A Phase 3, Randomized, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Guselkumab in Participants with Fistulizing, Perianal Crohn*s Disease

1. Aged 18 years (or the legal age of consent in the jurisdiction in which the
study is taking
place) or over.
2. Must have a diagnosis of Crohn*s disease with a minimum duration of at least
3 months
(confirmed by clinical evaluation and a combination of endoscopic, histological,
radiological, and/or biochemical investigations).
3. Has at least one active draining perianal fistula as a complication of
Crohn*s disease,
confirmed by screening MRI results.
4.2 Is naïve to biologics, or has previously demonstrated lack of initial
response (ie, primary
non-responders), responded initially but then lost response with continued
therapy (ie,
secondary non-responders), or were intolerant to a maximum of 2 classes of
biologic
agents at a dose approved for the treatment of Crohn's disease (ie, infliximab,
adalimumab, certolizumab pegol, vedolizumab, or approved biosimilars for these
agents). Please refer to Appendix 4 for details.
OR
History of failure to respond to, or tolerate, at least 1 of the following
therapies for the
treatment of Crohn's disease: oral corticosteroids (including budesonide and
beclomethasone dipropionate) or immunomodulators (AZA, 6-MP, MTX).
Participants with prior exposure to IL-12/23 or IL-23 agents are ineligible for
entry into
this protocol, with the exception of participants who have had exposure to
ustekinumab
at its approved labeled dosage AND have met the required 16 week washout
criterion
AND have not demonstrated failure or intolerance to ustekinumab. Please refer to
Appendix 5 for details.
5.1 Had a history of failure to respond to, or tolerate, at least 1 of the
following therapies
for fistula treatment: antibiotics (ie, ciprofloxacin, metronidazole) and/or
immunomodulators (AZA, 6-MP, MTX).Please refer to Appendix 3 for details.
Note: Participants refractory, intolerant or dependent on corticosteroids will
be
permitted to participate in the study.
6. Adhere to the following requirements for concomitant medication for the
treatment of
Crohn's disease. The following medications are permitted if doses meeting the
requirements listed below are stable or have been discontinued prior to
baseline and
within the timeframes specified below:
• Oral corticosteroids at a prednisone-equivalent dose at or below 20 mg/day, or
6 mg/day of budesonide, or 5 mg/day beclomethasone dipropionate, and on stable
dosing for at least 2 weeks or if recently discontinued, must have been stopped
for
at least 2 weeks.
• Conventional immunomodulators (ie, AZA, 6-MP, or MTX) for at least 12 weeks
and have been on a stable dose for at least 4 weeks or if recently
discontinued, must
have been stopped for at least 4 weeks.
• If receiving antibiotics as a primary treatment of luminal Crohn's disease,
all
antibiotics must be stopped prior to baseline.
7. If receiving enteral nutrition as a primary treatment for Crohn*s disease,
must have been
receiving for at least 2 weeks or if recently discontinued, must have been
stopped for at
least 2 weeks.
8. Screening laboratory test results within the following parameters, and if 1
or more of
the laboratory parameters is out of range, a single retest of laboratory values
is permitted
during the approximate 6-week screening period:
• Hemoglobin >=8.0 g/dL.
• White blood cells (WBCs) >=3.5 x 103/µL.
• Neutrophils >=1.5 x 103/µL.
• Platelets >=100 x 103/µL.
• Serum creatinine <=1.5 mg/dL.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
concentrations must be <=2 times the upper limit of normal range for the
laboratory
conducting the test.
• Direct (conjugated) bilirubin <1.0 mg/dL.
Must be otherwise healthy based on clinical laboratory tests performed at
screening. If
the results of the serum chemistry panel (including liver enzymes, hematology,
or
urinalysis) are outside the normal reference ranges, the participant may be
included
only if the investigator judges the abnormalities or deviations from normal to
be not
clinically significant or to be appropriate and reasonable for the population
under study.
This determination must be recorded in the participant's source documents and
initialed
by the investigator.
9.1 Are considered eligible according to the following tuberculosis (TB)
screening criteria:
• •Have no history of latent or active TB prior to screening. An exception is
made for
participants who have a history of latent TB and who have documentation of
having
completed appropriate treatment for latent TB within 5 years before the first
administration of study intervention. It is the responsibility of the
investigator to
verify the adequacy of previous anti-tuberculosis treatment and provide
appropriate documentation.
• Have no signs or symptoms suggestive of active TB upon medical history and/or
physical examination.
• Have had no recent close contact with a person with active TB.
• Within 8 weeks prior to the first administration of study intervention, have a
negative QuantiFERON-TB (or T-SPOT for sites in Japan) test result, or have a
newly identified positive QuantiFERON-TB (or T-SPOT for sites in Japan) test in
which active TB has been ruled out. Indeterminate or borderline results may have
the test repeated one time during screening. Please refer to Appendix 6 for
details.
Note: A negative tuberculin skin test result is additionally required if the
QuantiFERON-TB test is not approved/registered in the country in which this
protocol is being conducted. In Ukraine, while the QuantiFERON-TB test is not
approved/registered, it is acceptable, and an additional tuberculin skin test
is not
required. The QuantiFERON-TB test and the tuberculin skin test are not required
at screening for participants with a history of latent TB, if active TB has
been ruled
out, and if appropriate treatment has been completed as described above. Chest
radiographs must be obtained, and a TB specialist should be consulted per local
guidelines, in all cases when the QuantiFERON-TB test and/or the tuberculin skin
test for TB is positive or repeatedly indeterminate. Please refer to Appendix 7
for
details.
• Have a chest radiograph (both posterior-anterior and lateral views, or per
local/country regulations where applicable), taken <=12 weeks before the first
administration of study intervention and read by a qualified radiologist or
qualified
pulmonologist according to local clinical practice, with no evidence of current,
active TB or old, inactive TB. A chest CT scan is also acceptable if obtained
instead
of a chest radiograph outside of the protocol.
10. Male or female (according to their reproductive organs and functions
assigned by
chromosomal complement).
11. A woman of childbearing potential must have a negative serum pregnancy test
at
Screening and Week 0.
12. A woman must be (as defined in Section 10.21, Contraceptive and Barrier
Guidance)
a. Not of childbearing potential
b. Of childbearing potential and
Practicing a highly effective method of contraception (failure rate of <1% per
year
when used consistently and correctly) and agrees to remain on a highly effective
method while receiving study intervention and until 12 weeks after last dose -
the
end of relevant systemic exposure. The investigator should evaluate the
potential
for contraceptive method failure (eg, non-compliance, recently initiated) in
relationship to the first dose of study intervention. Examples of highly
effective
methods of contraception are presented in Appendix 21. Contraceptive and Barrier
Guidance. The method selected must meet local/regional regulations and
guidelines for highly effective contraception.
13.1 A woman must agree not to donate eggs (ova, oocytes) for the purposes of
assisted
reproduction during the study and for a period of 12 weeks after the last dose
of the
study interventions.
14.1 A male participant must wear a condom when engaging in any activity that
allo

1. Has a very severe luminal disease activity (defined as CDAI >=350).
2. Has any of the following:
• history of or concurrent rectovaginal fistulas, rectal and/or anal stenosis
(unless the
participant undergoes surgical dilation prior to baseline), diverting stomas
with
anastomotic leakage, abscess or collections which are not properly drained.
• colonic mucosal dysplasia or pre-cancerous lesions that have not been removed,
demyelinating disease, or systemic lupus erythematosus.
3. Has current complications of Crohn*s disease, such as symptomatic strictures
or
stenoses, short gut syndrome, or any other manifestation, that might be
anticipated to
require surgery, could preclude any fistula evaluation (both clinical and
radiological) to
assess response to therapy, or would possibly confound the ability to assess
the effect
of treatment with guselkumab.
4. Has a stool culture or other examination positive for an enteric pathogen,
including
Clostridioides difficile (formerly known as Clostridium difficile) toxin, in
the previous
4 months, unless a repeat examination is negative and there are no signs of
ongoing
infection with that pathogen.
5. Has a history of, or ongoing, chronic or recurrent infectious disease,
including but not
limited to, chronic renal infection, chronic chest infection (eg,
bronchiectasis), recurrent
urinary tract infection (eg, recurrent pyelonephritis or chronic non-remitting
cystitis),
or open, draining, or infected skin wounds or ulcers.
6. Has a history of serious infection (eg, hepatitis, sepsis, pneumonia, or
pyelonephritis),
including any infection requiring hospitalization, during the 8 weeks before
baseline.
7. Currently has a malignancy or has a history of malignancy within 5 years
before
screening (with the exception of a nonmelanoma skin cancer that has been
adequately
treated with no evidence of recurrence for at least 3 months [defined as a
minimum of
12 weeks] before the first study intervention administration or cervical
carcinoma in
situ that has been treated with no evidence of recurrence for at least 3 months
before
the first study intervention administration).
8. Has a known history of lymphoproliferative disease, including lymphoma, or
signs and
symptoms suggestive of possible lymphoproliferative disease, such as
lymphadenopathy, hepatomegaly, or splenomegaly, or monoclonal gammopathy of
undetermined significance.
9. Has a history of severe, progressive, or uncontrolled renal, genitourinary,
hepatic,
hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic,
psychiatric, or metabolic disturbances, or signs and symptoms thereof.
10. Has a transplanted organ (with exception of a corneal transplant >12 weeks
before
screening).
11. Is unable or unwilling to undergo multiple venipunctures because of poor
tolerability
or lack of adequate venous access.
12. Is unwilling to get a subcutaneous injection.
13. Has unstable suicidal ideation or suicidal behavior in the last 6 months
that may be
defined as a Columbia-Suicide Severity Rating Scale (C-SSRS) rating at
screening of:
Suicidal Ideation with Intention to Act (*Ideation level 4*), Suicidal Ideation
with
Specific Plan and Intent (*Ideation level 5*), or suicidal behavior (actual
suicide
attempt, interrupted suicide attempt, aborted suicide attempt, or preparatory
behaviors
for making a suicide attempt), and is considered to be at risk by the
investigator based
on an evaluation by a mental health professional. In addition, participants
with C-SSRS
ratings of Wish to be Dead (*Ideation level 1*), Non-Specific Active Suicidal
Thoughts
(*Ideation level 2*), Active Suicidal Ideation with Any Methods (Not Plan)
without
Intent to Act (*Ideation level 3*) or non-suicidal self-injurious behavior who
are
determined to be at risk by the investigator may not be randomized.
14. Presence of ulcerative colitis, indeterminate colitis, ischemic colitis,
fulminant colitis,
or toxic mega-colon.
15.1 Known allergies, hypersensitivity, or intolerance to guselkumab or its
excipients (refer
to the Investigator Brochure [IB Guselkumab 2022]), ciprofloxacin
16. Contraindications to the use of guselkumab per local prescribing
information.
17.1 Has received any of the following prescribed medications or therapies
within the
specified period:
• Intravenous corticosteroids received within 3 weeks of baseline
• Cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil received within
8
weeks of baseline
• 6-thioguanine received within 4 weeks of baseline
• Biologic agents:
• Anti-TNF therapy (eg, infliximab, etanercept, certolizumab pegol,
adalimumab, golimumab) received within 4 weeks of baseline
• Vedolizumab received within 4 weeks of baseline
• Has previously received a biologic agent targeting IL-12/23 or IL-23,
including but not limited to briakinumab, brazikumab, guselkumab,
mirikizumab, tildrakizumab and risankizumab
Note: Participants with prior exposure to IL-12/23 or IL-23 agents are
ineligible for entry into this protocol, with the exception of participants who
have had exposure to ustekinumab at its approved labeled dosage AND have
met the required washout criterion (16 weeks) AND have not demonstrated
failure or intolerance to ustekinumab. Please refer to Appendix 5 for details.
• Other immunomodulatory biologic agents received within 4 weeks of baseline
or within 5 half-lives of baseline, whichever is longer
• Any investigational intervention received within 4 weeks of baseline or
within 5
half-lives of baseline, whichever is longer
• Non-autologous stem cell therapy (eg, Prochymal), autologous adipose-derived
stem cells (eg, Darvadstrocel), natalizumab, efalizumab, or biologic agents that
deplete B- or T-cells (eg, rituximab, alemtuzumab, or visilizumab) received
within
6 months of baseline
• Treatment with apheresis (eg, Adacolumn apheresis) or parenteral nutrition for
Crohn*s disease within 3 weeks of baseline
Has received, or is expected to receive, any live virus or bacterial
vaccination within 4
weeks before the first administration of study intervention. For Bacille
Calmette-
Guérin (BCG) vaccine, see Exclusion Criterion 18
18. Has had a BCG vaccination within 1 year of Screening.
19. Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy
before
the planned first dose of study intervention.
20. Has received any investigational intervention received within 4 weeks of
baseline or
within 5 half-lives of baseline, whichever is longer.
21.1 Is a woman who is pregnant, or breastfeeding, or planning to become
pregnant while
enrolled in this study or within 12 weeks after the last administration of study
intervention.
22.1 Plans to father a child while enrolled in this study or within 12 weeks
after the last dose
of study intervention.
23.1 Any condition for which, in the opinion of the investigator, participation
would not be
in the best interest of the participant (eg, compromise the well-being) or that
could
prevent, limit, or confound the protocol-specified assessments. Vulnerable
participants
under protective measures must be excluded from the study.
24.1 Have undergone previous surgery, other than drainage and/or seton
placement and/or
fistula curettage for a draining fistula up to 6 weeks prior to baseline (Week
0). Had
major surgery, within 12 weeks before screening, or will not have fully
recovered from
surgery, or has had any kind of bowel resection within 6 months, or any other
intra-
abdominal or other major surgery within 12 weeks before baseline.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate
Infections or predisposition to infections
25. COVID-19 infection:
During the 6 weeks prior to baseline, has had any of the following: (a)
confirmed severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (test pos