The main goal of the proposed project is to compare two MTX dosing regimens to suppress ADA levels in patients with inflammatory bowel disease (IBD) with loss of response to anti-TNF agents, and to relate these findings to clinical and biochemical…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A composite primary endpoint will be used: i.e. percentage of patients with:
• Complete disappearance of measurable ADA,
AND
• Measurable IFX or ADL serum concentrations within 6 months after starting MTX
Secondary outcome
- Association of intracellular MTX-Glu1-5 concentrations in red blood cells
(RBCs) with reduction of immunogenicity
- Association of intracellular MTX-Glu1-5 concentrations in peripheral blood
mononuclear cell (PBMCs) with reduction of immunogenicity
- Association of plasma MTX concentrations (extracellular concentrations) with
reduction of immunogenicity
- Correlation of MTX-Glu-1-5 levels between RBCs and PBMCs
- Impact of HLA genotype on therapeutic effect of MTX
- Time to disappearance of ADA after addition of MTX
- Time to regained clinical and biochemical response after addition of MTX
- Proportion of patients in clinical remission at week 2, 6, 10, 14, 18, 22 and
26(defined by HBI <= 4 points, SCCAI <= 5 points)
- Evaluation of adverse events due to MTX treatment (using the PRO-CTCAE
questionnaire)
- Proportion of patients in biochemical remission at week 2, 6, 10, 14, 18, 22
and 26, defined by serum CRP level < 5 mg/l and fecal calprotectin levels < 250
mg/kg)
- Percentage of CD patients with quiescent perianal fistulas at week 2, 6, 10,
14, 18, 22 and 26, who had actively draining fistulas at baseline
- Percentage of patients with disappearance ADA (<12 AU/ml) combined with
therapeutic IFX and ADL serum concentrations at week 2, 6, 10, 14, 18 and 22
(primary endpoint at week 26)
Background summary
Up to 20% of IBD patients in the Western world receive treatment with
anti-tumor necrosis factor (TNF) agents. TNF inhibitors are among the most
powerful agents to treat Crohn's disease (CD) and ulcerative colitis (UC).
However, loss of response is seen in approximately 30% of patients, which is
often caused by formation of anti-drug antibodies (ADA), and this usually
results in increased clearance of the drug and low or even unmeasurable
anti-TNF serum concentrations. Immunogenicity might be triggered by specific
interactions between human leukocyte antigen (HLA) and the causative drug.
Recent studies have demonstrated a genetic association between HLA alleles and
susceptibility to delayed drug hypersensitivity of certain therapeutic agents
but for anti-TNF agents this has not be investigated so far.[1] There are
limited therapeutic options for patients who lose response to anti-TNF agents
due to immunogenicity. The anti-TNF dose can be intensified by increasing the
dose and/or shortening the treatment interval or patients can be switched to
another TNF blocker or to an agent with a different mode of action. An
alternative approach to overcome ADA formation is addition or reintroduction of
an immunomodulator (i.e. thiopurines or methotrexate (MTX)). Recent work from
others as well as from our own group showed that addition of MTX to anti-TNF
therapy is often beneficial in these circumstances.[2,3] After addition of MTX,
ADA decreased and anti-TNF serum concentrations increased in the vast majority
of patients resulting in recaptured clinical responses. Although MTX seems to
be a powerful approach to suppress immunogenicity of anti-TNF agents, available
evidence is derived from retrospective studies. Additionally, the minimum
required MTX dose that is needed to suppress neutralizing antibodies, resulting
in increased anti-TNF serum levels and recaptured clinical responses, remains
unknown. MTX is an inexpensive drug that is used for more than five decades to
treat various inflammatory diseases, such as psoriasis, rheumatoid arthritis
and Crohn*s disease (CD). Although MTX is generally well-tolerated, it can
produce (potential serious) side-effects. Therefore, MTX should be administered
in the minimally effective dose.
Study objective
The main goal of the proposed project is to compare two MTX dosing regimens to
suppress ADA levels in patients with inflammatory bowel disease (IBD) with loss
of response to anti-TNF agents, and to relate these findings to clinical and
biochemical outcomes.
Study design
We propose to perform a multi-center randomized study in CD and ulcerative
colitis (UC) patients with loss of response to IFX or ADL (based on clinical
and/or biochemical parameters) due to immunogenicity. All patients will be
started on MTX via subcutaneous (SC) injections (i.e. MTX will be added to IFX
or ADL). A randomization procedure will be applied and patients will be
randomized into two groups in a 1:1 ratio. No blinding will be performed.
Intervention
Addition of methotrexaat to anti-therapy (infliximab or adalimumab) according
to standard care (first 12 weeks 25 mg/week, followed by 15 mg/week) or a lower
methotrexaat dosing regime (first 12 weeks 25 mg/week, followed by 7.5 mg/week)
Study burden and risks
The aim of the study is to regain clinical response in IBD patients treated
with infliximab or adalimumab, who lose response due to the formation of ADA.
There are limited therapeutic options for patients who lose response to
anti-TNF agents due to immunogenicity. We expect that adding MTX to anti-TNF
therapy in these patients, will lead to a significant proportion of patients
regaining clinical response. This will postpone the need for switching
out-of-class therapy and will postpone the need for a colectomy. The goal is to
regain clinical response in order to regain a normal quality of life for each
IBD patient.
Blood samples will be taken 5 times on top of standard care with a negligible
risk and low burden.
Quality of life will be assessed at every study visit:
o 1 clinical disease activity questionnaire (SCCAI/HBI)
o 1 quality of life questionnaire (EQ-5D-5L)
At week 6 and week 26 (or at early withdrawl):
o patient reported outcome questionnaire (PRO-CTCAE)
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Age >= 18 years (both men and women)
- Confirmed diagnosis of CD or UC by endoscopy and histopathology
- Maintenance therapy with IFX or ADL, with or without thiopurines (i.e. azathioprine or mercaptopurine)
- Loss of response, defined by clinical parameters (i.e. HBI >4 points (CD), SCCAI >5 points (UC), and/or patients with actively draining perianal fistula (CD)) and/or with elevated inflammatory biomarkers (i.e. serum CRP >=5 mg/l and/or fecal calprotectin >=250 mg/kg))
- Detectable anti-drug antibodies (ADA) directed against IFX or ADL (>=12 AU/ml) using a drug-sensitive assay
- Sub-therapeutic IFX or ADL serum levels (IFX <3 µg/mL, ADL<5 µg/mL)
Exclusion criteria
- Prior intolerance to MTX
- Pregnancy or planned pregnancy in the coming year (men and women)
- Patients with total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, AST or ALT of more than 2 times the upper limit of normal
- Subjects with evidence of or suspected liver disease, such as primary sclerosing cholangitis or cirrhosis
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003594-95-NL |
| CCMO | NL68115.018.18 |