A Clinical Decision Support Tool May Help to Optimise Vedolizumab Therapy in Crohn's Disease

Parambir S. Dulai; Aurelien Amiot; Laurent Peyrin-Biroulet; Vipul Jairath; Melanie Serrero; Jerome Filippi; Siddharth Singh; Benjamin Pariente; Edward V. Loftus Jr; Xavier Roblin; Sunanda Kane; Anthony Buisson; Corey A. Siegel; Yoram Bouhnik; William J. Sandborn; Karen Lasch; Maria Rosario; Brian G. Feagan; Daniela Bojic; Caroline Trang-Poisson; Bo Shen; Romain Altwegg; Bruce E. Sands; Jean-Frederic Colombel; Franck Carbonnel

Disclosures

Aliment Pharmacol Ther. 2020;51(5):553-564. 

In This Article

Results

Patient Characteristics

The VICTORY consortium and GETAID populations had higher proportions of TNF-antagonist–exposed and female patients, and the participants were slightly older with longer disease duration at the time of VDZ treatment than subjects in the GEMINI 2 clinical trial (Table 1). Importantly, of the 173 CD patients in the GETAID cohort, only 55 had all the necessary baseline variables for calculation of the CDST. However, the patients with complete data had characteristics similar to the excluded patients (P > 0.20 for all comparisons; Table 1).

VDZ Exposure and Onset of Action

In the GEMINI 2 cohort, a significant linear trend was observed for measured VDZ concentrations when stratified by the CDST (Figure 1, Table S1). This observation was significant through week 52 of the study and was associated with significant differences in rapidity of onset of action and reduction in HBI (Figure 2, Table S2). Rates of anti-drug antibody formation were comparable between the low (n = 9/226, 3.98%), intermediate (n = 20/414, 4.83%) and high (n = 4/174, 2.30%) probability of response groups.

Figure 1.

GEMINI 2 clinical trial 52-week vedolizumab serum drug concentrations stratified by CDST. aAll values in table are median VDZ concentration (μg/mL) (IQR); post-dose concentration was measured 2 h after dosing. bLow probability; ≤13 points in CDST model at baseline. cIntermediate probability; >13 to ≤19 points in CDST model at baseline. dHigh probability; >19 points in CDST model at baseline. ****P < 0.0001, ***P < 0.001, **P < 0.01, and *P < 0.05. Bolded P values are statistically significant. CDST, clinical decision support tool; IQR, interquartile range; PK, pharmacokinetics; VDZ, vedolizumab

Figure 2.

GEMINI 2 clinical trial 52-week reduction in Harvey-Bradshaw Index stratified by CDST aAll values in table are mean HBI (SE). bLow probability; ≤13 points in CDST model at baseline. cIntermediate probability; >13 to ≤19 points in CDST model at baseline. dHigh probability; >19 points in CDST model at baseline. ****P < 0.0001, ***P < 0.001, and **P < 0.01. Bolded P values are statistically significant. CDST, clinical decision support tool; HBI, Harvey-Bradshaw Index; LS, least-squares; SE, standard error; Wk, week

There was no catch-up in HBI reductions in the low-probability group compared with the intermediate, or the intermediate compared with the high-probability group, and significant differences in HBI reductions from baseline remained at week 52. No significant differences between the probability groups were observed for concomitant use of steroids or immunomodulators.

GETAID Cohort

Rates of clinical remission at week 14 in the GETAID cohort were significantly higher among the intermediate or high-probability patients compared with the low-probability patients (P = 0.04). Similar trends were also observed at weeks 22 and 30 for both clinical remission and corticosteroid-free clinical remission (Figure 3A,B). Analysis of changes in mean HBI scores over time showed a significant reduction in HBI in the low-probability and intermediate- or high-probability groups (P < 0.01). Among patients receiving standard VDZ induction and every 8-week maintenance dosing (with no week 10 infusion), a significant group-time interaction for week 14 HBI reductions was observed, and patients in the intermediate- or high-probability groups had a more significant reduction in HBI during the first 14 weeks of therapy than those in the low-probability group (P = 0.045) (Figure 3C).

Figure 3.

GETAID vedolizumab cohort treatment outcomes stratified by CDST. (A) Treatment outcomes stratified by CDST in overall GETAID cohort. (B) Treatment outcomes stratified by CDST in GETAID cohort on Q8 week vedolizumab maintenance. (C) Reduction in HBI stratified by CDST. (D) Reduction in HBI after vedolizumab interval shortening (escalation) stratified by CDST. Low probability; ≤13 points in CDST model at baseline. Intermediate probability; >13 to ≤19 in CDST model at baseline. High probability; >19 points in CDST model at baseline. *P < 0.05. Abbreviations: CDST, clinical decision support tool; HBI, Harvey-Bradshaw index; Q8, every 8 weeks; REM, remission; SF-REM, steroid-free remission. High-probability group (n = 3); intermediate-probability group (n = 24); low-probability group (n = 28). Because of the small sample size of the high-probability group (a highly refractory population early in the period during which vedolizumab became available), it was combined with the intermediate-probability group for analyses

Response to Dose Optimisation or Interval Shortening for Lack of Response

The group-time interaction for reduction in HBI between the intermediate- or high-probability groups and the low-probability group was no longer significant after including low-probability patients who were dose optimised early with a week 10 VDZ infusion (exposure-efficacy-optimisation). There was also a numeric reduction in HBI among low-probability patients requiring interval shortening, with no change in HBI among intermediate-probability patients requiring interval shortening; however, this did not reach statistical significance (P > 0.20) (Figure 3D). None of the high-probability patients in GETAID required interval shortening for apparent lack of response.

In the VICTORY consortium, 38 patients underwent interval shortening for apparent lack of response (n = 11 low probability, n = 18 intermediate probability and n = 9 high probability). A clinical response was seen in 46% (n = 5/11) of the low-probability group, 39% (n = 7/18) of the intermediate-probability group and 0% (n = 0/9) of the high-probability group (P = 0.038 for comparison of high- or intermediate- vs low-probability groups).

Endoscopic Remission and Progression to Surgery

In the VICTORY consortium, cumulative 12-month rates for endoscopic remission were numerically lower in the low-probability group (35%) compared with the intermediate- (42%) or high-probability groups (53%). Likewise, cumulative 12-month rates for progression to surgery were numerically higher in the low-probability group (21%) compared with the intermediate- (17%) or high-probability groups (12%) (Figure 4).

Figure 4.

VICTORY consortium vedolizumab-treated rates of endoscopic remission and progression to surgery stratified by CDST. A, Cumulative rates of endoscopic remission. B, Cumulative rates of progression to surgery. Low probability; ≤13 points in CDST model at baseline. Intermediate probability; >13 to ≤19 in CDST model at baseline. High probability; >19 points in CDST model at baseline. High-probability group (n = 131), intermediate-probability group (n = 281), low-probability group (n = 89). Abbreviation: CDST, clinical decision support tool. Analysis of endoscopic remission limited to those patients with follow-up endoscopic assessments (n = 326; high probability n = 84; intermediate probability n = 172; low probability n = 70). Endoscopic remission defined as absence of ulcerations. Pairwise log-rank comparisons across the three probability groups for endoscopic remission: high vs low P < 0.001; high vs intermediate P = 0.076; low vs intermediate P = 0.002. Pairwise log-rank comparisons across the three probability groups for progression to surgery: high vs low P = 0.024; high vs intermediate P = 0.076; low vs intermediate P = 0.264

After adjusting for disease duration >2 years, ileal disease location history, age >60 years, prior CD-related hospitalisation, and smoking status, the adjusted HR (aHR) for high- vs low- or intermediate-probability groups remained significant for stratification of achieving endoscopic remission (aHR 2.06, 95% CI 1.33–3.21) and risk of surgery while on VDZ (aHR 0.50, 95% CI 0.26–0.95). The intermediate-probability group was significantly more likely to achieve endoscopic remission (aHR 2.47, 95% CI 1.26–4.87) vs the low-probability group; however, no significant difference was observed in risk of surgery between these two groups (aHR 0.86, 95% CI 0.51–1.47).

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