Table 4.
All serious adverse events, adverse events occurring in 10% or more of patients in any treatment group, and adverse events of special interest
| 14-day full-dose group (n=209) | 14-day low-dose group (n=102) | 6-day full-dose group (n=106) | Placebo group (n=99) | |
|---|---|---|---|---|
|
Any adverse event
| ||||
| Total adverse events | 207 (99%) | 101 (99%) | 106 (100%) | 98 (99%) |
| Blood and lymphatic system disorders | 181 (87%)* | 88 (86%)* | 85 (80%)* | 51 (52%) |
| Lymphopenia | 153 (73%)* | 70 (69%)* | 79 (75%)* | 19 (19%) |
| Leukopenia | 98 (47%)* | 49 (48%)* | 50 (47%)* | 23 (23%) |
| Neutropenia | 76 (36%)* | 39 (38%)* | 21 (20%) | 20 (20%) |
| Anaemia | 30 (14%) | 13 (13%) | 10 (9%) | 13 (13%) |
| Thrombocytopenia | 21 (10%) | 8 (8%) | 15 (14%) | 10 (10%) |
| Gastrointestinal disorders | 71 (34%) | 31 (30%) | 44 (42%)* | 26 (26%) |
| Nausea | 41 (20%) | 16 (16%) | 21 (20%) | 11 (11%) |
| Vomiting | 30 (14%)* | 8 (8%) | 14 (13%)* | 5 (5%) |
| General disorders and administration site conditions | 89 (43%) | 41 (40%) | 44 (42%) | 36 (36%) |
| Pyrexia | 44 (21%) | 18 (18%) | 28 (26%) | 20 (20%) |
| Fatigue | 22 (11%) | 9 (9%) | 15 (14%)* | 5 (5%) |
| Chills | 20 (10%)* | 5 (5%) | 13 (12%)* | 2 (2%) |
| Hepatobiliary disorders | 24 (12%) | 10 (10%) | 9 (9%) | 9 (9%) |
| Immune system disorders | 18 (9%) | 3 (3%) | 9 (9%) | 3 (3%) |
| Cytokine release syndrome† | 12 (6%)* | 2 (2%) | 8 (8%)* | 0 |
| Infections and infestations | 94 (45%) | 53 (52%) | 55 (52%) | 54 (55%) |
| Upper respiratory tract infection | 26 (12%) | 19 (19%) | 21 (20%) | 15 (15%) |
| Nasopharyngitis | 21 (10%) | 9 (9%) | 13 (12%) | 11 (11%) |
| Acute mononucleosis-like syndrome† | 15 (7%) | 4 (4%) | 5 (5%) | 8 (8%) |
| Injury, poisoning and procedural complications | 22 (11%) | 8 (8%) | 12 (11%) | 8 (8%) |
| Laboratory investigations | 190 (91%) | 93 (91%) | 99 (93%)* | 84 (85%) |
| Blood bicarbonate decreased | 83 (40%) | 57 (56%)* | 38 (36%) | 36 (36%) |
| Haemoglobin decreased | 66 (32%) | 32 (31%) | 38 (36%) | 30 (30%) |
| Aspartate aminotransferase increased | 72 (34%) | 25 (25%) | 35 (33%) | 30 (30%) |
| White blood cell count decreased | 79 (38%)* | 27 (27%) | 34 (32%)* | 18 (18%) |
| Alanine aminotransferase increased | 72 (34%)* | 25 (25%) | 31 (29%)* | 16 (16%) |
| Lymphocyte count decreased | 46 (22%)* | 16 (16%) | 25 (24%)* | 11 (11%) |
| Neutrophil count decreased | 41 (20%) | 17 (17%) | 25 (24%) | 14 (14%) |
| Blood alkaline phosphatase increased | 28 (13%)* | 18 (18%) | 16 (15%) | 25 (25%) |
| Blood sodium decreased | 37 (18%) | 17 (17%) | 14 (13%) | 15 (15%) |
| Platelet count decreased | 32 (15%) | 12 (12%) | 15 (14%) | 9 (9%) |
| Blood calcium decreased | 26 (12%) | 12 (12%) | 11 (10%) | 9 (9%) |
| γ-glutamyltransferase increased | 9 (4%)* | 7 (7%) | 5 (5%) | 10 (10%) |
| Metabolism and nutrition disorders | 133 (64%) | 64 (63%) | 69 (65%) | 64 (65%) |
| Hyponatraemia | 66 (32%) | 38 (37%) | 39 (37%) | 33 (33%) |
| Hypocalcaemia | 55 (26%) | 21 (21%) | 29 (27%) | 24 (24%) |
| Hypoalbuminaemia | 20 (10%) | 9 (9%) | 13 (12%) | 8 (8%) |
| Hypokalaemia | 16 (8%) | 7 (7%) | 9 (9%) | 11 (11%) |
| Hyperkalaemia | 20 (10%) | 11 (11%) | 12 (11%) | 11 (11%) |
| Musculoskeletal and connective tissue disorders | 29 (14%) | 17 (17%) | 14 (13%) | 8 (8%) |
| Nervous system disorders | 67 (32%) | 30 (29%) | 30 (28%) | 23 (23%) |
| Headache | 53 (25%)* | 25 (25%) | 26 (25%) | 15 (15%) |
| Renal and urinary disorders | 26 (12%) | 19 (19%) | 18 (17%) | 9 (9%) |
| Proteinuria | 24 (12%) | 17 (17%) | 12 (11%) | 9 (9%) |
| Respiratory, thoracic, and mediastinal disorders | 43 (21%) | 17 (17%) | 14 (13%) | 20 (20%) |
| Oropharyngeal pain | 18 (9%) | 7 (7%) | 8 (8%) | 11 (11%) |
| Skin and subcutaneous tissue disorders | 117 (56%)* | 58 (57%)* | 61 (58%)* | 21 (21%) |
| Rash (of special interest)† | 109 (52%)* | 55 (54%)* | 56 (53%)* | 20 (20%) |
| Any rash | 67 (32%)* | 44 (43%)* | 37 (35%)* | 11 (11%) |
| Pruritus | 32 (15%)* | 10 (10%) | 11 (10%) | 4 (4%) |
|
| ||||
|
Any serious adverse event
| ||||
| Total serious adverse events | 19 (9%) | 11 (11%) | 12 (11%) | 9 (9%) |
| Neutropenia | 1 (<1%) | 0 | 1 (1%) | 1 (1%) |
| Lymphopenia | 1 (<1%) | 0 | 0 | 0 |
| Eye disorders (corneal erosion, contact subcapsular) | 1 (<1%) | 0 | 1 (1%) | 0 |
| Abdominal pain | 1 (<1%) | 0 | 0 | 0 |
| Coeliac disease | 0 | 0 | 1 (1%) | 0 |
| Gastritis | 0 | 1 (1%) | 0 | 0 |
| Intestinal obstruction | 0 | 0 | 1 (1%) | 0 |
| Vomiting | 0 | 1 (1%) | 0 | 0 |
| Non-cardiac chest pain | 0 | 0 | 0 | 1 (1%) |
| Fever | 1 (<1%) | 0 | 0 | 0 |
| Hepatobiliary disorders | 1 (<1%) | 0 | 1 (1%) | 0 |
| Immune system disorders (hypersensitivity) | 1 (<1%) | 0 | 0 | 0 |
| Gastroenteritis, viral | 1 (<1%) | 0 | 1 (1%) | 0 |
| Anal abscess | 0 | 0 | 1 (1%) | 0 |
| Appendicitis | 1 (<1%) | 0 | 0 | 0 |
| Bronchitis | 0 | 1 (1%) | 0 | 0 |
| Cellulitis | 0 | 0 | 0 | 1 (1%) |
| Gastritis viral | 0 | 0 | 1 (1%) | 0 |
| Gastroenteritis | 0 | 0 | 1 (1%) | 0 |
| Infection | 0 | 0 | 1 (1%) | 0 |
| Paronychia | 0 | 0 | 0 | 1 (1%) |
| Pneumonia | 0 | 1 (1%) | 0 | 0 |
| Pulmonary tuberculosis | 0 | 1 (1%) | 0 | 0 |
| Tuberculosis | 0 | 0 | 0 | 1 (1%) |
| Injury, poisoning, and procedural complications | 1 (<1%) | 0 | 0 | 1 (1%) |
| Abnormal nuclear MRI of brain | 0 | 0 | 1 (1%) | 0 |
| Diabetic ketoacidosis | 5 (2%) | 3 (3%) | 1 (1%) | 0 |
| Hyperglycaemia | 1 (<1%) | 1 (1%) | 1 (1%) | 1 (1%) |
| Diabetes mellitus inadequate control | 1 (<1%) | 2 (2%) | 0 | 0 |
| Hypoglycaemic seizure | 1 (<1%) | 1 (1%) | 1 (1%) | 0 |
| Hypoglycaemic unconsciousness | 0 | 0 | 1 (1%) | 1 (1%) |
| Dehydration | 1 (<1%) | 0 | 0 | 0 |
| Ketosis | 0 | 0 | 0 | 1 (1%) |
| Metastatic malignant melanoma | 0 | 1 (1%) | 0 | 0 |
| Hypoglycaemic coma | 1 (<1%) | 0 | 0 | 0 |
| Complication of pregnancy | 0 | 0 | 0 | 1 (1%) |
| Depression | 0 | 1 (1%) | 1 (1%) | 0 |
| Epididymitis | 0 | 0 | 1 (1%) | 0 |
| Subclavian vein thrombosis | 1 (<1%) | 0 | 0 | 0 |
Data are number of patients (%). See webappendix pp 15–17 for actual blood count and liver function changes over time. No significant differences in serious adverse events were noted for any of the intervention groups versus placebo. Other adverse events occurring in less than 10% of patients in any treatment group were: cardiac disorders (including palpitations, bradycardia, cardiomyopathy), ear and labyrinth disorders (including ear pain, vertigo, tinnitus), eye disorders (including conjunctivitis), endocrine disorders (including goitre), neoplasms (benign, malignant, and unspecified, including cysts and polyps), psychiatric disorders (including anxiety, insomnia, depression), vascular disorders (including flushing), pregnancy, puerperium, and perinatal conditions, and reproductive system and breast disorders.
*
p<0·05 dose versus placebo.
†
Prespecified adverse event of special interest.