A Prospective Multicenter Randomized Controlled, Open-label Study to Compare the Efficacy of Subcutaneous Infliximab Monotherapy with Subcutaneous Infliximab and Concomitant Immunosuppression in the Treatment of Moderate to Severe Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that results
in progressive bowel damage and disability. Since curative therapy is not yet
available, CD is a lifelong disease and the aim of the therapy is to induce
remission in the short term and to maintain remission in the long term. The
recognition that chronic and untreated inflammation, even when asymptomatic,
ultimately leads to poor outcomes leads to treatment goals evolving towards a
combination of clinical and endoscopic remission.

A recent 1-year study showed that the efficacy and safety of the SC and IV
formulations are comparable and unaffected by switching patients from IV to SC
administration. Interestingly, the SC formulation of IFX has been associated
with lower immunogenicity (i.e., slower rate of anti-drug antibody formation)
compared to continuous IV treatment in both the RA (69 vs 33% in IV 3 mg / kg
vs SC 120 mg EOW through w30) as in the IBD population (54 vs 38% IV 5 mg / kg
vs SC 120/240 mg EOW through w30). In these studies, to our knowledge, patients
were not systematically assigned concomitant immunosuppressive therapy.
Long-term use of combination immunosuppressive therapy has been associated with
increased risk of infection and malignancy.

Administration of IFX in combination with immunosuppressant combination therapy
in CD leads to improved outcomes, and the benefit of combination therapy
appears to be primarily determined by the effect of thiopurines on the
pharmacokinetics and immunogenicity of infliximab in patients on combination
therapy. However, the literature data is conflicting on the long-term risk of
infection and malignancy in patients on combination treatment compared to
anti-TNF monotherapy, so monotherapy would be preferable in terms of long-term
safety.

The aim of this study is to investigate the efficacy of subcutaneous IFX in the
treatment of moderate to severe Crohn*s disease with and without concomitant
immunosuppression, as measured by the proportion of patients in
corticosteroid-free clinical remisison (as defined by a CDAI<150) and
endoscopic response (as defined by a SES-CD drop of at least 50%) at week 26.
We hypothesize that subcutaneous IFX monotherapy is non-inferior to
subcutaneous IFX with concomitant immunosuppression in inducing this combined
primary endpoint of CSF clinical remission and endoscopic response by week 26.

This is a randomized controlled multicentre trial to investigate the efficacy
of subcutaneous infliximab monotherapy compared to subcutaneous infliximab in
combination with concomitant immunosuppression in inducing CSF clinical
remission and endoscopic response after 26 weeks of treatment.

158 test subjects will participate in this study at approximately 13-20
locations in the Netherlands (peripheral and university hospitals). The
estimated enrollment is 0.5 patient / center / month, leading to an inclusion
duration of 16 months once all centers are open. First enrollment is expected
in Q1 2021.

Treatment Arms:
Group 1: Subcutaneous IFX monotherapy 240mg at week 0 and week 2 and then 120mg
EOW
Group 2: Subcutaneous IFX 240mg at week 0 and week 2 and then 120mg EOW in
combination with immunosuppressive

Randomly assigned to either of these groups in a 1:1 ratio. Randomization will
be stratified according to immunosuppressive use at screening.

After consent, the patient is centrally randomized (1: 1) to either infliximab
mono- or combination treatment. Following the screening procedure, patients
randomized to the monotherapy group will begin subcutaneous IFX monotherapy at
240 mg at weeks 0 and 2 and then 120 mg EOW thereafter.

Patients randomized to combination IFX therapy will also start on subcutaneous
IFX 240 mg at weeks 0 and 2 and then 120 mg EOW and will also receive
6-mercaptopurine 1-1.5 mg / kg (or if they are already on azathioprine or
thioguanine , they will receive a continuous dose of 2-2.5 mg / kg or 20 mg
once daily unless shunter status, metabolite levels or previous adverse events
suggest differently) or in case of adverse events or investigators individual
consideration, instead of thiopurine, methotrexate 15 mg/week s.c. in
combination with folic acid 5mg/week is to be started as soon as possible.

According to local protocols, if the dose of concomitant immunosuppression is
gradually built up, the target dose of concomitant immunosuppression should be
reached by week 2 of study product administration. Patients randomized to IFX
monotherapy will not receive concomitant immunosuppression, or if they are
already receiving concomitant immunosuppression, immunosuppressive treatment
will be discontinued on screening.

The aim of this study is to investigate the efficacy of subcutaneous IFX in the
treatment of moderate to severe Crohn's disease with and without concomitant
immunosuppression, as measured by the proportion of patients with
corticosteroid-free clinical remission (as defined by a CDAI <150). and
endoscopic response (as defined by an SES-CD decrease of at least 50%) at week
26.

Biopsies are collected during colonoscopy (five segment 2 biopsies) screening
and week 26. Additional blood samples from Infliximab serum concentrate and ADA
weeks 2, 4, 8, 14, 26. Thiopurine metabolites blood collection baseline, weeks
14, 26, (epi) genetic analysis baseline and week 26.

Risk:
Remsima subcutaneous injection and its combination with immunosuppressants can
reduce diarrhea and abdominal discomfort, but this is not certain. At any time
during this exam, your disease or your symptoms may return or get worse.

Complications can arise with a viewing examination of the bowel. During the
viewing examination, a tear or hole may develop in the intestinal wall. Or a
bleeding. This is uncommon and affects less than 1 in 1,000 people. Then we try
to treat you immediately. Sometimes you have to stay in hospital. And sometimes
we have to repair the complication with surgery.

Burden:
The administration of Inflectra by means of an abdominal injection at home
replaces the administration via the blood vessels in the hospital and reduces
the risk of inflammation from infusion.

Participating in this study may have disadvantages, you may experience adverse
effects of the drug. You may also be bothered by the measurements during the
examination, for example from a blood sample. Filling in the questionnaires can
be confronting. Participation in the study takes extra time and you must adhere
to agreements that are part of the study.

Benefit:
Literature data is conflicting on the long-term risk of infection and
malignancy in patients on combination treatment compared to anti-TNF
monotherapy, so monotherapy would be preferable in terms of long-term safety.

In the pivotal studies of subcutaneous IFX, the new formulation has been
associated with a lower immunogenicity compared to intravenous IFX, indicating
a potential for monotherapy alone. If subcutaneous IFX monotherapy proves to be
non-inferior in efficacy to combination therapy, this could provide a safer
treatment for patients with IBD with more flexibility, eliminating the infusion
unit capacity.