Background
Methods
Populations
Assessments
Data analysis
Ethics and good clinical practice
Results
Exposure
Canakinumab pooled dose | ||||||
---|---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | Placebo | Total | |
N = 20 | N = 247 | N = 268 | N = 137 | N = 354 | N = 1026 | |
Duration of exposure (months)
| 3.00 ± 0.0 | 7.29 ± 3.057 | 4.93 ± 2.985 | 6.79 ± 3.119 | 5.82 ± 3.250 | 6.02 ± 3.235 |
≥3, n (%) | 20 (100) | 247 (100) | 268 (100) | 137 (100) | 354 (100) | 1026 (100) |
≥4, n (%) | 0 | 185 (74.9) | 89 (33.2) | 91 (66.4) | 172 (48.6) | 537 (52.3) |
≥6, n (%) | 0 | 179 (72.5) | 87 (32.5) | 90 (65.7) | 166 (46.9) | 522 (50.9) |
≥8, n (%) | 0 | 116 (47.0) | 54 (20.1) | 56 (40.9) | 110 (31.1) | 336 (32.7) |
≥10, n (%) | 0 | 37 (15.0) | 19 (7.1) | 15 (10.9) | 35 (9.9) | 106 (10.3) |
Subject months of exposure | 60.00 | 1800.61 | 1320.22 | 929.68 | 2067.64 | 6178.14 |
Duration of follow-up (months)
| 5.08 ± 1.426 | 6.34 ± 2.243 | 3.40 ± 3.056 | 6.43 ± 1.691 | 4.93 ± 2.898 | 5.07 ± 2.885 |
<1, n (%) | 1 (5.0) | 2 (0.8) | 111 (41.4) | 0 | 73 (20.6) | 187 (18.2) |
≥1, n (%) | 19 (95.0) | 245 (99.2) | 157 (58.6) | 137 (100) | 281 (79.4) | 839 (81.8) |
≥2, n (%) | 18 (90.0) | 231 (93.5) | 115 (42.9) | 137 (100) | 252 (71.2) | 753 (73.4) |
≥3, n (%) | 18 (90.0) | 228 (92.3) | 114 (42.5) | 136 (99.3) | 251 (70.9) | 747 (72.8) |
≥4, n (%) | 18 (90.0) | 227 (91.9) | 109 (40.7) | 135 (98.5) | 247 (69.8) | 736 (71.7) |
≥6, n (%) | 0 | 123 (49.8) | 59 (22.0) | 62 (45.3) | 115 (32.5) | 359 (35.0) |
≥8, n (%) | 0 | 40 (16.2) | 22 (8.2) | 20 (14.6) | 40 (11.3) | 122 (11.9) |
≥10, n (%) | 0 | 12 (4.9) | 7 (2.6) | 5 (3.6) | 15 (4.2) | 39 (3.8) |
Subject months of follow-up | 101.58 | 1565.43 | 910.69 | 881.38 | 1744.57 | 5203.65 |
Demographic variable
| ||||||
Age (years) | 53.9 ± 9.07 | 54.4 ± 9.53 | 55.7 ± 10.05 | 54.9 ± 10.14 | 55.5 ± 9.65 | 55.2 ± 9.78 |
<65, n (%) | 17 (85.0) | 206 (83.4) | 210 (78.4) | 109 (79.6) | 285 (80.5) | 827 (80.6) |
≥65, n (%) | 3 (15.0) | 41 (16.6) | 58 (21.6) | 28 (20.4) | 69 (19.5) | 199 (19.4) |
Sex, n (%) | ||||||
Male | 10 (50.0) | 127 (51.4) | 138 (51.5) | 81 (59.1) | 203 (57.3) | 559 (54.5) |
Female | 10 (50.0) | 120 (48.6) | 130 (48.5) | 56 (40.9) | 151 (42.7) | 467 (45.5) |
Race, n (%) | ||||||
Caucasian | 19 (95.0) | 134 (54.3) | 168 (62.7) | 81 (59.1) | 218 (61.6) | 620 (60.4) |
Black | 1 (5.0) | 12 (4.9) | 8 (3.0) | 5 (3.6) | 14 (4.0) | 40 (3.9) |
Asian | 0 | 81 (32.8) | 77 (28.7) | 41 (29.9) | 97 (27.4) | 296 (28.8) |
Others | 0 | 20 (8.1) | 15 (5.7) | 10 (7.3) | 25 (7.0) | 70 (6.9) |
BMI (kg/m2), n (%) | ||||||
<30 | 9 (45.0) | 131 (53.0) | 115 (42.9) | 72 (52.6) | 183 (51.7) | 510 (49.7) |
≥30 | 11 (55.0) | 116 (47.0) | 153 (57.1) | 65 (47.4) | 171 (48.3) | 516 (50.3) |
HbA1c (%) | 7.6 ± 0.79 | 7.5 ± 0.80 | 7.1 ± 0.74 | 7.6 ± 0.76 | 7.4 ± 0.85 | 7.4 ± 0.81 |
FPG (mmol/L) | 8.8 ± 1.84 | 7.9 ± 1.87 | 7.7 ± 1.86 | 8.1 ± 1.56 | 8.0 ± 1.87 | 7.9 ± 1.83 |
Duration of type 2 diabetes (years) | 5.0 ± 3.62 | 4.6 ± 4.64 | 7.0 ± 6.89 | 4.8 ± 4.70 | 5.6 ± 5.45 | 5.5 ± 5.59 |
Subjects with IGT, n | 0 | 0 | 28 | 0 | 26 | 54 |
Diabetes complications, n (%) | ||||||
Retinopathy | NA | 3 (1.6) | 10 (4.6) | 1 (1.1) | 8 (3.3) | 22 (3.0) |
Neuropathy | NA | 25 (13.3) | 27 (12.4) | 11 (12.0) | 19 (7.8) | 82 (11.1) |
Nephropathy | NA | 2 (1.1) | 8 (3.7) | 4 (4.3) | 7 (2.9) | 21 (2.8) |
Use of statins, n (%) | 2 (10.0) | 64 (25.9) | 104 (38.8) | 32 (23.4) | 87 (24.6) | 289 (28.2) |
Demography
Safety and tolerability
Canakinumab pooled dose | Placebo | ||||
---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | ||
N = 20 | N = 247 | N = 268 | N = 137 | N = 354 | |
Any AEs
| |||||
n (%) | 10 (50.0) | 107 (43.3) | 103 (38.4) | 67 (48.9) | 134 (37.9) |
IR (%) | 16.31 | 10.28 | 16.45 | 12.14 | 11.45 |
Discontinuations due to any AEs
| |||||
n (%) | 1 (5.0) | 1 (0.4) | 0 | 2 (1.5) | 1 (0.3) |
IR (%) | 0.99 | 0.06 | 0.23 | 0.06 | |
Any serious AEs
| |||||
n (%) | 0 | 4 (1.6) | 5 (1.9) | 8 (5.8) | 10 (2.8) |
IR (%) | 0 | 0.26 | 0.55 | 0.94 | 0.58 |
Deaths
| |||||
n (%) | 0 | 0 | 0 | 0 | 0 |
AEs by primary SOCs (occurring in ≥5% of patients in any group)
| |||||
Infections and infestations | |||||
n (%) | 4 (20.0) | 54 (21.9) | 40 (14.9) | 30 (21.9) | 49 (13.8) |
IR (%) | 4.41 | 4.05 | 5.13 | 4.02 | 3.17 |
Musculoskeletal and connective tissue disorders | |||||
n (%) | 1 (5.0) | 22 (8.9) | 14 (5.2) | 11 (8.0) | 27 (7.6) |
IR (%) | 1.03 | 1.48 | 1.62 | 1.33 | 1.65 |
Gastrointestinal disorders | |||||
n (%) | 1 (5.0) | 12 (4.9) | 17 (6.3) | 12 (8.8) | 21 (5.9) |
IR (%) | 1.04 | 0.80 | 1.98 | 1.44 | 1.26 |
Cardiac disorders | |||||
n (%) | 1 (5.0) | 8 (3.2) | 4 (1.5) | 3 (2.2) | 12 (3.4) |
IR (%) | 1.04 | 0.53 | 0.44 | 0.35 | 0.71 |
Eye disorders | |||||
n (%) | 3 (15.0) | 5 (2.0) | 6 (2.2) | 2 (1.5) | 7 (2.0) |
IR (%) | 3.40 | 0.33 | 0.67 | 0.23 | 0.41 |
Renal and urinary disorders | |||||
n (%) | 1 (5.0) | 5 (2.0) | 5 (1.9) | 5 (3.6) | 3 (0.8) |
IR (%) | 1.04 | 0.32 | 0.55 | 0.58 | 0.17 |
Investigations | |||||
n (%) | 0 | 12 (4.9) | 13 (4.9) | 16 (11.7) | 15 (4.2) |
IR (%) | 0.79 | 1.50 | 1.96 | 0.89 | |
Skin and subcutaneous tissue disorders | |||||
n (%) | 0 | 10 (4.0) | 11 (4.1) | 7 (5.1) | 16 (4.5) |
IR (%) | 0.65 | 1.25 | 0.83 | 0.95 |
Adverse events
Preferred term | Canakinumab pooled dose | Placebo | |||
---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | ||
N = 20 | N = 247 | N = 268 | N = 137 | N = 354 | |
Nasopharyngitis | |||||
n (%) | 0 | 15 (6.1) | 10 (3.7) | 11 (8.0) | 21 (5.9) |
IR (%) | 1.00 | 1.15 | 1.31 | 1.26 | |
Bronchitis | |||||
n (%) | 0 | 9 (3.6) | 3 (1.1) | 1 (0.7) | 2 (0.6) |
IR (%) | 0.59 | 0.33 | 0.11 | 0.11 | |
Urinary tract infection | |||||
n (%) | 3 (15.0) | 7 (2.8) | 5 (1.9) | 5 (3.6) | 11 (3.1) |
IR (%) | 3.15 | 0.46 | 0.56 | 0.58 | 0.64 |
Upper respiratory tract infection | |||||
n (%) | 0 | 6 (2.4) | 3 (1.1) | 4 (2.9) | 4 (1.1) |
IR (%) | 0.39 | 0.33 | 0.47 | 0.23 | |
Arthralgia | |||||
n (%) | 0 | 5 (2.0) | 3 (1.1) | 3 (2.2) | 7 (2.0) |
IR (%) | 0.32 | 0.33 | 0.35 | 0.41 | |
Pain in extremity | |||||
n (%) | 0 | 5 (2.0) | 4 (1.5) | 3 (2.2) | 5 (1.4) |
IR (%) | 0.32 | 0.44 | 0.35 | 0.29 | |
Headache | |||||
n (%) | 4 (1.6) | 2 (0.7) | 5 (3.6) | 8 (2.3) | |
IR (%) | 0.26 | 0.22 | 0.58 | 0.47 | |
Cough | |||||
n (%) | 2 (0.8) | 3 (1.1) | 2 (1.5) | 7 (2.0) | |
IR (%) | 0.13 | 0.33 | 0.23 | 0.41 | |
Oropharyngeal pain | |||||
n (%) | 5 (2.0) | 0 | 2 (1.5) | 0 | |
IR (%) | 0.32 | 0.23 |
Serious adverse events
Canakinumab pooled dose | Placebo | ||||
---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | ||
N = 20 | N = 247 | N = 268 | N = 137 | N = 354 | |
Infections and infestations | |||||
n (%) | 0 | 1 (0.4) | 1 (0.4) | 3 (2.2) | 2 (0.6) |
IR (%) | 0.06 | 0.11 | 0.34 | 0.12 | |
Renal and urinary disorders | |||||
n (%) | 0 | 1 (0.4) | 2 (0.7) | 1 (0.7) | 1 (0.3) |
IR (%) | 0.06 | 0.22 | 0.11 | 0.06 | |
Gastrointestinal disorders | |||||
n (%) | 0 | 0 | 1 (0.4) | 1 (0.7) | 1 (0.3) |
IR (%) | 0.11 | 0.11 | 0.06 | ||
Cardiac disorders | |||||
n (%) | 0 | 0 | 0 | 1 (0.7) | 5 (1.4) |
IR (%) | 0.11 | 0.29 | |||
Hepatobiliary disorders | |||||
n (%) | 0 | 0 | 1 (0.4) | 0 | 1 (0.3) |
IR (%) | 0.11 | 0.06 | |||
General disorders and administration site conditions | |||||
n (%) | 0 | 0 | 0 | 0 | 1 (0.3) |
IR (%) | 0.06 | ||||
Musculoskeletal and connective tissue disorders | |||||
n (%) | 0 | 1 (0.4) | 0 | 0 | 1 (0.3) |
IR (%) | 0.06 | 0.06 | |||
Metabolism and nutrition disorders | |||||
n (%) | 0 | 0 | 0 | 2 (1.5) | 0 |
IR (%) | 0.23 | ||||
Investigations | |||||
n (%) | 0 | 0 | 0 | 1 (0.7) | 0 |
IR (%) | 0.11 | ||||
Neoplasms—benign, malignant and unspecified (including cysts and polyps) | |||||
n (%) | 0 | 0 | 0 | 1 (0.7) | 0 |
IR (%) | 0.11 | ||||
Injury, poisoning and procedural complications | |||||
n (%) | 0 | 0 | 1 (0.4) | 0 | 0 |
IR (%) | 0.11 | ||||
Nervous system disorders | |||||
n (%) | 0 | 1 (0.4) | 0 | 0 | 0 |
IR (%) | 0.06 | ||||
Reproductive system and breast disorders | |||||
n (%) | 0 | 1 (0.4) | 0 | 0 | 0 |
IR (%) | 0.06 |
Adverse events of special interest
Canakinumab pooled dose | Placebo | ||||
---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | ||
N = 20 | N = 247 | N = 268 | N = 137 | N = 354 | |
Infections | |||||
n (%) | 4 (20.0) | 54 (21.9) | 40 (14.9) | 30 (21.9) | 49 (13.8) |
IR (%) | 4.41 | 4.05 | 5.13 | 4.02 | 3.17 |
Hypersensitivity/allergy | |||||
n (%) | 0 | 9 (3.6) | 9 (3.4) | 6 (4.4) | 14 (4.0) |
IR (%) | 0 | 0.59 | 1.02 | 0.70 | 0.84 |
Thrombocytopenia | |||||
n (%) | 1 (5.0) | 7 (2.8) | 5 (1.9) | 4 (2.9) | 4 (1.1) |
IR (%) | 1.04 | 0.46 | 0.56 | 0.46 | 0.23 |
Hypertension | |||||
n (%) | 0 | 5 (2.0) | 3 (1.1) | 3 (2.2) | 6 (1.7) |
IR (%) | 0 | 0.32 | 0.33 | 0.35 | 0.35 |
Major adverse cardiovascular events (MACE) | |||||
n (%) | 0 | 3 (1.2) | 4 (1.5) | 2 (1.5) | 9 (2.5) |
IR (%) | 0 | 0.19 | 0.44 | 0.23 | 0.53 |
Hepatic disorders | |||||
n (%) | 0 | 1 (0.4) | 2 (0.7) | 6 (4.4) | 2 (0.6) |
IR (%) | 0 | 0.06 | 0.22 | 0.70 | 0.12 |
Vertigo | |||||
n (%) | 0 | 1 (0.4) | 5 (1.9) | 4 (2.9) | 6 (1.7) |
IR (%) | 0 | 0.06 | 0.56 | 0.46 | 0.3 |
Injection-site reactions | |||||
n (%) | 0 | 0 | 2 (0.7) | 0 | 2 (0.6) |
IR (%) | 0 | 0 | 0.22 | 0 | 0.12 |
Hypoglycaemia | |||||
n (%) | 0 | 0 | 2 (0.7) | 0 | 1 (0.3) |
IR (%) | 0 | 0 | 0.22 | 0 | 0.06 |
Changes in renal function | |||||
n (%) | 0 | 1 (0.4) | 1 (0.4) | 0 | 0 |
IR (%) | 0 | 0.06 | 0.11 | 0 | 0 |
Lymphoid organ toxicity | |||||
n (%) | 0 | 0 | 1 (0.4) | 0 | 0 |
IR (%) | 0 | 0 | 0.11 | 0 | 0 |
Malignancies | |||||
n (%) | 0 | 0 | 0 | 1 (0.7) | 0 |
IR (%) | 0 | 0 | 0 | 0.11 | 0 |
Neutropenia | |||||
n (%) | 0 | 1 (0.4) | 0 | 0 | 0 |
IR (%) | 0 | 0.06 | 0 | 0 | 0 |
Haematology and biochemistry abnormalities
Canakinumab pooled dose | Placebo | ||||
---|---|---|---|---|---|
Low dose | Intermediate dose | Medium dose | High dose | ||
I. Haematology parameters
| |||||
WBC (total) (109/L), N | 20 | 245 | 262 | 136 | 342 |
Any grade 1–4 abnormality, n | 0 | 19 | 18 | 10 | 14 |
IR (%) | 0.0 | 2.14 | 3.22 | 1.86 | 1.25 |
Dose trend test, P value | 0.0884 | ||||
G1 (<LLN–3.0), n (%) | 0 | 18 (7.3) | 15 (5.7) | 10 (7.4) | 13 (3.8) |
IR (%) | 0.0 | 2.03 | 2.68 | 1.86 | 1.16 |
G2 (<3.0–2.0), n (%) | 0 | 1 (0.4) | 4 (1.5) | 1 (0.7) | 1 (0.3) |
IR (%) | 0.0 | 0.11 | 0.68 | 0.18 | 0.09 |
Absolute neutrophil counts (Seg. + bands) (109/L), N | 20 | 222 | 258 | 93 | 288 |
Any grade 1–4 abnormality, n | 1 | 21 | 27 | 13 | 10 |
IR (%) | 0.89 | 2.68 | 4.95 | 4.61 | 1.22 |
Dose trend test, P value | 0.0001 | ||||
G1 (<LLN–1.5), n (%) | 0 | 17 (7.7) | 23 (8.9) | 13 (14.0) | 7 (2.4) |
IR (%) | 0.0 | 2.13 | 4.17 | 4.59 | 0.85 |
G2 (<1.5–1.0), n (%) | 1 (5.0) | 6 (2.7) | 7 (2.7) | 2 (2.2) | 2 (0.7) |
IR (%) | 0.89 | 0.74 | 1.26 | 0.66 | 0.24 |
Platelet counts (direct) (109/L), N | 20 | 245 | 260 | 136 | 342 |
Any grade 1–4 abnormality, n | 1 | 11 | 9 | 4 | 11 |
IR (%) | 0.92 | 1.23 | 1.57 | 0.73 | 1.00 |
Dose trend test, P value | 0.9488 | ||||
G1 (<LLN–75), n (%) | 1 (5.0) | 10 (4.1) | 9 (3.5) | 4 (2.9) | 11 (3.2) |
IR (%) | 0.92 | 1.11 | 1.57 | 0.73 | 1.00 |
G2 (<75–50), n (%) | 0 | 0 | 0 | 1 (0.7) | 0 |
IR (%) | 0.0 | 0.0 | 0.0 | 0.18 | 0.0 |
Absolute lymphocyte counts (109/L), N | 20 | 222 | 258 | 93 | 288 |
Any grade 1–4 abnormality, n | 0 | 2 | 3 | 1 | 7 |
IR (%) | 0.0 | 0.25 | 0.53 | 0.33 | 0.85 |
Dose trend test, P value | 0.2241 | ||||
G1 (<LLN–0.8), n (%) | 0 | 0 | 1 (0.4) | 0 | 3 (1.0) |
IR (%) | 0.0 | 0.0 | 0.18 | 0.0 | 0.36 |
G2 (<0.8–0.5), n (%) | 0 | 2 (0.9) | 2 (0.8) | 1 (1.1) | 4 (1.4) |
IR (%) | 0.0 | 0.25 | 0.36 | 0.33 | 0.48 |
Haemoglobin (g/L), N | 20 | 245 | 262 | 136 | 342 |
Any grade 1–4 abnormality, n | 8 | 49 | 36 | 31 | 76 |
IR (%) | 9.20 | 6.27 | 6.83 | 6.68 | 7.97 |
Dose trend test, P value | 0.1239 | ||||
G1 (<LLN–100), n (%) | 8 (40.0) | 49 (20.0) | 33 (12.6) | 30 (22.1) | 73 (21.3) |
IR (%) | 9.09 | 6.23 | 6.24 | 6.41 | 7.63 |
G2 (<100–80), n (%) | 1 (5.0) | 5 (2.0) | 3 (1.1) | 2 (1.5) | 5 (1.5) |
IR (%) | 0.90 | 0.54 | 0.51 | 0.36 | 0.44 |
II. Biochemistry parameters
| |||||
SGPT (ALT) (U/L), N | 20 | 245 | 262 | 136 | 343 |
Any grade 1–4 abnormality, n | 0 | 2 | 4 | 5 | 2 |
IR (%) | 0.0 | 0.21 | 0.69 | 0.88 | 0.17 |
Dose trend test, P value | 0.0158 | ||||
G1 (>3–5×ULN), n (%) | 0 | 2 (0.8) | 4 (1.5) | 5 (3.7) | 2 (0.6) |
IR (%) | 0.0 | 0.21 | 0.69 | 0.88 | 0.17 |
SGOT (AST) (U/L), N | 20 | 245 | 256 | 136 | 342 |
Any grade 1–4 abnormality, n | 0 | 1 | 0 | 2 | 0 |
IR (%) | 0.0 | 0.11 | 0.0 | 0.35 | 0.0 |
Dose trend test, P value | 0.0777 | ||||
G1 (>3–5×ULN), n (%) | 0 | 1 (0.4) | 0 | 2 (1.5) | 0 |
IR (%) | 0.0 | 0.11 | 0.0 | 0.35 | 0.0 |
Bilirubin (total) (μmol/L), N | 20 | 245 | 265 | 136 | 344 |
Any grade 1–4 abnormality, n | 0 | 0 | 3 | 4 | 6 |
IR (%) | 0.0 | 0.0 | 0.52 | 0.70 | 0.52 |
Dose trend test, P value | 0.6430 | ||||
G1 (>1.5–2×ULN), n (%) | 0 | 0 | 2 (0.8) | 3 (2.2) | 5 (1.5) |
IR (%) | 0.0 | 0.0 | 0.34 | 0.52 | 0.44 |
G2 (>2–3×ULN), n (%) | 0 | 0 | 2 (0.8) | 2 (1.5) | 0 |
IR (%) | 0.0 | 0.0 | 0.34 | 0.35 | 0.0 |
Alkaline phosphatase, serum (U/L), N | 20 | 245 | 263 | 136 | 344 |
Any grade 1–4 abnormality, n | 0 | 0 | 0 | 0 | 1 |
IR (%) | 0.0 | 0.0 | 0.0 | 0.0 | 0.09 |
Dose trend test, P value | 0.2357 | ||||
G1 (>2–3×ULN), n (%) | 0 | 0 | 0 | 0 | 1 (0.3) |
IR (%) | 0.0 | 0.0 | 0.0 | 0.0 | 0.09 |
G2 (>3–5×ULN), n (%) | 0 | 0 | 0 | 0 | 1 (0.3) |
IR (%) | 0.0 | 0.0 | 0.0 | 0.0 | 0.09 |
Creatinine (umol/L), N | 20 | 245 | 265 | 136 | 344 |
Any grade 1–4 abnormality, n | 1 | 10 | 11 | 6 | 10 |
IR (%) | 0.91 | 1.06 | 1.89 | 1.06 | 0.88 |
Dose trend test, P value | 0.3490 | ||||
G1 (>ULN–1.5×ULN), n (%) | 1 (5.0) | 10 (4.1) | 11 (4.2) | 6 (4.4) | 10 (2.9) |
IR (%) | 0.91 | 1.06 | 1.88 | 1.06 | 0.88 |
G2 (>1.5–3×ULN), n (%) | 0 | 1 (0.4) | 1 (0.4) | 0 | 0 |
IR (%) | 0.0 | 0.11 | 0.17 | 0.0 | 0.0 |