Summary of Available Evidence
The body of evidence comprising this review includes a phase III, double-blind, placebo-controlled RCT (VISIBLE 2) (N = 410),7 an ITC (NMA),8 and an OLE study (SC-3030, currently ongoing).9 The data were provided by the sponsor and critically appraised by CADTH reviewers.
VISIBLE 2 was designed to evaluate the efficacy and safety of maintenance treatment with vedolizumab SC injections in adult patients with moderately to severely active CD who achieved a clinical response at week 6 with open-label therapy of 300 mg vedolizumab IV infusion at weeks 0 and 2. Patients with a clinical response at week 6 were randomized to maintenance treatment with vedolizumab SC (108 mg vedolizumab SC every 2 weeks), or placebo in a 2:1 ratio. The primary outcome was the proportion of patients with clinical remission, defined as a CDAI score of at least 150 at week 52. Outcomes were obtained with validated tools. To control for an overall type I error rate in the comparison between vedolizumab SC and the placebo for the primary and secondary end points, a hierarchical approach was applied to the statistical testing.
During the maintenance phase, 59% of the study participants completed treatment, 61% in the vedolizumab SC group and 54% in the placebo group. The main reason for discontinuation in the maintenance phase was lack of efficacy (73% in the vedolizumab SC group and 71% in the placebo group among those who discontinued) followed by voluntary withdrawal and AEs. This difference in missing data could bias the results. Sensitivity analyses were performed to examine the robustness of the study findings to missing data assumptions, which were generally consistent with the primary results.
Subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and all secondary outcomes based on age, gender, race, duration of CD, geographic region, baseline disease activity, baseline fecal calprotectin, disease localization, clinical remission status at week 6, prior TNF alpha antagonist therapy, prior immunomodulator and TNF alpha antagonist failure, prior corticosteroid failure, prior immunomodulator failure, concomitant therapies, and worst prior treatment failure. Given the ▬ of the subgroups, they can be considered underpowered to detect a significant effect from modifiers.
The VISIBLE 2 study was powered to assess the primary outcome of clinical remission after 52 weeks but was not sufficient to assess other secondary end points. This limitation contributed to the findings of numerically greater but not statistically significant differences between treatment arms for all secondary end points, such as enhanced clinical response and corticosteroid-free clinical remission. In addition, statistical significance was not achieved for the secondary efficacy end point of “enhanced clinical response at week 52,” and statistical significance cannot be formally claimed for any of the end points ranked after this end point, including “corticosteroid-free remission.”
Long-term safety and efficacy of vedolizumab SC in the study population were evaluated in an OLE study of VISIBLE 2, namely SC-3030. This long-term extension study assessed the long-term safety and tolerability of vedolizumab SC in the treatment of CD. Due to the limitation associated with uncontrolled open-label clinical trials, results of this study should be interpreted with caution.
The ITC submitted by the sponsor evaluated the comparative effectiveness and safety of vedolizumab SC relative to other comparators with similar indications. The authors of the review performed an NMA of ▬▬▬▬▬. The key limitations of this NMA included heterogeneity across the included clinical trials in both study design and patient characteristics, and the limited number of trials for certain outcomes.
Interpretation of Results
Efficacy
In VISIBLE 2, more patients in the vedolizumab SC group achieved clinical remission at week 52 (primary efficacy end point) when compared to placebo, with an adjusted risk difference of 13.7% (95% CI, 3.8 to 23.7; P = 0.008). In addition, numerically higher enhanced clinical response at week 52 was observed in the vedolizumab SC group compared with the placebo group; however, the between-group difference did not reach statistical significance (52% versus 44.8%, P = 0.167). Consequently, statistical significance cannot be formally claimed for any of the end points ranked after this end point in the hierarchy; for example, corticosteroid-free remission at week 52. A numerically higher rate of corticosteroid-free remission at week 52 was reported for the vedolizumab group (45.3%) compared with placebo (18.2%). Note that all study participants in the VISIBLE 2 study received 2 induction doses of vedolizumab IV prior to randomization, including those assigned to the placebo arm. Due to several factors, including a possible durable response to IV induction and high corticosteroid use during the maintenance phase (▬ in both treatment groups), a relatively high placebo response of 44.8% at week 52 was observed.
For patient-reported outcomes, total scores in the IBDQ (a disease-specific HRQoL assessment tool) suggested improvements for both treatment groups: change from baseline was 63.3 points in the vedolizumab SC group and 55.1 points in the placebo group. It is unclear whether the between-group difference is clinically meaningful. Similar results were observed for the results of EQ-5D VAS and index scores.
Based on the results of the sponsor-submitted NMA, ▬▬▬▬▬. Little should be inferred regarding comparative ▬▬▬▬▬ efficacy or safety based solely on this submitted NMA. The applicability of sponsor’s NMA is affected by the limited size of the evidence base (i.e., ▬▬▬▬▬), potential limitations in the submitted analysis, and heterogeneity in trial design and patient populations across trials. Overall, the ability to draw firm conclusions based on these results is limited.
Results of an ongoing, long-term extension study (SC-3030) suggest that ▬▬▬▬▬; however, results of this study should be interpreted with caution, due to the inherent limitations of an uncontrolled, open-label clinical trial.
Harms
Overall, data from the VISIBLE 2 trial, the NMA, and the long-term extension SC-3030 study do not provide important concerns in terms of AEs or SAEs, or harms of special interest established a priori in this review. The incidence of TEAEs was 73.5% in the vedolizumab SC group and 76.1% in the placebo group. The most common AEs were worsening of CD disease activity, abdominal pain, nasopharyngitis, arthralgia, and upper respiratory tract infections. The incidence of SAEs was comparative between the 2 groups: 8.4% in the vedolizumab SC group and 10.4% in the placebo group. The incidence of withdrawals due to AEs was higher in the placebo group (8.2%) compared to vedolizumab SC (4%).
Based on the results of the sponsor-submitted NMA, ▬▬▬▬▬
In the long-term extension study of the VISIBLE 2 study (SC-3030) to assess the long-term safety and tolerability of vedolizumab SC in the treatment of CD, the interim results suggest that ▬▬▬▬▬
Cost
The average annual drug cost of vedolizumab SC is $21,458 per patient and may be considered cost-neutral when compared to the current list price of vedolizumab IV. Where the price of vedolizumab has been negotiated, in line with the 2016 CADTH recommendation, similar price reductions would be required for vedolizumab SC.
When compared to adalimumab and SEB infliximab (Renflexis), vedolizumab SC is expected to lead to increased annual costs of $967 and $8,596 per patient, respectively, for maintenance treatment. Conversely, vedolizumab SC may be associated with annual cost savings of $4,031 and $8,499 per patient when compared to infliximab (Remicade) and ustekinumab, respectively, for maintenance treatment.
