Introduction
Vedolizumab (VDZ) is efficacious to induce and maintain clinical remission in Crohn’s disease (CD). However, prospective data about its efficacy including endoscopy in early CD are lacking.
Aims & Methods
We conducted a prospective multi-centre international (Belgium, the Netherlands and Hungary) open label trial comparing the efficacy and safety of VDZ therapy in patients with early or late moderate-severe active CD (Crohn’s Disease Activity Index [CDAI] 220-450 and presence of ulcers at endoscopy). Early CD was defined as diagnosis <2 years and treatment naïve or only treated with corticosteroids and/or immunomodulators; late CD was defined as diagnosis >2 years and previously treated with corticosteroids, immunomodulators and anti-tumor necrosis factor agents. Patients received intravenous VDZ (300 mg) at weeks 0-2-6 and q8 weeks thereafter for a total of 52 weeks, with an extra infusion at w10 in the absence of a CDAI drop <70. Ileocolonoscopy was performed at baseline, w26 and w52 and all procedures were centrally read. The sample size was calculated for 1/3 early and 2/3 late CD. An extremely strict primary composite endpoint was used: proportion of patients with clinical and endoscopic remission (CDAI≤150 and Simple Endoscopic Score for CD [SES-CD]<4) at both w26 and w52. Key secondary endpoints included the proportion of patients with absence of ulcers, proportion of patients with endoscopic response (SES-CD reduction ≥50%) at w26 and w52 and safety.
Results
We recruited 86 early and 174 late CD patients, of whom 52 early and 104 late CD patients completed w52 (insufficient clinical response and adverse events were the main reasons for early withdrawal). Baseline characteristics including disease activity parameters were similar across both groups (median total SES-CD 9 [6-17] and 12 [7-17], median CDAI 254.7 [235.7-287.2] and 259 [235.2-314.5] for early and late CD, respectively), apart from disease duration and age (median disease duration 0 [0-1] and 11 [5.5-15.5], median age 29.5 [23.8-45.3] and 36 [28-48] for early and late CD, respectively). The primary endpoint was reached in 31.4% vs. 8.6% (p=0.001; ITT) and 45.0% vs. 16.0% (p<0.001; per protocol [PP]) of patients with early vs. late CD (Table 1). All key secondary endpoints were also met in favour of patients with early CD (Table 1). Serious adverse events (SAEs) occurred in 4.7% of patients with early vs. 27% of patients with late CD (p<0.0001) and included infection (1.2 vs 7.5%) bowel obstruction (0 vs 2.3%), exacerbation of CD (2.3 vs 4%), abdominal pain (0 vs 1.7%) and malignancy (0 vs 1.7%).
Table 1. Primary composite endpoint and key secondary endpoints (ITT and PP analysis)
|
| Early vs late CD
(ITT)
| Early vs late CD
(PP)
| P values
(ITT/PP)
|
|---|
Primary composite endpoint
|
|
|
|
|
Clinical and endoscopic remission^
| w26 and w52
| 31.4% vs 8.6%
| 45.0 vs 16.0%
| 0.001*; <0.001*
|
|
|
|
|
|
Separate primary outcome measures
|
|
|
|
|
Clinical remission
| w26
w52
| 62.8% vs 37.4%
59.3% vs 43.7%
| 77.1% vs 57.0%
67.1% vs 54.7%
| <0.001*; 0.006*
0.018*; 0.076
|
Endoscopic remission
| w26
w52 | 55.8% vs 27.6%
51.2% vs 27.0%
| 67.6% vs 39.7%
62.0% vs 37.3%
| <0.001*; <0.001*
<0.001*; <0.001*
|
Key secondary endpoints
|
|
|
|
|
Absence of ulcers
| w26
w52
| 52.3% vs 24.1%
47.7% vs 23.0%
| 63.4% vs 34.7%
57.7% vs 31.7%
| <0.001*; <0.001*
<0.001*; <0.001*
|
Endoscopic response
| w26
w52
| 64.0% vs 34.5%
57.0% vs 35.6%
| 82.1% vs 49.6%
71.0% vs 49.2%
| <0.001*; <0.001*
0.001*; 0.003*
|
^Defined as CDAI≤150 and SES-CD <4; ~Defined as SES-CD reduction by ≥50%.
Conclusion
VDZ treatment is more effective and safer in early than in late CD (IIS Funded by Takeda Nederland B.V. [IISR-2014-100757]; LOVE-CD EudraCT number 2014-005376-29).
Disclosure
GD: served as advisor and/or speaker for Abbvie, Alimentiv, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Polpharm, Prometheus biosciences, Prometheus laboratories, Procise diagnostics, Protagonist, Sandoz, Setpoint, Spyre, Takeda, Tillotts and Ventyx.
ML: consultancy/ lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Central reader for Alimentiv. Grant received from Galapagos and NFU.
FB: reports grants/research supports from AbbVie, Amgen, Takeda, Janssen, honoraria or consultation fees from AbbVie, Amgen, Arena, MSD, Celgene, Kabi-Fresenius, Takeda, Ferring, Pfizer, Norgine, Janssen and participation in a company sponsored speaker's bureau for AbbVie, MSD, Takeda, Ferring, Pfizer, Janssen.
PB: has received research grants from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
FH: has served on advisory boards or as speaker for Abbvie, Janssen, MSD, Takeda, Pfizer, Celltrion, Teva, Sandoz, Amgen and Pendopharm, and has received independent research funding from Janssen, Abbvie, Pfizer and Takeda.
EC: has no conflicts of interest.
LO: has no conflicts of interest.
MH: has no conflicts of interest.
TM: has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, Janssen, Sandoz, MundiPharma, Phytotec, Roche, Fresenius and Teva.
SV: financial support for research from: AbbVie, J&J, Pfizer, Takeda and Galapagos and receives speakers’ and/or consultancy fees from: AbbVie, Abivax, AbolerlsPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, Astrazeneca, BioraTherapeutics, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech Roche, Gilead, GSK, Hospira, lmidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, Microbiotica, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma.
