Long-term Safety of Vedolizumab for Inflammatory Bowel Disease

Edward V. Loftus Jr; Brian G. Feagan; Remo Panaccione; Jean-Frédéric Colombel; William J. Sandborn; Bruce E. Sands; Silvio Danese; Geert D'Haens; David T. Rubin; Ira Shafran; Andrejus Parfionovas; Raquel Rogers; Richard A. Lirio; Séverine Vermeire


Aliment Pharmacol Ther. 2020;52(8):1353-1365. 

In This Article


Study Design

GEMINI LTS (NCT00790933/EudraCT 2008-002784-14) was a Phase 3, single-arm, open-label, multinational study conducted in patients with moderately to severely active UC or CD (Figure 1). GEMINI LTS enrolled patients from a long-term Phase 2 study (UC and CD; NCT00619489), three Phase 3 studies (GEMINI 1 [UC; NCT00783718/EudraCT 2008-002782-32]; GEMINI 2 [CD; NCT00783692/EudraCT 2008-002783-33]; GEMINI 3 [CD; NCT01224171/EudraCT 2009-016488-12]) and included a cohort of vedolizumab-naïve (de novo) patients with UC or CD. Additional details regarding the GEMINI trials can be found in the Supporting Information and in previously published reports.[5–7] Data presented herein were collected from approximately 400 study sites in 39 countries between 22 May 2009 and 31 October 2017.

Figure 1.

GEMINI LTS patient enrolment. Patients were eligible for enrolment in GEMINI LTS who had completed the Phase 2 long-term safety study or one of the three Phase 3 GEMINI studies. In addition, a cohort of vedolizumab-naïve patients were recruited directly into GEMINI LTS. CD, Crohn's disease; HBI, Harvey-Bradshaw Index; IV, intravenous; LTS, long-term safety; Q4W, every 4 weeks; UC, ulcerative colitis

Study Treatment

Patients entering the study from a prior vedolizumab study and de novo patients received vedolizumab 300 mg intravenously (IV) every 4 weeks (Q4W). Treatment duration varied by patient and continued if there was sustained clinical benefit or until loss to follow-up for any reason, including vedolizumab approval and access to commercially available drug, or the presence of an expanded-access programme at the local study site.

Study Assessments and Endpoints

The primary objective of GEMINI LTS was to evaluate the LTS profile of vedolizumab. Patients were evaluated per study protocol at visits at least every 4 weeks where vital signs, concomitant medications, adverse events (AEs) and serious AEs (SAEs; including signs and symptoms of progressive multifocal leukoencephalopathy [PML]) were recorded. A PML symptom checklist was administered before each dosing. AEs, captured in response to questioning from study personnel during study visits and spontaneously reported throughout the study, were coded according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs of special interest were predefined as infections (including PML), malignancies, infusion-related reactions, and hepatobiliary events. Infusion reactions were defined as any AE that occurred on the calendar day of or 1 calendar day after any vedolizumab infusion or any event defined by the investigator as infusion-related.

Exploratory endpoints were related to HRQOL, clinical outcomes and IBD-related procedures and hospitalisations. Patient-reported HRQOL outcomes were assessed using validated tools including the Inflammatory Bowel Disease Questionnaire (IBDQ), the 36-item Short-Form Health Survey (SF-36), and the European Quality of Life-5 Dimension (EQ-5D) Questionnaire.[11–13] A total IBDQ score was calculated by summing the scores from four subdomains (bowel symptoms, emotional function, social function and systemic function) for a final score ranging from 4 to 224 (higher scores indicated better QOL). An increase of ≥16 points in the total score represented a clinically meaningful improvement in patient QOL. For the total SF-36 score, results from the physical component summary and the mental component summary were summed and converted to a percentage on the scale from 0 to 100 (higher scores indicated better QOL). EQ-5D total score was calculated from individual scores from 5 domains—mobility, self-care, usual activities, pain/discomfort and anxiety/depression—with scores of 1, 2 or 3 possible for each domain. The EQ-5D visual analog scale (VAS) score was a self-assigned rating of overall health with a score ranging from 0 as the worst to 100 as the best possible health. An increase of ≥7 points in EQ-5D VAS score represented a clinically meaningful improvement in patient QOL. HRQOL outcomes were obtained at enrolment, Week 28, every 24 weeks for the first 4 years and yearly from Year 5 onward.

Clinical outcomes included changes in partial Mayo score in patients with UC or in Harvey-Bradshaw Index (HBI) score in patients with CD. For patients with UC, clinical response was defined by a reduction in the partial Mayo score of ≥2 points and ≥25% from baseline (defined as the screening visit for de novo patients and as the last visit of the previous trial for rollover patients), with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of ≤1 point; clinical remission was defined by a partial Mayo score of ≤2 with no individual subscore of >1. For patients with CD, clinical response was defined as ≥3-point decrease from baseline in the HBI score, and clinical remission was defined by an HBI score ≤4. Major IBD-related events such as hospitalisations, surgeries, or other procedures deemed related to UC or CD by the investigator were recorded.

Statistical Analyses

The safety population was defined as all patients who received any dose of vedolizumab in GEMINI LTS. The efficacy population consisted of all patients in the safety population who had ≥1 post baseline disease activity measurement.

All study endpoints were evaluated descriptively using point estimates and 95% confidence intervals (CIs). The incidence of AEs was calculated as exposure-adjusted incidence rates, defined as the number of patients experiencing the event per 1000 person-years (PYs) of exposure (defined as the first dose of vedolizumab in GEMINI LTS). Sub-group analyses were performed according to prior tumour necrosis factor (TNF) antagonist failure status. TNF antagonist failure status was not collected in the long-term Phase 2 study; hence, these patients were excluded from all assessments of prior TNF antagonist status. Changes from baseline in efficacy endpoints were assessed using the original baseline assessment before patients received their first dose of vedolizumab (ie from the start of the original study prior to enrolment in GEMINI LTS or, if de novo enrolment, from the start of GEMINI LTS). Efficacy outcomes were analysed post hoc using a last-observation-carried-forward (LOCF) approach.