 (3–9) | 6 (3–8) | 7 (3–10) |
Days from symptoms onset to randomisation, median (IQR) | 9 (7–11) | 9 (7–11) | 10 (8–12) |
n/N (%) | |||
≤ 7 | 74/275 (26.9) | 40/139 (28.8) | 34/136 (25.0) |
8–13 | 187/275 (68.0) | 94/139 (67.6) | 93/136 (68.4) |
≥ 14 | 14/275 (5.1) | 5/139 (3.6) | 9/136 (6.6) |
COVID-19 vaccination, number of injections, n/N (%) | |||
0 injection | 175/275 (63.6) | 87/139 (62.6) | 88/136 (64.7) |
≥ 1 injection | 96/275 (34.9) | 49/139 (35.2) | 47/136 (34.6) |
Unknown | 4/275 (1.5) | 3/139 (2.2) | 1/136 (0.7) |
WHO disease progression score, n/N (%) | |||
6 (severe disease) | 236/275 (85.8) | 121/139 (87.1) | 115/136 (84.6) |
7–9 (critical disease) | 39/275 (14.2) | 18/139 (12.9) | 21/136 (15.4) |
Concomitant medications, n/N (%) | |||
Remdesivir | 8/275 (2.9) | 6/139 (4.3) | 2/136 (1.5) |
Systemic corticosteroids | 261/275 (94.9) | 133/139 (95.7) | 128/136 (94.1) |
Anticoagulants | 250/275 (90.9) | 130/139 (93.5) | 120/136 (88.2) |
Biochemistry, median (IQR) | |||
Lymphocyte count (109 cells/L) | |||
N | 268 | 135 | 133 |
Median (IQR) | 0.8 (0.5–1.1) | 0.8 (0.6–1.2) | 0.7 (0.5–1.0) |
Neutrophil count (109 cells/L) | |||
N | 268 | 135 | 133 |
Median (IQR) | 6.0 (4.2–8.3) | 6.0 (4.2–8.4) | 6.0 (4.2–8.3) |
C-reactive protein (mg/L) | |||
N | 268 | 134 | 134 |
Median (IQR) | 87 (49–140) | 77 (35–126) | 95 (55–149) |
Ferritin (ng/mL) | |||
N | 228 | 116 | 112 |
Median (IQR) | 1121 (595–1887) | 1039 (609–1887) | 1206 (559–1883) |
Lactate dehydrogenase (U/L) | |||
N | 235 | 120 | 115 |
Median (IQR) | 404 (321–518) | 397 (318–526) | 436 (323–514) |
Procalcitonin (ng/mL) | |||
N | 187 | 95 | 92 |
Median (IQR) | 0.2 (0.1–0.3) | 0.2 (0.1–0.4) | 0.1 (0.1–0.3) |
D-dimer (μg/L FEU) | |||
N | 243 | 119 | 124 |
Median (IQR) | 900 (600–1500) | 844 (620–1360) | 904 (594–1592) |
SARS-CoV2 serostatus | |||
N | 124 | 65 | 59 |
Negative | 46/124 (37.1) | 21/65 (32.3) | 25/59 (42.4) |
Positive | 78/124 (62.9) | 44/65 (67.7) | 34/59 (57.6) |
Nasopharyngeal viral load, (Log copies/10000 cells) median (IQR)* | |||
N | 124 | 65 | 59 |
Median (IQR) | 3.2 (2.1–4.5) | 3.2 (2.3–4.5) | 3.2 (1.8–4.5) |
Viral load value < LOQ | 18/124 (14.5) | 9/65 (13.9) | 9/59 (15.3) |
Efficacy endpoints
Baricitinib group (N = 139) | Placebo group (N = 136) | Adjusted Absolute difference (95% CI) | Adjusted OR (95% CI) | P-value* | |
---|---|---|---|---|---|
Mortality | |||||
Number of deaths at day 61 | 21 | 21 | |||
Proportion (95% CI) at day 61 | 15.1 (9.6–22.2) | 15.4 (9.8–22.6) | − 0.1 (− 8.3–8.0) | 0.99 (0.50–1.95) | 0.9733 |
Number of deaths at day 28+ | 14 | 18 | |||
Proportion (95% CI) at day 28+ | 10.1 (5.6–16.3) | 13.2 (8.0–20.1) | − 2.9 (− 10.1–4.3) | 0.75 (0.35–1.59) | 0.4480 |
Disease progression | |||||
Number of progressions at day 28 | 25 | 27 | |||
Proportion (95% CI) at day 28 | 18.0 (12.0–25.4) | 19.9 (13.5–27.6) | − 1.2 (− 10.0–7.4) | 0.92 (0.49–1.72) | 0.7943 |
Baricitinib group (N = 139) | Placebo group (N = 136) | Unadjusted sHR or OR (95% CI) | Adjusted sHR or OR (95% CI) | p value* | |
---|---|---|---|---|---|
Sustained recovery | |||||
Number of recoveries at day 91 | 107 | 106 | |||
Cumulative incidence at day 91% (95% CI) | 78.8 (72.6–85.4) | 79.1 (72.9–85.8) | 0.99 (0.76–1.28) | 0.98 (0.75–1.28) | 0.8604 |
Hospital discharge | |||||
Number of discharges at day 91 | 111 | 107 | |||
Cumulative incidence at day 91% (95% CI) | 83.8 (77.7–90.3) | 79.8 (73.1–87.1) | 1.14 (0.88–1.47) | 1.14 (0.87–1.48) | 0.3490 |
Ordinal scale at day 15 – n (%) | 0.94 (0.60–1.48) | 0.95 (0.60–1.50) | 0.8296 | ||
Mild (WHO score 1–3) | 81 (58.3) | 74 (54.4) | |||
Moderate (WHO score 4–5) | 15 (10.8) | 18 (13.2) | |||
Severe (WHO score 6) | 10 (7.2) | 8 (5.9) | |||
Critical (WHO score 7–9) | 24 (17.2) | 26 (19.1) | |||
Death (WHO score 10) | 25 (6.5) | 10 (7.4) | |||
Ordinal scale at day 29 – n (%) | 1.13 (0.69–1.84) | 1.14 (0.70–1.87) | 0.5986 | ||
Mild (WHO score 1–3) | 96 (69.0) | 89 (65.4) | |||
Moderate (WHO score 4–5) | 97 (7.9) | 14 (10.3) | |||
Severe (WHO score 6) | 3 (2.2) | 4 (3.0) | |||
Critical (WHO score 7–9) | 4 (10.8) | 11 (8.1) | |||
Death (WHO score 10) | 14 (10.1) | 18 (13.2) |
Subgroup analyses
Safety
Baricitinib (N = 139) | Placebo (N = 136) | Adjusted incidence rate ratio (95% CI) | p value* | |||
---|---|---|---|---|---|---|
Person-months (PM): 349 | Person-Months (PM): 349 | |||||
n of events | N of pts (%) | n of events | N of pts (%) | |||
Serious adverse events (SAEs) | 148 | 46 (33.1) | 155 | 51 (37.5) | 0.93 (0.74–1.17) | 0.550 |
Respiratory, thoracic and mediastinal disorders | 51 | 52 | ||||
Acute respiratory distress syndrome | 21 | 21 | ||||
Pulmonary embolism | 8 | 13 | ||||
Respiratory failure | 13 | 7 | ||||
Pneumothorax | 3 | 5 | ||||
Hypoxia | 1 | 2 | ||||
Respiratory distress | 0 | 2 | ||||
Acute respiratory failure | 1 | 0 | ||||
Haemoptysis | 1 | 0 | ||||
Obstructive airways disorder | 1 | 0 | ||||
Pleural effusion | 1 | 0 | ||||
Pleuritic pain | 1 | 0 | ||||
Pneumonitis | 0 | 1 | ||||
Pulmonary hypertension | 0 | 1 | ||||
Infections and infestations | 63 | 54 | ||||
Pneumonia | 26 | 25 | ||||
Pneumonia bacterial | 10 | 8 | ||||
Septic shock | 8 | 4 | ||||
Bacteraemia | 4 | 6 | ||||
Bronchopulmonary aspergillosis | 0 | 3 | ||||
COVID-19 pneumonia | 3 | 0 | ||||
Sepsis | 1 | 2 | ||||
Cytomegalovirus infection reactivation | 2 | 0 | ||||
Fungaemia | 2 | 0 | ||||
Superinfection bacterial | 1 | 1 | ||||
Bacterial infection | 1 | 0 | ||||
Candida pneumonia | 1 | 0 | ||||
Device related bacteraemia | 1 | 0 | ||||
Disseminated aspergillosis | 0 | 1 | ||||
Hepatitis B reactivation | 0 | 1 | ||||
Herpes simplex | 1 | 0 | ||||
Infectious pleural effusion | 0 | 1 | ||||
Mediastinitis | 1 | 0 | ||||
Prostatitis Escherichia coli | 0 | 1 | ||||
Septic arthritis staphylococcal | 0 | 1 | ||||
Staphylococcal bacteraemia | 1 | 0 | ||||
General disorders and administration site conditions | 8 | 5 | ||||
Multiple organ dysfunction syndrome | 6 | 5 | ||||
Chest pain | 1 | 0 | ||||
Death | 1 | 0 | ||||
Renal and urinary disorders | 10 | 13 | ||||
Acute renal failure | 7 | 4 | ||||
Acute kidney injury | 2 | 6 | ||||
Renal failure | 1 | 2 | ||||
Chronic kidney disease | 0 | 1 | ||||
Blood and lymphatic system disorders | 0 | 4 | ||||
Anaemia | 0 | 2 | ||||
Bicytopenia | 0 | 1 | ||||
Thrombocytopenia | 0 | 1 | ||||
Cardiac disorders | 5 | 5 | ||||
Cardiac disorder | 2 | 2 | ||||
Cardiac failure | 1 | 1 | ||||
Acute coronary syndrome | 0 | 1 | ||||
Acute myocardial infarction | 0 | 1 | ||||
Bradycardia | 1 | 0 | ||||
Myocarditis / pericarditis | 1 | 0 | ||||
Injury, poisoning and procedural complications | 0 | 1 | ||||
Hand fracture | 0 | 1 | ||||
Nervous system disorders | 2 | 3 | ||||
Coma | 2 | 0 | ||||
Facial paralysis | 0 | 1 | ||||
Haemorrhage intracranial | 0 | 1 | ||||
Subarachnoid haemorrhage | 0 | 1 | ||||
Gastrointestinal disorders | 0 | 3 | ||||
Ileus | 0 | 1 | ||||
Intestinal ischaemia | 0 | 1 | ||||
Rectal haemorrhage | 0 | 1 | ||||
Vascular disorders | 4 | 4 | ||||
Deep vein thrombosis | 2 | 3 | ||||
Circulatory collapse | 1 | 0 | ||||
Hypotension | 1 | 0 | ||||
Peripheral artery thrombosis | 0 | 1 | ||||
Congenital, familial and genetic disorders | 0 | 1 | ||||
Atrial septal defect | 0 | 1 | ||||
Investigations | 5 | 9 | ||||
Transaminases increased | 4 | 8 | ||||
Blood bilirubin increased | 0 | 1 | ||||
C-reactive protein increased | 1 | 0 | ||||
Musculoskeletal and connective tissue disorders | 0 | 1 | ||||
Spondylolisthesis | 0 | 1 | ||||
Drug-related SAEs | 41 | 25 (18.0) | 59 | 28 (20.6) | 0.77 (0.52–1.16) | 0.213 |
Respiratory, thoracic and mediastinal disorders | 10 | 14 | ||||
Pulmonary embolism | 5 | 8 | ||||
Respiratory failure | 2 | 2 | ||||
Acute respiratory distress syndrome | 1 | 2 | ||||
Acute respiratory failure | 1 | 0 | ||||
Obstructive airways disorder | 1 | 0 | ||||
Pneumonitis | 0 | 1 | ||||
Pneumothorax | 0 | 1 | ||||
Renal and urinary disorders | 3 | 6 | ||||
Acute kidney injury | 2 | 5 | ||||
Chronic kidney disease | 0 | 1 | ||||
Renal failure | 1 | 0 | ||||
Infections and infestations | 22 | 23 | ||||
Pneumonia | 8 | 9 | ||||
Pneumonia bacterial | 5 | 3 | ||||
Bacteraemia | 0 | 3 | ||||
Cytomegalovirus infection reactivation | 2 | 0 | ||||
Sepsis | 1 | 1 | ||||
Superinfection bacterial | 1 | 1 | ||||
Bacterial infection | 1 | 0 | ||||
Bronchopulmonary aspergillosis | 0 | 1 | ||||
COVID-19 pneumonia | 1 | 0 | ||||
Candida pneumonia | 1 | 0 | ||||
Hepatitis B reactivation | 0 | 1 | ||||
Infectious pleural effusion | 0 | 1 | ||||
Mediastinitis | 1 | 0 | ||||
Prostatitis Escherichia coli | 0 | 1 | ||||
Septic arthritis staphylococcal | 0 | 1 | ||||
Septic shock | 0 | 1 | ||||
Staphylococcal bacteraemia | 1 | 0 | ||||
General disorders and administration site conditions | 1 | 3 | ||||
Multiple organ dysfunction syndrome | 1 | 3 | ||||
Blood and lymphatic system disorders | 0 | 2 | ||||
Anaemia | 0 | 1 | ||||
Bicytopenia | 0 | 1 | ||||
Cardiac disorders | 1 | 1 | ||||
Acute coronary syndrome | 0 | 1 | ||||
Cardiac failure | 1 | 0 | ||||
Investigations | 2 | 8 | ||||
Transaminases increased | 1 | 7 | ||||
Blood bilirubin increased | 0 | 1 | ||||
C-reactive protein increased | 1 | 0 | ||||
Vascular disorders | 2 | 2 | ||||
Deep vein thrombosis | 1 | 1 | ||||
Circulatory collapse | 1 | 0 | ||||
Peripheral artery thrombosis | 0 | 1 |