Introduction
Due to lack of published data on ustekinumab (UST) use in Greece, we aimed to generate local real-world evidence (RWE) on UST treatment persistence and clinical outcomes [including patient-reported outcomes (PROs)] in patients with Crohn’s Disease (CD).
Aims & Methods
REASSURE is an ongoing, non-interventional, 24-month prospective study of adult (18-80 years old) patients with CD, who commenced therapy with UST as 1st, 2nd or 3rd biologic therapy as per approved label in Greece. Harvey-Bradshaw Index (HBI) and PROs are collected by routine assessments at baseline (start of UST) and every 6 months thereafter. PROs include the Inflammatory Bowel Disease Questionnaire (IBDQ), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, and the Work Productivity and Activity Impairment Questionnaire in CD (WPAI:CD). Interim analysis was performed when all enrolled patients completed 1 year of follow-up.
Results
Between April 2019 and March 2022, 169 eligible patients [median (Interquartile range, IQR) age at baseline: 45 (35.0-54.0) years; bio-naïve: 35.5%; employed: 43.8%] were enrolled in 19 gastroenterology clinics and completed 1-year of follow-up. The median time from CD diagnosis to UST initiation was 7.0 (1.8-13.0) years.
The 12-month persistence rate was 84.0% (95% Confidence Interval: 78.5-89.5%). Over a median treatment duration of 12.3 months, a median of 7.0 (6.0 - 8.0) intravenous (IV) and subcutaneous (SC) injections were received. At 12 months, 14.2% (24/169) of patients discontinued UST (mean duration of 6.3 months) due to lack/loss of efficacy (10/24), safety issues (8/24), loss to follow-up (3/24), patient’s decision (2/24) and death (1/24; unrelated to UST).
The baseline median values for total ΗΒΙ (8.0), IBDQ (166.0), FACIT-F (33.0), WPAI:CD work productivity loss (30.0), and activity impairment scores (35.0) significantly improved (p<0.01) at 12 months, with median changes of -4.0, 17.1, 4.0, -10.0, and 10.0, respectively, among paired observations. Similar improvements were noted in the subgroups per treatment line. The UST-related adverse events (AE) and serious AE rates were 18.3% (31/169) and 4.7% (8/169) respectively. Baseline data and 12-month outcomes are shown in Table 1.
Table 1: Baseline characteristics and 12-month study outcomes
| Overall (N=169) | Bio-naïve (1L) (N=60) | Bio-experienced (N=109) | UST as 2L (N=60) | UST as 3L (N=49) |
| Time from CD diagnosis to UST initiation, median (IQR), years | 7.0 (1.8-13.0) | 1.3 (0.3-6.2) | 10.1 (5.9-15.9) | 8.2 (3.8-11.7) | 12.9 (9.0-22.1) |
| N | npt (%) | N | npt (%) | N | npt (%) | N | npt (%) | N | npt (%) |
Baseline characteristics
Age ≤50 years
Females
At least 1 comorbidity
Prior CD-related surgery
Prior systemic treatment for CD a
Stricturing and/or penetrating disease
Extraintestinal manifestations
Steroid-dependent/refractory disease
Maintenance UST dosage: 90 mg SC Q8W
UST initiated as monotherapy | 169
169
169
169
169
162
167
149
169
169 | 106 (62.7)
86 (50.9)
93 (55.0)
54 (32.0)
158 (93.5)
70 (43.2)
61 (36.5)
24 (16.1)
152 (89.9)
99 (58.6) | 60
60
60
60
60
57
60
55
60
60 | 31 (51.7)
25 (41.7)
33 (55.0)
3 (5.0)
49 (81.7)
19 (33.3)
19 (31.7)
10 (18.2)
50 (83.3)
37 (61.7) | 109
109
109
109
109
105
107
94
109
109 | 75 (68.8)
61 (56.0)
60 (55.0)
51 (46.8)
109 (100.0)
51 (48.6)
42 (39.3)
14 (14.9)
102 (93.6)
62 (56.9) | 60
60
60
60
60
57
59
52
60
60 | 45 (75.0)
30 (50.0)
35 (58.3)
24 (40.0)
60 (100.0)
27 (47.4)
23 (39.0)
5 (9.6)
56 (93.3)
32 (53.3) | 49
49
49
49
49
48
48
42
49
49 | 30 (61.2)
31 (63.3)
25 (51.0)
27 (55.1)
49 (100.0)
24 (50.0)
19 (39.6)
9 (21.4)
46 (93.9)
30 (61.2) |
| Overall persistence to UST treatment (At Month 12b) | 169 | 142 (84.0) | 60 | 52 (86.7) | 109 | 90 (82.6) | 60 | 53 (88.3) | 49 | 37 (75.5) |
| No disease activity based on HBI c (At Month 12) | 131 | 102 (77.9) | 49 | 42 (85.7) | 82 | 60 (73.2) | 49 | 37 (75.5) | 33 | 23 (69.7) |
IBDQ response d
At Month 12 (as observed)
At Month 12 (imputed)g | 126
165 | 65 (51.6)
72 (43.6) | 49
59 | 25 (51.0)
28 (47.5) | 77
106 | 40 (51.9)
44 (41.5) | 47
58 | 24 (51.1)
25 (43.1) | 30
48 | 16 (53.3)
19 (39.6) |
FACIT-F significant improvement e
At Month 12 (as observed)
At Month 12 (imputed)g | 130
167 | 66 (50.8)
71 (42.5) | 51
60 | 26 (51.0)
27 (45.0) | 79
107 | 40 (50.6)
44 (41.1) | 49
60 | 23 (46.9)
24 (40.0) | 30
47 | 17 (56.7)
20 (42.6) |
CMI in work productivity loss f
At Month 12(as observed)
At Month 12 (imputed)g | 41
51 | 23 (56.1)
25 (49.0) | 18
20 | 10 (55.6)
10 (50.0) | 23
31 | 13 (56.5)
15 (48.4) | 17
22 | 10 (58.8)
11 (50.0) | 6
9 | 3 (50.0)
4 (44.4) |
a Including: biologic agents, corticosteroids, immunosuppressants, salicylates, antibiotics
b For three patients (of whom one patient was bio-naïve and the other two patients initiated UST as 3LT) persistence to treatment with UST at 12 months post-baseline was unknown.
c No disease activity was defined as an HBI score of 0-4 points, for patients remaining on UST.
d IBDQ response was defined as an IBDQ score change of ≥16 points from baseline.
e FACIT-F significant improvement was defined as a FACIT-F score change of ≥4 points from baseline.
f CMI in work productivity loss is defined as a decrease in WPAI:CD work productivity loss score of ≥7% from baseline.
g Data imputation was performed using last observation carried forward analysis.
Abbreviations: CD: Crohn's Disease, CMI: Clinically Meaningful Improvement; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; HBI: Harvey-Bradshaw Index; IBDQ: Inflammatory Bowel Disease Questionnaire, IQR: Interquartile Range; IV: intravenous, N: number of patients with available data, Q8W: every 8 weeks, SC: subcutaneous, UST: ustekinumab; WPAI:CD: Work Productivity and Activity Impairment Questionnaire in Crohn's Disease; 1/2/3L: First/Second/Third Line |
Conclusion
These data provide evidence for high persistence rate of UST in patients with CD in a real-world setting in Greece and demonstrate favorable effects on disease activity and PROs, accompanied by a predictable safety profile.
Disclosure
This study was sponsored by Janssen - Cilag, Greece.
Giorgos Bamias Advisor/lecturer fees: Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (Grants/Honoraria) from: Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials for: Abbvie, Takeda.
Gerassimos J. Mantzaris has served as consultant/advisor board member and/or speaker for AbbVie, Aenorasis, Dr Falk, Ferring, Janssen, Merck Sharp & Dohme, Pfizer, Takeda, Vianex and has received research grants from: AbbVie, Genesis, Merck Sharp & Dohme, and Takeda.
Christos Gkamaloutsos, Ioannis Kanistras and Angeliki Kekki are employees of Janssen - Cilag, Greece.
Konstantinos Thomopoulos has not disclosed any conflicts
Maria Tzouvala has received clinical research funding from: AbbVie, Janssen, Takeda, consulting and/or speaking fees from: Janssen, AbbVie, Pfizer, MSD, Amgen and has served as advisory board member for: Janssen, AbbVie, Vianex, Amgen, Pfizer, Ferring
Ioannis Koutroubakis has received support by Abbvie, Genesis, Faran, Ferring, Janssen, MSD, Pfizer, Vianex, Viatris and Takeda
Vasileios Delis has no conflicts to disclose
Christos Liatsos has received clinical research funding from: Janssen, Excelya GR, EPSILON HEALTH, and speaking fees from: Boston SCI, Amgen, Galenica
Stergios Vradelis has no conflicts to disclose
Theodosios Sdonas has not disclosed any conflicts
Georgios Papatheodoridis Αdvisor/lecturer for Abbvie, Albireo, Amgen, Dicerna, Genesis, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche and Takeda; Research grants from Abbvie, Gilead and Takeda
Dimitrios Christodoulou has received speaking fees from Janssen, MSD, Galenica
Konstantina Paraskeva: has received clinical research funding from Janssen
Ioannis Goulis has received clinical research funding from: BMS, Janssen; consulting and/or speaking fees from: Janssen, Vianex and has served as advisory board member for: Vianex
Georgios Germanidis has received clinical research funding from Janssen
Vasileios Xourgias has not disclosed any conflicts.
Andreas Protopapas has no conflicts to disclose
Konstantinos Soufleris has received honoraria from: Abbvie, Janssen, Pfizer, MSD, Takeda, Amgen.
Ioannis Pachiadakis has received clinical research funding from Janssen
Evanthia Zambeli has received clinical research funding from BMS, Janssen, consulting and/or speaking fees from Janssen, Takeda, Abbvie, Pfizer, Amgen, and has served as advisory board member for Takeda, Janssen.
Spyridon Michopoulos has received clinical research funding from Janssen, Takeda, BMS, consulting and/or speaking fees from Takeda, and has served as advisory board member for Takeda
