Subcutaneous Interval Lengthening of Vedolizumab for Economic Research (SILVER)

Subcutaneous Vedolizumab Drug De-escalation Using Therapeutic Drug Monitoring in Inflammatory Bowel Disease: a Randomized Controlled Pilot Study

Rationale: Subcutaneous vedolizumab is an effective maintenance therapy for patients with inflammatory bowel disease. Patients using subcutaneous vedolizumab (every 2 weeks) have higher vedolizumab serum trough concentrations than those who are treated with intravenous vedolizumab (every 4-8 weeks). Since biologic therapies such as vedolizumab are expensive, lengthening of the injection interval (de-escalation) is of interest to reduce health care costs. However, maintaining remission while extending vedolizumab injection intervals has not been evaluated yet but represents a critical component of both medical and societal costs. Studies have suggested that higher vedolizumab serum concentrations are associated with superior clinical outcomes. Our strategy is to administer subcutaneous vedolizumab with prolonged intervals using therapeutic drug monitoring, i.e. dose based on vedolizumab concentrations, to reduce medical and societal costs while preserving remission.

Objectives: To evaluate whether subcutaneous vedolizumab therapeutic drug monitoring (TDM)-guided de-escalation will be cost-effective, compared to normal dosing regimen in patients with inflammatory bowel disease in remission. The secondary objective is to investigate the efficacy of TDM-guided de-escalation subcutaneous vedolizumab dosing compared to standard dosing.

Study design: This is a single-centre, randomized controlled, open-label pilot study.

Study population: 40 patients with inflammatory bowel disease (Crohn's disease or ulcerative colitis) in steroid-free clinical and biochemical remission with subcutaneous vedolizumab maintenance therapy of 108 mg every other week for at least 6 months.

Intervention: Patients will be randomized (1:1) to the 'TDM-guided subcutaneous vedolizumab de-escalation' strategy versus 'standard care' (e.g. continuing standard subcutaneous vedolizumab dosing regimen of 108 mg every other week).

Main study parameters/endpoints: Primary endpoint: cost-effectiveness of the TDM-guided de-escalation group compared to the standard dosing group over 48 weeks. Secondary endpoints include: proportion of patients with sustained clinical remission (based on Harvey-Bradshaw Index or Simple Clinical Colitis Activity Index), proportion of patients with (sustained) biochemical remission (based on c-reactive protein and fecal calprotectin), pharmacokinetic differences (vedolizumab levels and immunogenicity), safety and quality of life (measured by SIBDQ and EQ-5D-5L).

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases
• Intervention / Treatment: Drug: Vedolizumab Injection

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Suzanne Anjie, MD; Phone Number: +31655592173; Email: s.i.anjie@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC
    • Contact: Suzanne Anjie, MD; Phone Number: +31655592173; Email: s.i.anjie@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of Crohn's disease or ulcerative colitis
• Clinical and biochemical remission: absence of active inflammatory intestinal symptoms, fecal calprotectin <250 ug/g and CRP <5 mg/g, HBI <5 or SCCAI <4
• Steroid free remission for at least 6 months whilst being treated with subcutaneous vedolizumab at a stable dose of 108mg every other week.

Exclusion Criteria:

• Absence of written informed consent;
• Presence of anti-drug antibodies against vedolizumab, these levels will be determined in case the vedolizumab concentration is below 1 ug/ml;
• Concomitant oral glucocorticosteroid usage;
• Imminent need for IBD-related surgery as judged by the treating clinician;
• Actively draining peri-anal fistula;
• Patients with short bowel syndrome, an ostomy or a symptomatic stricture;
• Active participation in another interventional trial;
• Pregnancy or lactation;
• Other significant medical conditions that might interfere with this study (such as current/recent malignancy, immunodeficiency syndromes and psychiatric illness);
• Impossibility to measure outcomes, e.g. planned relocation, language issues, short life expectancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Continuing subcutaneous vedolizumab every other week
Experimental: Intervention; Therapeutic drug monitoring guided de-escalation	Drug: Vedolizumab Injection; Based on therapeutic drug monitoring, patients could be de-escalated based on a pharmacokinetic model: Dosing interval Trough Target 20 mg/L Adjust dosing interval to: 2 weeks < 33 mg/L 2 weeks 2 weeks 33 - 46 mg/L 3 weeks 2 weeks ≥ 46 mg/L 4 weeks 3 weeks < 20 mg/L 2 weeks 3 weeks 20 - 29 mg/L 3 weeks 3 weeks ≥ 29 mg/L 4 weeks 4 weeks < 13 mg/L 2 weeks 4 weeks 13 - 20 mg/L 3 weeks Version number: 6.1, 24-06-2024 22 of 44 4 weeks ≥ 20 mg/L 4 week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost-effectiveness	Medical and societal expenses will be measured troughout the study. The primary outcome is at the end of the study at Week 48. Cost-effectiveness will be measured by using a cost-questionnaire developed with the health economics department, including health-related, work-related and societal costs.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Quality of Life	Quality of life will be measured by EQ-5D-5L questionnaire	multipe times between baseline and 48 weeks
Biochemical parameters	CRP	multipe times between baseline and 48 weeks
Biochemical parameters	Fecal calprotectin	multipe times between baseline and 48 weeks
Pharmacokinetic aspects	Vedolizumab concentrations	multipe times between baseline and 48 weeks
Pharmacokinetic aspects	Anti-drug antibodies	multipe times between baseline and 48 weeks
Difference in Quality of Life	Quality of life will be measured by SIBDQ	multipe times between baseline and 48 weeks
Clinical outcomes	Clinical outcomes will be measured troughout the study. For ulcerative colitis patients: Simple Clinical Colitis Activity Index.	multipe times between baseline and 48 weeks
Clinical outcomes	Clinical outcomes will be measured troughout the study. For Crohn's disease patients: Harvey-Bradshaw Index.	multipe times between baseline and 48 weeks

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: G.R.A.M. D'Haens, MD PhD, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: June 22, 2023
• First Submitted That Met QC Criteria: September 2, 2024
• First Posted (Actual): September 4, 2024

Study Record Updates

• Last Update Posted (Actual): September 4, 2024
• Last Update Submitted That Met QC Criteria: September 2, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Intestinal Diseases; Gastrointestinal Agents; Vedolizumab
• Other Study ID Numbers: NL80854.018.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No