Introduction: Dose escalation is a common strategy to address inadequate or lost response in patients
(pts) with Crohn’s disease (CD); dose escalations or alternative dosing regimens are
permitted in certain cases by the Summary of Product Characteristics (SmPC) of various
biologic treatments. Given lack of recent data, we aimed to evaluate real-world data
in pts with moderately to severely active CD in Germany to identify and characterize
real-world dosing and escalation patterns for advanced biologic therapies.
Methods: We retrospectively analyzed data from the WIG2 benchmark database (anonymized healthcare
claims). Adults (≥18 years) with moderately to severely active CD in Germany who started
a new biologic therapy from 2020–2021 were included. Pts were required to have≥1 prescription
for a CD-indicated biologic index drug (adalimumab, infliximab, ustekinumab, or vedolizumab)
in the same quarter as≥1 CD diagnostic code, without a diagnostic code for ulcerative
colitis. Analyses were conducted in the total group and stratified by biologic-naïve
and -experienced pts. Dose escalations were defined as a>30% increase of the prescribed
daily dose (PDD) compared with the minimum SmPC-recommended defined daily dose (DDD).
Results: In total, 816 German pts with CD from the WIG2 database who received≥1 advanced index
therapy were included in this analysis. Baseline characteristics indicated demographic
variations among pts receiving different index therapies, as well as between biologic-naïve
and biologic-experienced pts ([Table 1]). Mean doses of index biologic therapies during the first 365 treatment days ([Table 2]) predominantly exceeded the SmPC-recommended minimum maintenance dose, especially
in biologic-experienced pts. Within 12 months of maintenance dose initiation, pts
having≥1 dose escalation ranged from 50% of pts treated with adalimumab to 86% treated
with ustekinumab; dose escalation was generally more frequent in biologic-experienced
pts. Mean time to dose escalation ranged from 95.3 days with ustekinumab to 123.2
days with vedolizumab, while the mean duration of dose escalation ranged from 54.9
days with vedolizumab to 131.4 days with ustekinumab ([Table 3]).
Table 1 Baseline characteristics
|
Index drug
|
Group
|
N
|
Mean age, years (SD)
|
Male sex, n (%)
|
|
Adalimumab
|
Total
|
328
|
40.1 (14.3)
|
143 (43.6)
|
|
Biologic-naïve
|
260
|
40.4 (14.8)
|
110 (42.3)
|
|
Biologic-experienced
|
68
|
38.9 (12.6)
|
33 (48.5)
|
|
Infliximab
|
Total
|
220
|
37.7(13.5)
|
104 (47.3)
|
|
Biologic-naïve
|
136
|
38.8 (14.8)
|
75 (55.2)
|
|
Biologic-experienced
|
84
|
35.9 (11.0)
|
29 (34.5)
|
|
Ustekinumab
|
Total
|
237
|
40.7 (14.9)
|
103 (43.5)
|
|
Biologic-naïve
|
63
|
44.6 (16.0)
|
28 (44.4)
|
|
Biologic-experienced
|
174
|
39.3 (14.2)
|
75 (43.1)
|
|
Vedolizumab
|
Total
|
177
|
41.9 (15.5)
|
81 (45.8)
|
|
Biologic-naïve
|
56
|
44.1 (18.2)
|
21 (37.5)
|
|
Biologic-experienced
|
121
|
40.9 (14.0)
|
60 (49.6)
|
SD, standard deviation.
Table 2 Prescribed maintenance dose of index advanced biologic therapies.
|
Index drug
|
Administration route
|
Group
|
Na
|
Mean PDD,b mg/day (SD)
|
Percent of minimum DDD,b mean (SD)
|
|
Adalimumab
|
s.c.
|
Total
|
254
|
3.11 (0.98)
|
108.8 (34.2)
|
|
Biologic-naïve
|
198
|
3.02 (0.83)
|
105.8 (28.9)
|
|
Biologic-experienced
|
56
|
3.42 (1.36)
|
119.5 (47.5)
|
|
Infliximab
|
i.v.
|
Total
|
129
|
8.78 (3.34)
|
129.4 (48.1)
|
|
Biologic-naïve
|
78
|
8.77 (3.56)
|
127.0 (46.9)
|
|
Biologic-experienced
|
51
|
8.81 (3.00)
|
133.0 (50.1)
|
|
s.c.
|
Total
|
39
|
9.29 (3.13)
|
108.2 (36.5)
|
|
Biologic-naïve
|
23
|
8.87 (1.19)
|
103.3 (13.9)
|
|
Biologic-experienced
|
16
|
9.89 (4.70)
|
115.3 (54.8)
|
|
Ustekinumab
|
s.c.
|
Total
|
194
|
1.45 (0.37)
|
136.3 (35.2)
|
|
Biologic-naïve
|
51
|
1.37 (0.27)
|
129.3 (25.6)
|
|
Biologic-experienced
|
143
|
1.47 (0.40)
|
138.8 (37.9)
|
|
Vedolizumab
|
i.v.
|
Total
|
74
|
6.63 (2.76)
|
124.1 (51.6)
|
|
Biologic-naïve
|
23
|
5.74 (1.31)
|
107.5 (24.5)
|
|
Biologic-experienced
|
51
|
7.02 (3.14)
|
131.5 (58.7)
|
|
s.c.
|
Total
|
63
|
7.48 (1.48)
|
96.9 (19.2)
|
|
Biologic-naïve
|
18
|
6.75 (1.40)
|
87.4 (18.1)
|
|
Biologic-experienced
|
45
|
7.77 (1.43)
|
100.7 (18.5)
|
aPatients with at least two application-specific prescriptions of respective index
drug in maintenance phase. bDDD and PDD are based on total prescribed dosage within the first 365 treatment days:
Percentage values represent the PDD compared with the minimum recommended daily dose
according to the SmPC. Values>100% indicate higher than minimum recommended dosing
DDD, defined daily dose; i.v., intravenous; PDD, prescribed daily dose; s.c., subcutaneous; SD, standard deviation
Table 3 Dose escalationsa, time-to dose escalation, and duration of escalated advanced biologic
therapies.
|
Index drug
|
Group
|
N
|
Patients with dose escalation, n (%)
|
Mean time to dose escalation,b days (SD)
|
Mean duration of dose escalation,b days (SD)
|
|
Adalimumab
|
Total
|
254
|
127 (50.0)
|
120.0 (113.2)
|
75.4 (74.7)
|
|
Biologic-naïve
|
198
|
95 (48.0)
|
114.0 (110.6)
|
69.3 (67.0)
|
|
Biologic-experienced
|
56
|
32 (57.1)
|
139.3 (120.5)
|
95.0 (93.7)
|
|
Infliximab
|
Total
|
157
|
108 (68.8)
|
113.5 (115.4)
|
82.8 (84.7)
|
|
Biologic-naïve
|
97
|
62 (63.9)
|
121.2 (118.1)
|
87.5 (88.1)
|
|
Biologic-experienced
|
60
|
46 (76.7)
|
102.6 (111.6)
|
76.2 (79.7)
|
|
Ustekinumab
|
Total
|
194
|
167 (86.1)
|
95.3 (115.4)
|
131.4 (101.6)
|
|
Biologic-naïve
|
51
|
44 (86.3)
|
102.2 (119.2)
|
139.9 (109.0)
|
|
Biologic-experienced
|
143
|
123 (86.0)
|
93.0 (114.3)
|
128.6 (99.1)
|
|
Vedolizumab
|
Total
|
127
|
73 (57.5)
|
123.2 (118.5)
|
54.9 (67.7)
|
|
Bio-naïve
|
38
|
18 (47.4)
|
129.6 (126.7)
|
59.1 (95.8)
|
|
Bio-experienced
|
89
|
55 (61.8)
|
121.4 (116.8)
|
53.6 (58.0)
|
aDefined as>30% over minimal maintenance defined daily dose (based on the dosage between
two prescriptions). bOnly patients who escalated dose were included. SD, standard deviation.
Conclusion: Our analysis of dosing patterns showed that maintenance dosing frequently exceeded
the SmPC-recommended minimum across the analyzed advanced biologic therapies. Further,
dose escalations were common during maintenance therapy.
