Are 18 to 65 years of age, inclusive, at enrollment date.
2. Have a diagnosis of CD that has been endoscopically or radiographically
confirmed. A colonoscopy will be required at baseline to document mucosal disease
activity. SES-CD will be obtained with minimum score of 7.
3. Have active CD symptoms as defined by a CDAI score between 220 and 350 and
demonstrate active symptoms as defined by continued weight loss, abdominal pain
and/or diarrhea not controlled by standard therapy.
4. The participant must have active CD symptoms and therefore have had an inadequate
response to, loss of response to, or intolerance to at least 1 of the following
agent groups in control of their disease (as defined below for each individual
agent group: Corticosteroids or Immunomodulators or TNF-alpha sign antagonists or
Anti-integrin antibodies)
a. Corticosteroids. i. Signs and symptoms of persistently active disease despite a history of at
least one 4-week induction regimen that included a dose. equivalent to prednisone greater than or equal to 30 mg PO once daily (QD) for 2
weeks or intravenously (IV) for 1 week OR. ii. One failed attempt to taper corticosteroids to below a dose equivalent to
prednisone 10 mg PO QD or to taper to below a dose. of 9 mg of budesonide OR. iii. History of intolerance of corticosteroids at the discretion of the principal
investigator (PI) (including but not limited to Cushing s. syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection)
b. Immunomodulators. i. Signs and symptoms of persistently active disease despite a history of at
least one 12-week regimen of oral azathioprine (AZA) (greater than or equal to
2.5 mg/kg/Day) or 6-MP (greater than or equal to 1.5 mg/kg/Day) OR. ii. Signs and symptoms of persistently active disease despite a history of at
least one 12-week regimen of MTX (greater than or equal to 25 mg/week) OR. iii. History of intolerance of at least one immunomodulator (including but not
limited to nausea/vomiting leading to discontinuation,
abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia,
thiopurine methyltransferase genetic mutation, or. serious infection)
c. TNF-alpha sign antagonists with signs and symptoms of persistently active
disease despite a history of receiving infliximab, adalimumab, or certolizumab at
a dose approved for the treatment of CD and:
i. Patient had an inadequate response after completing the full induction
regimen, per approved product labeling. ii. Responded initially but then lost response with continued therapy. iii. Patient had a significant adverse event response which precluded further use
including but not exclusion of infusion reaction, serum. sickness and/or lupus-like rash.
d. Anti-integrin antibodies: with signs and symptoms of persistently active
disease despite a history of receiving an anti-integrin antibody agent
(natalizumab or vedolizumab) at a dose approved for the treatment of CD and:
i. Patient had an inadequate response after completing the full induction
regimen, per approved product labeling. ii. Responded initially but then lost response with continued therapy. iii. Patient had a significant adverse event response which precluded further use
including but not exclusion of infusion reaction, serum. sickness and/or lupus-like reaction.
5. At the discretion of the PI, concomitant medications will be permitted if the
following conditions are met prior to baseline assessment (Day-1):
a. 5-aminosalicylic acid (ASA)-based compounds are permissible if:
i. Oral 5-ASA-based compounds must be at a stable dose for at least 3 weeks prior
to baseline or. ii. Recently discontinued oral 5-ASA-based compounds must have been discontinued
at least 3 weeks prior to baseline or. iii. Rectal 5-ASA-based compounds are not permissible during the study and must
have been discontinued at least 3 weeks prior to baseline.
b. Corticosteroids (e.g., prednisone, budesonide) are permissible if:
i. Oral corticosteroids must be at a prednisone-equivalent dose of less than or
equal to 40 mg/day, or 9 mg/day of budesonide, and have been at a stable dose for
at least 3 weeks prior to baseline or. ii. Discontinuation of oral corticosteroids must have been completed at least 3
weeks prior to baseline or. iii. Parenteral (subcutaneous, intramuscular, or IV) or rectal corticosteroids
are not permitted during the study and must not have been used within a 3-week
period prior to baseline. c. CD-specific antibiotics are permissible if using an antibiotic for treatment
of CD ( a CD-specific antibiotic i.e., metronidazole, ciprofloxacin, rifaximin,
ampicillin, sulfonamide and tetracycline)
i. Participants must have been using the antibiotic for at least 3 weeks before
baseline at a stable dose or. ii. If not currently using a CD-specific antibiotic, the stop date must have been
at least 3 weeks prior to baseline.
d. Immunomodulators are permissible if:
i. Participants receiving chronic (i.e., greater than or equal to 12 weeks)
treatment with AZA, 6-MP, or MTX prior to baseline must be on a stable dose for
at least 6- 8 weeks prior to baseline and must continue on this same dose during
the study. OR. ii. Participants who have discontinued therapy with AZA, 6-MP, or MTX must have
stopped the medication at least 4 weeks prior to baseline. OR. iii. Participants must not have received therapy with other known
immunomodulators (e.g., cyclosporine, tacrolimus, sirolimus, pentoxifylline, or
mycophenolate mofetil) or experimental agents (e.g., granulocyte- or macrophage
colony stimulating factor) for at least. 8 weeks or 5 half-lives of agent from baseline, whichever is longer.
e. The use of Anti-TNF and Anti-integrin therapy or other biological therapy listed
below will not be permitted and the following washout period will be required in order
for participant to be eligible:
i. Three months washout prior to baseline for certolizumab or natalizumab.
ii. Two months washout prior to baseline for adalimumab, infliximab, and vedolizumab.
iii. 8 week washout prior to baseline for cyclosporine, pimecrolimus, tacrolimus, and any
other systemic immunosuppressant.
6. Participants must agree to have samples of their blood and tissue stored for potential
future research use.
7. Participants must have a primary medical care provider.
8. Male participants must agree to employ birth control measures to prevent pregnancy in
female partners from start of treatment, and continuing through 3 months post treatment.
9. Females of childbearing potential must not be breast-feeding, possibly or actually
pregnant, must not have had unprotected intercourse for one month prior to dosing, and must
agree not to become pregnant beginning from enrollment in the study to at least 6 months
after the end of treatment. Participants must remain completely abstinent of potentially
reproductive sexual intercourse (e.g. due to a committed lifestyle) or to consistently use
BOTH a barrier method with a spermicide (male or female condom) AND ALSO one of the below
listed methods of birth control:
1. Continuous/daily hormonal methods including oral contraceptive pills, patch,
implant/injection, etc.
2. Surgical sterilization of either partner, of sufficient duration to be effective, and
NOT known to have failed.
3. Intrauterine device.
EXCLUSION CRITERIA:
1. Presence of clinically significant systemic infection (e.g., chronic or acute
infection, urinary tract infection, or upper respiratory tract infection) within three
months of screening.
2. History or presence of recurrent or chronic infection (e.g., viral infection
[including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV)],
bacterial infection, systemic fungal infection, or syphilis).
3. Positive for tuberculosis (TB) via QuantiFERON-Gold (QFT-G). Individuals who are known
to have received the tuberculosis vaccine will be administered the QFT- G. Patients
can not have received tuberculosis vaccine within 12 months prior to start of study
and can not receive tuberculosis vaccine while on study or within 12 months from the
time of conclusion of study participation.
4. Has a history of active tuberculosis (TB) or a chest x-ray (CXR) with findings
suggestive of old TB infection including calcified nodular lesions, apical fibrosis,
or pleural scarring), acute or chronic HBV, HCV, HIV, or opportunistic infections. 5. A conduction abnormality on baseline electrocardiogram (ECG) that in the opinion of a
cardiologist, is deemed significant.
6. At the discretion of the principal investigator, off-label use of any small molecule
therapeutics that are immune modulators (e.g., naltrexone) within 90 days of beginning
screening or at any time during the 30 days of the screening window.
7. Presence of abnormal hematological and biochemical parameters, including:
1. Neutrophil count < 1500 cells/mm3.
2. Hemoglobin < 9 g/dL.
3. Platelet count less than or equal to 150,000 cells/mm3.
4. Creatinine greater than or equal to 1.2 times the upper limit of normal (ULN).
5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater
than or equal to 1.5 times ULN.
6. Prothrombin time-international normalized ratio (PT-INR) > 1.0 ULN. 7. Serum bilirubin level > 1.0 times ULN.
8. Individuals on chronic anticoagulation medications.
9. Stool sample positive for GI pathogens potentially causing disease (as assessed by
FilmArray GI panel for 22 viral, bacterial, and parasitic organisms that can cause
infectious diarrhea [GI pathogen panel]). The principal investigator will consult with
an infectious disease specialist to review results and decide whether treatment is
warranted.
10. Presence of cytomegalovirus (CMV) infection as defined by positive immunohistochemical
staining on tissue intestine biopsy.
11. History of low-grade or high-grade colonic mucosal dysplasia.
12. History of bowel surgery other than perianal (e.g., fistulotomy, seton placement, or
abscess drainage) within 6 months prior to beginning the CDAI screening diary or
drawing screening blood samples.
13. Presence of surgical changes to gut anatomy that preclude administration of clinical
activity indices; this includes but is not limited to ileostomy, colostomy, or
subtotal colectomy with ileorectal anastomosis.
14. Known or suspected short bowel syndrome.
15. Requirement of parenteral, total parenteral, elemental oral, or nasogastric nutrition.
16. History or current evidence of cancer, other than non-melanomatous cancer of the skin,
or participants that have undergone excision of basal cell carcinoma, squamous cell
carcinoma of the skin. All patients receiving ustekinumab will be monitored for the
appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those
with a medical history of prolonged immunosuppressant therapy and those with a history
of PUVA treatment will be followed closely.
17. Unwillingness or inability to comply with study requirements.
18. Presence of only small bowel CD that is inaccessible by standard colonoscopy for
harvest of research biopsies. Individuals with only upper gastrointestinal CD or only
perianal fistulizing CD are also excluded for this reason.
19. Refusal to abstain from using COX-2 inhibitors or non-steroidal anti-inflammatory
drugs (NSAIDs) throughout the study agent administration period.
20. Has uncontrolled diabetes. 21. Is taking anti-seizure medication, such as valproic acid or its derivative (i.e.,
Depakote)
22. Presence of any condition that, in the opinion of the principal investigator,
contraindicates participation in this study.
23. Has participated in another investigational trial within 8 weeks (or 5 half-lives of
any investigational study agent), whichever is greater, prior to the pre-trial
(screening) visit. The window will be derived from the last date of treatment on the
previous trial.
