Subcutaneous vedolizumab drug de-escalation using therapeutic drug monitoring in inflammatory bowel disease: a randomized controlled pilot study

Crohn*s disease (CD) and ulcerative colitis (UC) are the two main entities of
inflammatory bowel disease (IBD). IBD is a chronic inflammatory disorder of the
gastrointestinal tract, characterized by a relapsing and remitting course.
Because of the high risk of relapse, the majority of patients require
maintenance therapy. Subcutaneous (SC) vedolizumab is proven to be an effective
maintenance therapy in CD and UC. The recommended dose regimen of SC
vedolizumab as a maintenance treatment is 108 mg once every 2 weeks.

Globally, IBD-related costs are increasing, driven by growing costs of
expensive medication partly caused by increased use of biologics and small
molecules. With the advent of biological agents, a decrease in inpatient and
outpatient costs was expected. Contrary to this speculation, a recent
systematic review described relatively stable extent of costs during different
time periods. It is of utmost importance to reduce the costs of these expensive
biologicals, without increasing the in- and outpatient costs, to decrease the
financial burden on hospitals, insurance companies and the government.
Therefore, our primary aim will not only focus on the costs of vedolizumab, but
also include all IBD-related in- and outpatient costs. We hypothesize that
TDM-guided de-escalation will be more cost-effective in daily practice.

Recent studies observed an association between SC vedolizumab serum levels and
efficacy in both CD and UC, which raises the idea of implementing therapeutic
drug monitoring (TDM) for SC vedolizumab, i.e. dosing based on serum trough
concentrations. As most biologics, SC vedolizumab pharmacokinetics vary widely
between patients. Due to this diversity, the amount of medication required
differs per patient to stay above a certain trough level. Thus, it is
conceivable that TDM could be an attractive approach to rapidly extend the dose
injection intervals while preserving clinical efficacy.
Our study group developed a population pharmacokinetic model, which allows for
individualized SC vedolizumab treatment with a variable injection interval. The
model is based on observations from 62 patients with IBD that participated in
the vedolizumab IV to SC switch study and gave us the opportunity to make a TDM
algorithm. Based on the pharmacokinetic data of the VISIBLE studies, both for
CD as UC, we determined a therapeutic threshold for SC vedolizumab of 26 µg/mL.
We hypothesize that our TDM algorithm will estimate the timing of the next
injection based on vedolizumab concentrations, making personalized medicine
possible and probably save costs. In the VISIBLE I trial, the median serum
vedolizumab concentration was higher in patients receiving the SC agent (39.8
mg/mL; 90% CI, 20.8-75.4 mg/mL) versus IV dosing (32.2 µg/mL; 90% CI, 16.5-60.7
µg/mL) at a standard dosing regimen. Because of these favourable
pharmacokinetics, i.e. higher trough levels, we speculate that the intervals
can be safely extended using our algorithm.
Immunogenicity, i.e. the formation of anti-drug antibodies, is uncommon with
both SC and IV vedolizumab. However, neutralizing antibodies may arise in
patients with sub therapeutic trough levels and are related with reduced
treatment efficacy. Therefore, the development of immunogenicity must be
prevented. Since we use a TDM algorithm that can prevent sub therapeutic
dosing, the risk of immunogenicity and thus loss of response will be minimized.

This study has been transitioned to CTIS with ID 2024-517502-28-01 check the CTIS register for the current data.

Our explorative pilot study wants to observe whether TDM can attribute to an
efficient dose de-escalation strategy of SC vedolizumab in patients with IBD in
order to reduce costs. In this study we will compare costs and clinical
efficiency of TDM-guided de-escalation using vedolizumab concentrations versus
standard dosing. We expect that overall costs, medical and societal, will be
lower in the *TDM-guided de-escalation* strategy. Overexposed patients can
de-escalate SC vedolizumab timely, whilst being sufficient to control the
disease with an adequate drug serum levels to maintain remission.

This study is a single-centre, randomized controlled (1:1), open label pilot
study with a duration of 48 weeks. At screening, the following data will be
collected: age, gender, diagnosis and classification according to Montreal (age
of onset, disease location and behaviour/extent), disease duration, prior
medical and surgical history including prior biologic treatment, concomitant
medical treatment, body weight and height, smoking status, vedolizumab trough
level measurements, anti-drug antibodies against vedolizumab, HBI or SCCAI,
FCP, CRP and routine laboratory tests. When patients have undergone one or more
of the following screening procedures within 12 weeks before signing the
informed consent form in the context of standard care, it is allowed to use
these data as screening procedures: routine laboratory tests, vedolizumab serum
concentration, anti-drug antibodies against vedolizumab and FCP.

Patients will be randomized 1:1 to either the intervention group (TDM-guided
de-escalation strategy) or the control group (standard of care: SC vedolizumab
108 mg every other week).

Patients in the intervention group will reduce SC vedolizumab dose by
prolonging the dose-interval using a TDM-algorithm if possible. The SC
vedolizumab injection interval will be extended based on vedolizumab
concentrations, we maintain a threshold of 26 µg/mL. At baseline, a serum
vedolizumab concentration will be measured for all patients. Patients
randomized to the intervention group will be de-escalated using TDM algorithm
if possible.
The patient draws blood by a finger prick test and sends it to Sanquin for
examination of capillary vedolizumab concentration at week 8, 14, 24, 30 and
40. Samples taken at week 8, 24 and 40 are obtained only to verify that the
vedolizumab concentration is not decreasing too rapidly. In that case, an
adjustment of the interval can be made based on the algorithm to prevent from
significant decrease. Samples drawn at week 0, 14 and 30 will be used to adjust
the dosing interval of the SC vedolizumab. In the following week, the result
will be completed and the study doctor will determine the adjustment of the
injection interval. Changes in the injection interval will be made in whole
weeks and will not be extended longer than once every 4 weeks.

At 8, 14, 24, 30 and 40 weeks after inclusion, all participating patients will
be interviewed via telephone to assess for symptoms and potential disease
activity. All questionnaires (SIBDQ, EQ-5D-5L, HBI or SCCAI,
cost-questionnaire) will be completed by the patient during or prior to these
interviews. All questionnaires will be performed at the outpatient clinic at
screening and end of study (after 48 weeks).

Based on concentration measurements, the injection interval will be adjusted to
every 2, 3 or 4 weeks. During screening, a serum concentration measurement will
be performed in all patients, followed by a finger prick in patients in the
intervention group after 8, 14, 24, 30 and 40 weeks. There are 3 moments in the
study where the injection interval can be adjusted, and extra control moments
to prevent the concentration from falling too far.

There is a risk of disease flare if the injection interval is prolonged.
However, patients will be closely monitored for clinical and biochemal signs of
disease activity and pharmacokinetics to minimize the risk of a disease flare.