Clinical Trials

Inclusion Criteria:

• Confirmed diagnosis of CD for at least 3 months prior to Baseline. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the investigator, must be available.
• SES-CD (excluding the presence of narrowing component) ≥ 6 (or ≥ 4 for subjects with isolated ileal disease), as confirmed by a central reader.
• Average daily liquid/very soft SF ≥ 4.0 AND/OR average daily AP score ≥ 2.0 at Baseline.
• Demonstrated an inadequate response or intolerance to one or more conventional and/or biologic therapies, in the opinion of the investigator, as defined below:
  • Oral locally acting steroids
  • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone; OR
  • Inability to taper oral budesonide at or below 6 mg/day without recurrent active disease; OR
  • Intravenous or oral corticosteroids
  • Signs and symptoms of persistently active disease despite a history of at least one induction regimen consisting of a dose equivalent to prednisone (or equivalent) ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week; OR
  • Inability to taper corticosteroids at or below a dose equivalent to prednisone 10 mg/day without recurrent active disease; OR
  • Immunosuppressants
  • Signs and symptoms of persistently active disease despite a history of at least one 12 weeks regimen of the following:
    • AZA: ≥ 2.0 mg/kg/day (≥ 1 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, OR a documented 6-thioguanine nucleotide (6-TGN) level of > 235 pmol/8 × 108 RBC at a dose < 2 mg/kg/day OR documentation that a dose reduction was required due to elevated 6-MP levels (> 5700 pmol/8 ×108  erythrocytes); OR
    • 6-MP: ≥ 1 mg/kg/day (≥ 0.6 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, (or a 6-TGN level of > 235 pmol/8 ×  108 RBC); OR
    • MTX (≥25 mg/week subcutaneous [SC] or intramuscular); OR
    • Tacrolimus (for subjects in Australia, Japan or Taiwan only): documented trough level of ≥5 ng/mL.
    • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study.
  • Biologic therapies for CD
    • At least one 6-week induction regimen of infliximab (≥5 mg/kg intravenous [IV] at Baseline and Weeks 2, and 6); OR
    • At least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous [SC] dose at Baseline, followed by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at Baseline, followed by one 40 mg SC dose at Week 2, in countries where this dosing regimen is approved]); OR
    • At least one 4-week induction regimen of certolizumab pegol (400 mg SC at Baseline and Weeks 2, and 4); OR
    • At least one 6-week induction regimen of vedolizumab (300 mg IV at Baseline and Weeks 2, and 6); OR
    • At least one 8-week induction regimen of ustekinumab [260 mg (≤55 kg) or 390 mg (> 55 to ≤85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at Week 8]; OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit of the above biologics.
    • Intolerance to corticosteroids may include depression, severe insomnia, osteopenia, cushingoid features, etc. Intolerance to AZA/6-MP should include elevations of liver enzymes, pancreatitis, etc., and may include subjects with known thiopurine methyltransferase (TPMT) genetic mutation or low activity. Intolerance to a biologic may include, but not be limited to infusion-related reaction, rash, serum sickness, anaphylaxis,  elevated liver enzymes, demyelination, congestive heart failure, infection, etc. Demonstration of intolerance requires no minimum dose or duration of use.
    • Note: Non-bio-IR subjects who have received prior biologic for up to 1 year but have not failed may be enrolled; however, subjects must have discontinued the biologic for reasons other than  inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for intolerance or inadequate response to oral locally acting steroids, systemic steroids (prednisone or equivalent), and/or immunosuppressants as defined above.

Exclusion Criteria:

• Subject on CD-related antibiotics who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on oral aminosalicylates who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on corticosteroids who meets the following:
  • prednisone or equivalent dose > 30 mg/day; or
  • budesonide > 9 mg/day; or
  • has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline.
• Subject on MTX who:
  • has not been on the current course for ≥ 42 days prior to Baseline, and
  • has not been on a stable dose for ≥ 28 days prior to Baseline;
• Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular (IM) anti-infectives within 14 days prior to the Baseline Visit
• Subject requiring or receiving any parenteral nutrition and/or exclusive enteral nutrition.
• Subject who received oral or parenteral traditional Chinese medicines within 30 days prior to Baseline.
• Subject who received any live vaccination within 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) after the last dose of study drug. 
• Subject who received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline.
• Subject who received azathioprine (AZA) or 6-mercaptopurine (6-MP) within 10 days of Baseline.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject who received nonsteroidal anti-inflammatory drugs (NSAIDs) within 7 days prior to Baseline, except topical NSAIDs and low dose aspirin for cardiovascular protection. 
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers from Screening through the end of the study (refer to Table 1 for examples of commonly used strong CYP3A inhibitors and inducers).
• Subject who received any of the following agents:
  • adalimumab, certolizumab, golimumab, infliximab, natalizumab, vedolizumab, within 8 weeks prior to Baseline; or 
  • ustekinumab within 12 weeks prior to Baseline;
  • Note: If there is proper documentation of an undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Any investigational agent within 30 days or 5 half-lives prior to Baseline, whichever is longer, or is currently enrolled in another interventional study.
• Subject with previous exposure to a JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib) within 30 days from Baseline.
  • Note: Subjects who received a JAK inhibitor prior to study entry may be enrolled if they have not had inadequate response or loss of response.
•  Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject received IV corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject has received therapeutic enema or suppository (i.e., rectal aminosalicylates/corticosteroids), other than required for endoscopy, within 14 days prior to endoscopy used for Screening or during the Screening period.
• Subject who received apheresis (e.g., Adacolumn apheresis) within 60 days prior to Screening or during the Screening Period. 
• Subject has cannabis use either recreational or for medical reasons within 14 days prior to Baseline or any history of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation except for local stem cell therapy for complex perianal fistula.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• Subject with the following ongoing known complications of CD:
  • abscess (abdominal or peri-anal);
  • symptomatic bowel strictures;
  • > 2 entire missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure;
  • fulminant colitis,
  • toxic megacolon;
  • or any other manifestation that might require surgery while enrolled in the study;
  • Subject with ostomy or ileoanal pouch;
  • Subject diagnosed with conditions that could interfere with drug absorption including but not limited to short gut or short bowel syndrome; 
  • Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of > 3 bowel resections.
  • Subject with positive Clostridium difficile (C. difficile) toxin stool assay during Screening. 
• Any active, chronic or recurrent infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, disseminated (even a single episode) herpes simplex, or HIV infection. Active HBV, HCV and HIV are defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) positive (+) subjects;
• HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab); 
  • HIV: confirmed positive anti-HIV antibody (HIV Ab) test;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure.
  • Subject has active TB or meets TB exclusionary parameters. 
  • History of any malignancy except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
  • Prior or current gastrointestinal dysplasia, other than completely removed low-grade dysplastic lesions in any biopsy performed during or before the Screening endoscopy.
  • History of gastrointestinal perforation (other than appendicitis or mechanical injury), diverticulitis or significantly increased risk for gastrointestinal perforation per investigator judgment.
  • Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or within 30 days after the last dose of study drug.
  • History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
  • Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug:
    • Serum AST or ALT > 2.0 × upper limit of normal (ULN); 
    • Total WBC count < 2500/µL;
    • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
    • Hemoglobin < 9 g/dL;
    • Platelet count < 100,000/µL; 
    • Absolute neutrophil count (ANC) < 1200/µL;
    •  Absolute lymphocyte count (ALC) < 750/µL. 37. Any of the following cardiovascular conditions or thrombotic conditions:
    • recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
    • current uncontrolled hypertension as defined by a confirmed systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg;
    • prior history of thrombotic events including deep venous thrombosis and pulmonary embolism;
    • known inherited conditions that predispose to hypercoagulability. 
• History of clinically significant medical conditions or any other reason that in the opinion of the investigator would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug or would put the subject at risk by participating in the study.
• For Japan subjects only: positive result of beta-D-glucan or 2 consecutive indeterminate results of beta-D-glucan during the Screening Period.