Study Design and Study Population
This was a prospective observational cohort study of a switch from maintenance IV to SC vedolizumab treatment in a population of adult IBD patients. The study was conducted at the Skane University Hospital, Sweden, with a 6-month follow-up period. Consecutive patients were approached regarding participation. Inclusion criteria comprised signed informed consent; diagnosis of CD, UC or IBD-unclassified; and ongoing maintenance treatment with IV vedolizumab (previously received ≥3 doses of IV vedolizumab). Exclusion criteria comprised noticeable difficulties handling an SC injector pen, inability to give informed consent, or inability to comply with study procedures. The study was performed in accordance with the principles of the Declaration of Helsinki. Ethical permission was granted by the regional research ethics committee in Lund, Sweden (DNR 2018/761). All patients provided written informed consent to participation before study entry.
Patients were enrolled between December 2020 and June 2021. The study included a baseline visit, scheduled at the time-point when the patient should have received the next dose of IV vedolizumab, and a follow-up visit 6 months after the switch. A subset of patients, that was the first to be enrolled, could be evaluated also after 12 months. Additional visits were scheduled on demand in case of a suspected disease flare or potential side effects. All patients were switched to a dose of 108 mg vedolizumab SC every 2 weeks regardless of previous dose or dosing interval on IV vedolizumab. All conventional IBD treatments were permitted during the study and changes in the treatment regimen were allowed if clinically indicated. Dose optimization of SC vedolizumab to 108 mg weekly was done at the discretion of the treating physician based on a combination of clinical symptoms and biomarker levels. Any changes in treatment regimen throughout the study period were recorded.
Baseline data recorded included diagnosis (CD, UC or IBD-unclassified), gender, age at diagnosis, age at inclusion, weight, height, smoking status, time on IV vedolizumab before the switch, IV vedolizumab dose and dosing interval at inclusion, previous and current IBD treatment, disease characteristics according to the Montreal classification, and disease activity at baseline.
Study Endpoints and Definitions
The primary endpoint was change in disease activity defined by faecal calprotectin levels at 6 months after the switch to SC vedolizumab treatment. Faecal calprotectin is a sensitive and non-subjective measure of disease activity that is not affected by placebo or nocebo effects. It reacts to an early increase in subclinical inflammatory activity and is expected to change earlier than clinical symptom levels in the event of a diminished therapeutic effect.
Secondary endpoints were [all refer to 6 months of follow-up unless otherwise indicated] (a) change in remission rates defined by a faecal calprotectin <150 μg/g and clinical disease activity indices: for CD patient-based Harvey Bradshaw Index (HBI)[7,8] ≤4 or Patient-Reported Outcomes (PRO)2-CD ≤11 and for UC Simple Clinical Colitis Activity Index (SCCAI) ≤2 or PRO2-UC = 0. PRO2 scores were applied in accordance with the STRIDE documents. Briefly, the PRO2-CD is the sum of the daily soft or liquid stool frequency and abdominal pain (multiplied by the weighting factors 2 and 5, respectively) items from the Crohn's Disease Activity Index, whereas the PRO2-UC is the simple sum of the stool frequency and rectal bleeding items from the Mayo score; (b) change in the laboratory biomarker plasma C-reactive protein (CRP); (c) change in clinical disease activity defined by the patient-based HBI for CD and the SCCAI for UC, as well as symptom levels according to the Patient-Reported Outcomes (PRO)-2 criteria as described in the STRIDE documents; (d) subgroup analyses of patients that were dose optimised on IV vedolizumab, and patients with perianal CD, respectively; (e) subgroup analysis of patients that completed 12 months of follow-up, including drug persistence (11 patients that had not completed 12 months of follow-up but remained on the drug were censored), and evaluation of faecal calprotectin and plasma CRP levels. When all patients had completed the first 6 months of follow-up, the study was closed and thus not all patients completed 12 months of follow-up; (f) adverse events and local injection reactions; (g) serum vedolizumab trough levels and relation to faecal calprotectin levels (patients categorised into quartiles based on serum vedolizumab trough levels and median faecal calprotectin levels calculated per quartile), and SC vedolizumab dose optimization rates; (h) patient experience of switching from IV to SC treatment, overall injection experience and patient satisfaction with various aspects of the injector pen [see below for details]; (i) health-related quality-of-life using the Short Health Scale (SHS)[13,14] which is a validated four-item questionnaire (symptom burden, social function, disease-related worry and general well-being; each item scored 0–5 with an SHS composite score ranging from 0 to 20) and (j) annualised cost savings per patient with SC as compared to IV treatment.
Faecal calprotectin levels were analysed using an enzyme-linked immunosorbent assay (ELISA; PhiCal, Calpro AS). Serum vedolizumab trough levels were analysed by a Clinical and Laboratory Standards Institute (CLSI) validated in-house developed chemiluminescence ELISA at the Karolinska Institute (Stockholm, Sweden). Both methods are used in clinical routine care and the analyses were performed in clinical laboratories.
Adverse events that occurred after study entry considered related or of possible relation to SC vedolizumab treatment or switch were documented. Local injection reactions including discomfort, pain, burning sensation and erythema; and patient satisfaction with the injector pen, overall injection experience, the experience of switching from IV to SC treatment; were evaluated using structured questionnaires (see Table 1 and Table S1 for details on items, questions asked and response options). The questions and response options were adapted from previously published questionnaires used in similar studies.[15–17]
Annualised treatment costs for IV treatment included the cost of an appointment with a nurse for drug administration and the cost of the drug. Treatment costs of SC treatment included annual drug costs only. The rates of patients that were dose escalated on IV and SC treatment, respectively, were accounted for in the calculation.
Data are presented as mean values with standard deviation (SD), or median values with interquartile range (IQR) as appropriate. Prism 9 for Mac OS X version 9.3.1 (GraphPad Software, Inc.) was used for statistical analyses and to graph data. The paired-samples Student's t-test alternatively the Wilcoxon matched-pair signed-rank test was used to compare baseline and follow-up data for changes in laboratory biomarkers, disease activity indices and quality-of-life scores as appropriate depending on data scale type and data distribution. Missing data are shown by presenting numbers of data points in the figures. The complete case analysis method was applied, which together with an account of discontinued patients and data point numbers presented, was deemed to give the most adequate description of the cohort.[18,19] The approach was verified by performing sensitivity analyses comprising best- and worst-case scenario calculations (i.e. missing data equals relapse and remission, respectively), neither of which altered the statistical significance as compared with the complete case analysis. Regarding faecal calprotectin-missing data, the missing-at-random assumption is plausible and the complete case analysis is thus adequate to apply. The Kruskal–Wallis test was used to assess differences in faecal calprotectin levels between patient groups stratified by serum vedolizumab trough level quartiles during IV and SC vedolizumab treatment, respectively. The chi-square test was used to compare remission rates between groups. Kaplan–Meier survival analysis was used to calculate drug persistence. A statistically significant test result was defined by p < 0.05.
Aliment Pharmacol Ther. 2022;55(11):1389-1401. © 2022 Blackwell Publishing