A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Treat-Through Study to Evaluate the Efficacy and Safety of Mirikizumab in Patients with Moderately to Severely Active Crohn's Disease

1. (AMAM Main Trial): have given written informed consent approved by the
Ethical Review Board (ERB) governing the site.
1. (AMAM Adolescent Addendum): the investigator, or a person designated by the
investigator, will obtain written informed consent approved by the Ethical
Review Board (ERB) from each study participant or the participant's
parent/legal guardian and the subject*s assent, when applicable, before any
study-specific activity is performed. The investigator will retain the original
copy of each
participant's signed consent/assent document.
2. (AMAM Main Trial): are male or female patients >=18 and <=80 years of age at
the time of initial screening.
2. (AMAM Adolescent Addendum):are male or female patients 15 to <18 years of
age weighing >40 kgs with moderate to severely active CD as defined in points 5
and 6 below at the time of initial
screening/consent.
[2a] male patients: no male contraception required except in compliance with
specific local
government study requirements,
[2b] female patients: women of childbearing potential:
A. must test negative for pregnancy prior to initiation of treatment as
indicated by
a negative serum pregnancy test at the screening visit followed by a negative
urine pregnancy test within 24 hours prior to exposure.
AND
B. must agree to either remain abstinent, if complete abstinence is their
preferred
and usual lifestyle, or remain in same-sex relationships, if part of their
preferred and usual lifestyle, without sexual relationships with males.
Periodic abstinence (for example, calendar, ovulation, symptothermal, or
post-ovulation methods), declaration of abstinence just for the duration of a
trial, and withdrawal are not acceptable methods of contraception.
OR
must use 2 effective methods of contraception for the entirety of the study.
Abstinence or contraception must continue following completion of study
drug administration for 20 weeks.
i. Two effective methods of contraception (such as male or female condoms
with spermicide, diaphragms with spermicide, or cervical sponges) will be
used. The participant may choose to use a double barrier method of
contraception. Barrier protection methods without concomitant use of a
spermicide are not a reliable or acceptable method. Thus, each barrier
method must include use of a spermicide. It should be noted that the use
of male and female condoms as a double barrier method is not considered
acceptable because of the high failure rate when these methods are
combined.
ii. Of note, 1 of the 2 methods of contraception may be a highly effective
(less than 1% failure rate) method of contraception (such as combination
oral contraceptives, implanted contraceptives, or intrauterine devices).
women not of childbearing potential may participate and include those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral
oophorectomy, or
tubal ligation), congenital anomaly such as mullerian agenesis; or
B postmenopausal - defined as either:
i. a woman at least 40 years of age with an intact uterus, not on hormone
therapy, who has had either
* cessation of menses for at least 1 year without an alternative medical
cause AND
* at least 6 months of spontaneous amenorrhea with a folliclestimulating
hormone (FSH) level >40 mIU/mL; or
ii. a woman 55 years or older not on hormone therapy, who has had at least
6 months of spontaneous amenorrhea; or
iii. a woman at least 55 years of age with a diagnosis of menopause prior to
starting hormone replacement therapy.
[3] have venous access sufficient to allow blood sampling and IV administration
as per the
protocol.
Disease-Specific Inclusion Criteria
[4] have had a diagnosis of CD or fistulizing CD established at least 3 months
prior to
enrollment confirmed by clinical, endoscopic, and histological criteria.
Note: A histopathology report supporting the diagnosis of CD must be available
in the
source documents prior to randomization, in order to satisfy this inclusion
criterion. If a
histopathology report supporting the diagnosis of CD is not available in the
source
documents prior to randomization, the investigator can obtain additional
biopsies for this
purpose at the screening endoscopy (sent to the local histopathology
laboratory).
[5] have moderately to severely active CD as defined by unweighted daily
average SF >=4
(loose and watery stools defined as Bristol Stool Scale Category 6 or 7) AND/OR
unweighted daily average AP >=2 at baseline (Visit 2).
[6] enrollment of a subset of participants with a SES-CD score >=3 and <7 (for
patients with isolated ileal disease SES-CD >=3 and <4) and presence of at least
one large ulcer (in the ileum, colon, or both) that results in a minimum score
of 2 for the component of *size of ulcers* and a minimum score of 1 for the
component of *ulcerated surface*.
[7] Participants with a family history of colorectal cancer, personal history
of increased
colorectal cancer risk, age >50 years, or other known risk factor must be up-to
date on
colorectal cancer surveillance per local guidelines. If not, this documentation
of negative
colorectal cancer surveillance may be performed according to local guidelines
during
screening.
Prior Medication Failure Criteria
[8] Participants must have an inadequate response to, loss of response to, or
intolerance to at
least 1 of the medications described in Inclusion Criterion [8a] OR [8b]. For
the relevant
medication specified in these criteria, documentation of dose, frequency, route
of
administration, and duration of the qualifying failure is required.
[8a] Conventional-failed patients: Patients who have an inadequate response to,
loss
of response to, or are intolerant to at least one of the following medications:
o corticosteroids
* corticosteroid-refractory disease, defined as signs and/or symptoms of
active CD despite oral prednisone (or equivalent) at doses of at least
30 mg/day for a minimum of 4 weeks.
* corticosteroid-dependent disease, defined as:
a. an inability to reduce corticosteroids below the equivalent of prednisone
10 mg/day or budesonide below 3 mg/day within 3 months of starting
corticosteroids without a return of signs and/or symptoms of active CD;
or
b. a relapse within 3 months of completing a course of corticosteroids.
* history of intolerance of corticosteroids (which includes evidence of a
side-effect sufficiently serious as to precluding continued treatment with
corticosteroids including, but not limited to, Cushing*s syndrome,
osteopenia/osteoporosis, hyperglycemia, or neuropsychiatric sideeffects,
including insomnia, associated with corticosteroid treatment).
o immunomodulators:
* signs and/or symptoms of persistently active disease despite at least 3
months* treatment with one of the following:
* oral AZA (>=1.5 mg/kg/day) or 6-MP (>=0.75 mg/kg/day) or MTX 25 mg
(intramuscular or SC weekly) or
* oral AZA or 6-MP within a therapeutic range as judged by thioguanine
metabolite testing, or
* a combination of a thiopurine and allopurinol within a therapeutic range as
judged by thioguanine metabolite testing.
Discontinuation despite clinical benefit does not qualify as having failed or
being
intolerant to CD conventional therapy.
[8b] Biologic-failed patients: Participants who have an inadequate response to,
loss
of response to, or are intolerant to an approved biologic therapy for CD (such
as
anti-TNF antibodies or anti-integrin antibodies). Investigators must be able to
document an adequate history of induction and/or maintenance dose use.
Participants should fulfill 1 of the following criteria:
o Inadequate response: Signs and symptoms of persistently active disease
despite induction treatment at the approved induction dosing, that was
indicated in the product label at the time of use,
OR
o Loss of response: Recurrence of signs and symptoms of active disease
following prior clinical benefit during treatment with approved maintenance
dosing.
OR
o Intolerance: History of intolerance to inflixim

Participants will be excluded from study enrollment if they meet any of the
following criteria
within the screening period, unless otherwise specified below.
For rescreening activities within the screening period, see Section 5.4.
Gastrointestinal Exclusion Criteria
[12] are participants who:
[12a] have a current diagnosis of UC, IBD-unclassified (formerly known as
indeterminate
colitis).
[12b] currently have or are suspected to have an abscess. Recent cutaneous and
perianal
abscesses are not exclusionary if drained, adequately treated and resolved at
least 3 weeks
prior to baseline or 8 weeks prior to baseline for intra-abdominal abscesses,
provided that
there is no anticipated need for any further surgery.
[13] have a stoma, ileoanal pouch or ostomy.
[14] have had a bowel resection within 6 months, or any kind of intra-abdominal
surgery
within 3 months of baseline (Visit 2).
[15] have complications of CD such as symptomatic strictures or stenosis, short
gut syndrome,
or any other manifestation that might be anticipated to require surgery within
6 months
after screening, could preclude the use of the SES-CD, CDAI, or PRO to assess
response
to therapy, or would possibly confound the ability to assess the effect of
treatment.
Adenoma, Dysplasia, and Gastrointestinal Cancer Exclusion Criteria
[16] have any history or current evidence of cancer of the gastrointestinal
tract.
[17] have any current sporadic adenoma without dysplasia that has not been
removed. Once
completely removed, the patient is eligible for study.
[18] have any evidence of colonic dysplasia.
Criteria for Discontinuing Prohibited Medications
[19] have received any of the following for treatment of CD within the time
frames specified
below:
[19a] corticosteroid enemas, corticosteroid suppositories or a course of IV
corticosteroids within 2 weeks prior to screening endoscopy.
[19b] 5-ASA enemas or 5-ASA suppositories within 2 weeks prior to screening
endoscopy.
[19c] immunomodulatory medications, including oral cyclosporine, IV
cyclosporine,
tacrolimus, mycophenolate mofetil, thalidomide or Janus kinase inhibitors within
4 weeks prior to the screening endoscopy.
* AZA, 6-MP, and MTX are allowed at stable doses (Appendix 10.7).
* Other immunomodulatory medications should be discussed with the sponsor prior
to screening.
[19d] anti-TNF antibodies (for example, infliximab, adalimumab, or certolizumab
pegol) within 4 weeks prior to screening endoscopy.
[19e] anti-integrin antibodies (for example, vedolizumab) within 4 weeks prior
to
screening endoscopy.
[19f] agents that deplete B or T cells (for example, rituximab, alemtuzumab, or
visilizumab) within 12 months of baseline (Visit 2). Patients remain excluded if
there is evidence of persistent targeted lymphocyte depletion at the time of
screening endoscopy.
[19g] any investigational nonbiologic therapy within 4 weeks prior to the
screening
endoscopy or within 5 half-lives prior to the screening endoscopy, whichever is
longer.
[19h] any investigational biologic therapy within 8 weeks prior to the screening
endoscopy or within 5 half-lives prior to the screening endoscopy, whichever is
longer.
[19i] leukocyte apheresis (leukapheresis, for example, Adacolumn) within 3 weeks
prior to screening endoscopy.
[19j] interferon therapy within 8 weeks prior to screening endoscopy.
[19k] natalizumab within 12 months prior to screening endoscopy.
[20] have ever received anti-IL-23p19 antibodies (for example, risankizumab
[BI-655066],
brazikumab [MEDI-2070], guselkumab [CNTO1959], or tildrakizumab [MK-3222]) for
any indication, including investigational use.
[21] Subjects who discontinued an anti-IL 12/23p40 antibody (for example,
ustekinumab) due
to primary nonresponse or secondary loss of response or intolerance OR who
received
more than the IV induction dose and 1 SC dose are not eligible.
Note: Participants who have received up to the IV induction dose and one SC
dose of
anti-IL 12/23p40 antibodies (for example, ustekinumab), may be enrolled.
However,
these participants must have discontinued treatment for a nonclinical reason
(for example,
change of insurance) and discontinued at least 8 weeks prior to screening
endoscopy.
Enrollment of participants meeting this criterion will be limited to
approximately 10% of
total enrollment.
[22] require systemic corticosteroids for non-CD conditions (except
corticosteroids to treat
adrenal insufficiency).
Infectious Disease Exclusion Criteria
[23] are participants who
[23a] have evidence of active tuberculosis (TB), or
[23b] have a past history of active TB, without documented appropriate
treatment by the
World Health Organization (WHO) and/or the Centers for Disease Control and
Prevention (CDC), or
[23c] are diagnosed with latent tuberculosis infection (LTBI) at screening
and/or have a
past history of LTBI and have not started a course of an appropriate TB
prophylaxis regimen (Section 8.2.6).
Participants diagnosed with LTBI at screening and/or history of LTBI without
appropriate treatment (aligned with WHO/CDC guidance in place at the time of
treatment) may be allowed to rescreen and may be eligible for the study,
provided they
fulfill all the criteria described in Section 8.2.6.
[24] have received a Bacillus Calmette-Guérin (BCG) vaccination within 12
months or
received live attenuated vaccine(s) within 3 months of screening or intend to
receive such
during the study.
[25] have human immunodeficiency virus/acquired immune deficiency syndrome
(HIV/AIDS).
[26] have acute or chronic hepatitis B infection; or test positive for
hepatitis B virus (HBV) at
screening, which is defined as:
* positive for hepatitis B surface antigen (HBsAg+)
OR
* negative for hepatitis B surface antigen (HBsAg-) and positive for
anti-hepatitis B
core antibody (anti-HBc+) in conjunction with detectable HBV DNA (see
Section 8.2.8).
[27] have current hepatitis C infection; or test positive for hepatitis C virus
(HCV) at
screening, defined as:
* positive for hepatitis C antibody and detectable HCV RNA (see Section 8.2.9).
Note: Participants with a previous HCV infection that has been successfully
treated with
anti-viral therapy are not excluded (see Section 8.2.9).
[28] have tested positive for C. difficile toxin or for other intestinal
pathogens within 30 days
of screening endoscopy or test positive at screening for C. difficile toxin or
for other
intestinal pathogens. Participants with a confirmed diagnosis of
cytomegalovirusassociated
colitis should have adequate treatment and resolution of symptoms at least 3
months prior to screening endoscopy (See Section 8.2.5).
[29] have serious, opportunistic, or chronic/recurring extraintestinal
infections. Participants
may be eligible for entry into the study if they have been adequately treated
and off
antibiotics for 30 days without recurrence of symptoms prior to screening. Such
extraintestinal infections include but are not limited to the following:
[29a] infections requiring IV antibiotics.
[29b] infections requiring hospitalization.
[29c] infections that are considered *opportunistic* (see Appendix 10.5).
[29d] chronic, recurrent infections (for example, osteomyelitis, recurring
cellulitis).
Participants with only recurrent, mild, and uncomplicated orolabial and/or
genital
herpes may be discussed with the medical monitor to determine the relevance of
this infection for entry into the study,
Participants with an opportunistic infection or chronic, recurrent infection
(within
the last 60 days prior to Visit 2) should be discussed on a case-by-case basis
with the
medical monitor.
[30] have a current or recent acute, active nonserious extraintestinal
infection for which signs
and/or symptoms are present or treatment, if indicated, is not yet complete 2
weeks prior
to screening.
[31] have evidence of active/infectious herpes zoster infection <=8 weeks prior
to screening.
Herpes zoster infections remain active until all vesicles are dry and crusted