A phase II, multicenter, randomized, double-blind, multiple dose, placebo-controlled, parallel-group study to evaluate the efficacy, pharmacokinetics, and safety of BI 655066, an IL-23 p19 antagonist monoclonal antibody, in patients with moderately to severely active Crohn's disease, who are naïve to, or were previously treated with anti-TNF therapy.

Crohn*s disease is a chronic inflammatory bowel disease (IBD) that may affect
any part of the gastrointestinal tract from mouth to anus, causing a wide
variety of symptoms.
The intensity of inflammation of the bowel can vary widely; people with Crohn's
disease experience chronic recurring periods of *flare-ups* (fast progression
of disease called acute phase) and remission (quiet periods which nearly do not
require treatment called the chronic phase).
About 35.000 Dutch people and 15.000 Belgian people have IBD. 1000 subjects are
newly diagnosed per year. The disease is mainly diagnosed between the age of
15-30 years.
After diagnosing the disease medicinal treatment will be started to compromise
the inflammation, and to suppress the appearance of new inflammatory spots. In
addition to that prescriptions to prevent anemia and diarrhea are also
frequently prescribed.
Nearly 80% of Crohn*s disease patients require long medicinal treatment and
guidance from a medical specialist. These drugs may work, but also have
negative side effects; many patients show to be intolerant to anti-TNF, which
is most frequently prescribed.
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BI 655066 is an experimental drug, what will be used in patients with Crohn*s
disease for the first time. It was studied in a clinical trial with 31 patients
with psoriasis, a skin disease.
BI 655066 is a *humanized monoclonal antibody* specific to IL-23 p19; this
means that BI655066 neutralizes a protein *IL-23 p19*, which is involved in the
progression of Crohn*s disease. Neutralizing this protein will have effect in
less decrease of the health condition of subjects with Crohn*s disease.
Research physicians will be allowed only to include subjects where the current
therapy standard is ineffective or not effective enough as of effective date of
local AM1 for the Netherlands.

the main objectives of the study are to evaluate the efficacy of different
doses of BI655066
+
to evaluate the pharmacokinetics (how the body handles the study drug) and
pharmacokinetics (interaction of the study drug with the body) for subjects
with Crohn's disease.

This study consists of 3 parts:

Period 1
The score of the Crohn's Disease Activity Index (CDAI) will be assessed by the
research physician to determine a subjects eligibility for the trial.
In part 1 subjects will ave a chance of 1:1:1 of assignment to one of the
treatment arms of the study, on top of their use of standard of care
medication.
(placebo : 200mg BI655066 : 600mg BI655066)
During the first 12 weeks (period 1) medication (or placebo) will be
administered on the randomisation visit, after 2 weeks and after 12 weeks.

Period 2
After the first period the research physician will determine the Crohn's
Disease Activity Index (CDAI) again at visit 6 of period 1, to assess
eligibility for period 2.
a) Whenever a subject reached "deep remission" (definition, see study
protocol), a period of 14 weeks "washout" (=no drug) will start. This is
expected to be acceptable due to the long T1/2 time of BI655066. Subjects will
be monitored during this period as well; in case of " flare-ups" of the
disease, a change to active treatment is possible.
or
b) Whenever a subject did not reach "deep remission", active treatment with the
highest dose of BI655066 will be started. this will be irrespective of the
treatment a subject received during the first 12 weeks.

With this strategy any subject is guaranteed that, whenever recieving placebo,
this will not take longer than 12 weeks & after that every subject (eligible to
continue on period 2 and 3) can continue on active drug.

Period 3
When subjects return after 26 weeks for visit E1, the research physicians will
assess a subject's clinical remission (definition, see study protocol).
a) Whenever there is clinical remission, the subject is allowed to continue in
period 3 and will be treated with subcutaneous therapy untill the end of the
study. (week 65)
or
b) whenever there is no clinical remission, this may suggest that a subject did
not benefit from the past 26 weeks of treatment. These subjects will be asked
to discontinue the trial, as it is considered unethical to let them continue
beyond this point. the investigator will discuss the left options with the
study subject.

also see study protocol, flowchart + chapter 4.1.1:

perdiod 1:
BI655066 / placebo dosed 200 of 600 mg IV on visits 2,4,5

period 2:
if deep remission is seen on V6 (week 12) of period 1, a washoutperiod will
start untill wk26. (based on T1/2 this is expected to be acceptable)

if there is NO deep remission seen on V6 (week 12) of period 1 / or there is a
worsening of disease during the mentioned washout period (confirmed by
colonoscopy) , 1 course (3x IV treatment, each 4 weeks apart) open label
therapy 600 mg IV will be given.

period 3:
if a patient shows clinical remission on week 26, the 3rd period may start with
180 mg SC on visits E1, E2, E3 en E4.
if a patient does not show clinical remission on week 26, the study will end
according to protocol.

The burden for subjects will mainly be based on the visits a subject is
requested to bring to the hospital & the kind of examinations a subject is
requested to undergo during the trial with trial purposes:
In respect to time investments subjects will be in close contacxt with their
study physician for a period of 65 weeks. Depending of the specific visit, this
visit will take 2 to 6 hours of the subject*s time per visit. In total every
patient will be requested to spend an estimate of 48 hours (in this timeframe
of 65 weeks total) at the hospital for interviews with the study staff and to
undergo examinations.
During 3 to 4 visits the time spent onsite by the subject will take 4 to 6
hours per visit, due to the fact a colonoscopy needs to be performed. Only when
there is a *flare* during period 2 of the study (week 12-26), an extra
colonoscopy will be requested from the subject, which may maximize the total
amount of examinations to 4 (instead of 3); this is only expected in rare
cases.
The performer of the colonoscopy will most probably ask patients to bring some
familiar person to the clinic with them, to stay with the subject during the
examination and to bring them home after the clinic visit.
With respect to invasive procedures, subjects will be asked to undergo more
frequent colonoscopies compared to the normal clinical standard. For this study
colonoscopies are required to evaluate the effect of the investigational drug.

Description of risks a subject is exposed to when participating in this trial:
- there is a chance of 1:3 for a subject to be treated with placebo during the
first 12 weeks. This may cause a (temporarily) deterioration in their state of
health. After this 12 week period, all patients will be treated with BI655066.
- There is a chance that subjects (despite of their study treatment arm)
experience side effects of the procedure of a colonoscopy. These side effects
are in nature of the procedure not different from the normal clinical
treatment. This colonoscopy is a common procedure to Crohn*s disease subjects
and will be performed by experts to that procedure. The chance to experience
side effects , is thus the same, but may only occur more frequent as the
colonoscopies occur more frequent.