Digital Features for this article can be found at https://doi.org/10.6084/m9.figshare.14328938 |
This long-term safety analysis confirms the established safety profile of baricitinib 2 mg in atopic dermatitis. |
There was no further increase in rates for adverse events, serious adverse events, or serious infections with long-term baricitinib 2-mg therapy as compared to rates with baricitinib 2 mg in the placebo-controlled period. Baricitinib 2 mg showed no increase in anemia, neutropenia, lymphopenia, or elevated liver enzymes compared to placebo. |
There was an increase in cases of herpes simplex with baricitinib 2 mg compared with placebo, with lower rates for prolonged baricitinib 2 mg exposure. There was no increase in the risk of eczema herpeticum with baricitinib 2 mg. |
A longer treatment duration is needed to appropriately assess the risk of malignancies and cardiovascular events. |
1 Introduction
2 Methods
2.1 Study Designs and Patients
2.2 Analysis Sets
2.3 Safety Outcomes
2.4 Statistical Analysis
3 Results
3.1 Patients
Placebo-controlled (to week 16) | All-bari-2-mg-AD | ||
---|---|---|---|
Placebo (N = 889) | Baricitinib 2 mg (N = 721) | All-bari-2-mg-AD (N = 1598) | |
Age (years) | 36.3 (13.7) | 36.7 (13.9) | 36.7 (14.2) |
Female, n (%) | 365 (41.1) | 282 (39.1) | 662 (41.4) |
Duration since AD diagnosis (years) | 24.6 (15.0) | 24.8 (14.6) | 24.7 (15.1) |
BMI (kg/m2) | 25.7 (5.4) | 26.3 (6.0) | 26.1 (5.6) |
Geographic region, n (%) | |||
Central/South America and Mexico | 76 (8.5) | 56 (7.8) | 177 (11.1) |
USA/Canada (including Puerto Rico) | 187 (21.0) | 176 (24.4) | 405 (25.3) |
Asia (excluding Japan) | 99 (11.1) | 62 (8.6) | 135 (8.4) |
Japan | 134 (15.1) | 101 (14.0) | 163 (10.2) |
Europe | 365 (41.1) | 297 (41.2) | 637 (39.9) |
Rest of world | 28 (3.1) | 29 (4.0) | 81 (5.1) |
Prior topical therapy, n (%) | |||
Topical corticosteroids | 783 (88.1) | 632 (87.7) | 1437 (89.9) |
Topical calcineurin inhibitor | 461/809 (57.0) | 358/625 (57.3) | 749/1495 (50.1) |
Prior systemic therapy, n (%) | |||
Cyclosporine | 265/800 (33.1) | 271/628 (43.2) | 450/1551 (29.0) |
vIGA-AD score of 4a, n (%) | 384/840 (45.7) | 318/684 (46.5) | 615/1314 (46.8) |
EASIb | 30.7 (12.5) | 30.3 (12.9) | 30.4 (12.8) |
Percentage body surface area affected | 49.5 (23.0) | 48.7 (23.3) | 48.6 (23.2) |
Itch NRSc | 6.9 (2.1) | 6.8 (2.2) | 6.9 (2.1) |
Placebo-controlled (to week 16) | All-bari-2-mg-AD | ||
---|---|---|---|
Placebo (N = 889) | Baricitinib 2 mg (N = 721) | All-bari-2-mg-AD (N = 1598) | |
Exposure | |||
Total patient-years | 252.7 | 210.6 | 1434.2 |
No. of patients with ≥ 52 weeksa, n (%) | – | – | 729 (45.6) |
No. of patients with ≥ 104 weeks, n (%) | – | – | 34 (2.1) |
Median duration, days | 113 | 113 | 330 |
Maximum exposure, days | 168 | 128 | 869 |
AEs, n (%) [IR]b | |||
Any treatment-emergent AE | 460 (51.6) [277.6] | 421 (57.9) [325.5] | 1032 [159.6] |
Serious AE | 24 (2.7) [9.2] | 12 (1.6) [5.2] | 68 [4.7] |
Interruption of the study drug because of AE | 18 (2.0) [7.0] | 28 (3.5) [12.0] | 118 [8.4] |
Discontinuation of the study drug because of AE | 17 (1.8) [6.1] | 14 (1.9) [6.2] | 56 [3.8] |
Death | 0 | 0 | 0 |
Infections, n (%) [IR]b | |||
Treatment-emergent infections | 252 (28.4) [117.0] | 251 (34.4) [146.0] | 732 [80.6] |
Serious infections | 6 (0.7) [2.5] | 4 (0.5) [1.4] | 22 [1.5] |
Skin infections requiring antibiotic treatment | 46 (5.4) [19.0] | 37 (5.5) [19.1] | 37 [2.6] |
Herpes simplex cluster | 23 (2.8) [9.8] | 27 (3.8) [13.2] | 108 [7.7] |
Herpes simplex | 8 (0.9) [3.2] | 13 (2.0) [7.1] | 38 [2.6] |
Oral herpes | 10 (1.3) [4.5] | 12 (1.5) [5.0] | 58 [4.0] |
Kaposi’s varicelliform eruption | 0 | 1 (0.2) [0.7] | 5 [0.3] |
Genital herpes simplex | 0 | 1 (0.1) [0.3] | 2 [0.1] |
Genital herpes | 1 (0.2) [0.7] | 0 | 2 [0.1] |
Ophthalmic herpes simplex | 0 | 0 | 3 [0.2] |
Herpes opthalmic | 0 | 0 | 2 [0.1] |
Eczema herpeticum | 4 (0.4) [1.3] | 0 | 15 [1.0] |
Eczema herpeticum cluster | 4 (0.4) [1.3] | 1 (0.2) [0.7] | 20 [1.4] |
Eczema herpeticum | 4 (0.4) [1.3] | 0 | 15 [1.0] |
Kaposi’s varicelliform eruption | 0 | 1 (0.2) [0.7] | 5 [0.3] |
Herpes zoster | 3 (0.3) [1.0] | 6 (0.8) [2.7] | 30 [2.1] |
Tuberculosis | 0 | 0 | 0 |
Opportunistic infection excluding tuberculosisc | 1 (0.1) [0.4] | 1 (0.1) [0.3] | 3 [0.2] |
Malignancy, n (%) [IR]b | |||
Malignancies other than NMSC | 2 (0.2) [0.66] | 0 | 5 [0.34] |
NMSC | 1 (0.2) [0.68] | 0 | 4 [0.27] |
Cardiovascular AEs of special interest, n (%) [IR]b | |||
MACEd,e | 0 | 0 | 2/1561 [0.14] |
DVTd | 0 | 0 | 0 |
PEd | 0 | 0 | 0 |
Peripheral venous thrombosisd | 0 | 0 | 1/1561 [0.07] |
Arterial thromboembolic eventc | 0 | 0 | 1 [0.07] |
Gastrointestinal disorder, n (%) [IR]b | |||
Gastrointestinal perforation | 0 | 0 | 0 |
Ocular AEs, n (%) [IR]b | |||
Conjunctival disorders | 18 (2.4) [8.7] | 15 (2.0) [6.8] | 51 [3.5] |
3.2 TEAEs
Placebo-controlled (to week 16)a | All-bari-2-mg-AD | ||
---|---|---|---|
Placebo (N = 889) [PYE = 252.7] n (adj %) [adj IR] | Baricitinib 2 mg (N = 721) [PYE = 210.6] n (adj %) [adj IR] | All-bari-2-mg-AD (N = 1598) [PYE = 1434.2] n [IR] | |
Treatment-emergent adverse event by preferred term with frequency of at least 2% in any treatment group in the placebo-controlled dataset | |||
Nasopharyngitis | 93 (10.6) [39.0] | 74 (10.3) [36.9] | 231 [17.8] |
Headache | 30 (3.5) [12.7] | 40 (6.3) [22.3] | 96 [6.8] |
Upper respiratory tract infection | 23 (2.4) [8.5] | 34 (4.5) [15.4] | 104 [7.4] |
Nausea | 11 (1.1) [3.9] | 19 (2.3) [7.8] | 29 [2.0] |
Diarrhea | 17 (2.0) [7.0] | 16 (2.0) [6.7] | 35 [2.4] |
Herpes simplex | 8 (0.9) [3.2] | 13 (2.0) [7.1] | 38 [2.6] |
Permanent discontinuation of the study drug because of adverse event by system organ class | |||
Skin and subcutaneous tissue disordersb | 4 (0.4) [1.3] | 2 (0.2) [0.7] | 12 [0.8] |
Infections and infestations | 3 (0.3) [1.1] | 2 (0.3) [1.0] | 9 [0.6] |
Investigations | 2 (0.3) [1.1] | 2 (0.3) [1.0] | 6 [0.4] |
Nervous system disorders | 2 (0.2) [0.7] | 2 (0.2) [0.8] | 4 [0.3] |
Blood and lymphatic system disorders | 3 (0.3) [0.9] | 1 (0.1) [0.4] | 1 [0.1] |
Congenital, familial, and genetic disorders | 0 | 1 (0.1) [0.4] | 1 [0.1] |
Eye disorders | 0 | 1 (0.1) [0.7] | 1 [0.1] |
Gastrointestinal disorders | 1 (0.1) [0.4] | 1 (0.1) [0.3] | 5 [0.3] |
General disorders and administration-site conditions | 0 | 1 (0.1) [0.3] | 4 [0.3] |
Psychiatric disorders | 0 | 1 (0.2) [0.7] | 1 [0.1] |
Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 2 (0.2) [0.7] | 0 | 4 [0.3] |
Renal and urinary disorders | 0 | 0 | 1 [0.1] |
Respiratory, thoracic, and mediastinal disorders | 0 | 0 | 1 [0.1] |
Cardiac disorders | 0 | 0 | 2 [0.1] |
Injury, poisoning, and procedural complications | 0 | 0 | 2 [0.1] |
Musculoskeletal and connective tissue disorders | 0 | 0 | 1 [0.1] |
Vascular disorders | 0 | 0 | 1 [0.1] |
3.3 AEs of Special Interest
3.3.1 Infections
3.3.2 Cardiovascular Events
3.3.3 Malignancies
3.3.4 Gastrointestinal Disorders
3.3.5 Conjunctival Disorders
3.3.6 Laboratory Evaluation
Placebo-controlled (to week 16) | All-bari-2-mg-AD | ||
---|---|---|---|
Placebo (N = 889) | Baricitinib 2 mg (N = 721) | All-bari-2-mg-AD (N = 1598) | |
Creatinine phosphokinase | |||
Increase to ≥ Grade 1 (> ULN and ≤ 2.5× ULN) | 84/783 (10.7) | 125/638 (19.6) | 314/1314 (23.9) |
Increase to ≥ Grade 2 (> 2.5× ULN and ≤ 5× ULN) | 26/856 (3.0) | 33/697 (4.7) | 99/1492 (6.6) |
Increase to ≥ Grade 3 (> 5× ULN and ≤ 10× ULN) | 16/865 (1.8) | 16/703 (2.3) | 48/1520 (3.2) |
Increase to ≥ Grade 4 (> 10× ULN) | 10/869 (1.2) | 8/706 (1.1) | 26/1534 (1.7) |
Hemoglobin | |||
Increase to ≥ Grade 1 (< 7.27 mmol (Fe)/L [female]/8.18 mmol (Fe)/L [male] and ≥ 6.2 mmol (Fe)/L) | 38/818 (4.6) | 42/659 (6.4) | 104/1420 (7.3) |
Increase to ≥ Grade 2 (< 6.2 mmol (Fe)/L and ≥ 4.9 mmol (Fe)/L) | 4/870 (0.5) | 3/706 (0.4) | 13/1540 (0.8) |
Increase to ≥ Grade 3 (< 4.9 mmol (Fe)/L and ≥ 4.0 mmol (Fe)/L) | 0 | 0 | 0 |
Neutrophils | |||
Increase to ≥ Grade 3 (< 1.0 billion/L and ≥ 0.5 billion/L) | 0 | 1/707 (0.1) | 2/1542 (0.1) |
Lymphocytes | |||
Increase to ≥ Grade 3 (< 0.5 billion/L and ≥ 0.2 billion/L) | 2/868 (0.2) | 1/707 (0.1) | 8/1542 (0.5) |
Platelets | |||
Thrombocytosis ≤ 600 billions/L to > 600 billions/L | 0 | 8/706 (1.1) | 15/1538 (1.0) |
LDL cholesterol | |||
Increase to borderline high (≥ 3.36 mmol/L and < 4.14 mmol/L), high (≥ 4.14 mmol/L and < 4.91 mmol/L), or very high (≥ 4.91 mmol/L) | 41/643 (6.4) | 64/540 (11.9) | 229/1154 (19.8) |
HDL cholesterol | |||
Increase to high (≥ 1.55 mmol/L) | 73/524 (13.9) | 92/438 (21.0) | 254/921 (27.6) |
Triglycerides | |||
Increase to very high (≥ 5.65 mmol/L) | 8/789 (1.0) | 4/632 (0.6) | 12/1415 (0.8) |
Alanine aminotransferase | |||
≥ 3× ULN | 9/872 (1.0) | 5/709 (0.7) | 26/1551 (1.7) |
≥ 5× ULN | 1/872 (0.1) | 1/709 (0.1) | 2/1551 (0.1) |
≥ 10× ULN | 0 | 0 | 1/1551 (0.1) |
Aspartate aminotransferase | |||
≥ 3× ULN | 9/872 (1.0) | 5/709 (0.7) | 25/1551 (1.6) |
≥ 5× ULN | 5/872 (0.6) | 2/709 (0.3) | 11/1551 (0.7) |
≥ 10× ULN | 1/872 (0.1) | 0 | 0 |