Vedolizumab Intravenous (IV) Compared to Placebo in Chinese Participants With Crohn's Disease.

The drug being tested in this study is called vedolizumab. Vedolizumab will be administered as an intravenous (IV) infusion in Chinese participants. This study will investigate the efficacy and safety of vedolizumab IV as induction and maintenance therapy in participants with moderately to severely active Crohn's Disease (CD).

The study will enroll approximately 300 moderately to severely active Chinese patients with CD.

Induction Phase: participants will be randomized 2:1 to receive:

* Vedolizumab IV 300 mg
* Placebo IV

Participants will receive vedolizumab 300 mg or matching placebo, intravenous (IV) infusion at Weeks 0, 2, and 6 in the induction phase. At Week 10, participants will be assessed for clinical response. Results of Week 10 clinical response will determine the treatment pathway in the maintenance phase.

Maintenance Phase: participants who achieved clinical response at Week 10 will continue to receive the same treatment as they received in Induction Phase; every 8 weeks (Q8W) starting at Week 14. Participants who received vedolizumab IV or placebo in the Induction Phase and did not achieve clinical response at Week 10 will receive vedolizumab every 4 weeks (Q4W) starting at Week 14.

This multi-center trial will be conducted in China. The overall time to participate in this study is 60 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone, 6 months after last dose of study drug for a long-term follow-up safety survey.

• Vedolizumab IV (Drug): Vedolizumab IV infusion
• Placebo (Drug): Vedolizumab placebo-matching

Primary outcomes

• Percentage of Participants With Enhanced Clinical Response in the Induction Phase at Week 10 [Week 10]: Enhanced clinical response was defined as ≥100-point decrease from Baseline in the Crohn's Disease Activity Index (CDAI) score at Week 10. A CDAI is a multi-item instrument which measures severity of active Crohn's Disease monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score is equal to sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity.

Secondary outcomes

• Percentage of Participants With Clinical Remission in the Induction Phase at Week 10 [Week 10]: Clinical remission was defined as CDAI score of ≤150 points at Week 10. A CDAI is a multi-item instrument which measures severity of active Crohn's Disease monitored over 7 days includes participant reported symptoms, physician-assessed signs, and laboratory markers. CDAI score is equal to sum of weighted scores for subjective items (number of liquid/soft stools, degree of abdominal pain, general well-being); and objective items (use of anti-diarrhoeal medication, abdominal mass, haematocrit, presence of extraintestinal manifestation, body weight). CDAI scores range approximately from 0 to 600, higher scores indicating greater disease activity

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Has a diagnosis of Crohn's disease (CD) established at least 3 months prior to Screening by clinical and endoscopic evidence corroborated by a histopathology report. Cases of CD established at least 6 months prior to randomization for which a histopathology report is not available will be considered based on the weight of evidence supporting the diagnosis and excluding other potential diagnosis, and must be discussed with the sponsor on a case-by-case basis prior to randomization.
2. Has moderately to severely active CD as determined by a Crohn's Disease Activity Index (CDAI) score of 220 to 400 within 7 days prior to the first dose of study drug and 1 of the following:

   * C-reactive protein (CRP) level >2.87 mg/L during the Screening Phase, OR
   * Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each >0.5 cm in diameter) or 10 aphtous ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent with CD, within 4 months prior to randomization, OR
   * Fecal calprotectin >250 μg/g stool during the Screening Phase in conjunction with computed tomography enterography (CTE), magnetic resonance enterography (MRE), contrast enhanced small bowel radiography, or wireless capsule endoscopy revealing CD ulcerations (aphthae not sufficient), within 4 months prior to Screening
3. Has CD involvement of the ileum and/or colon, at a minimum.
4. Has extensive colitis or pancolitis of >8 years duration or limited colitis of >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months prior to initial screening (may be performed during Screening if not performed in previous 12 months).
5. Has 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 (may be performed during Screening).
6. Has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:

   * Corticosteroids.
   * Immunomodulators.
   * Tumor necrosis factor-alpha (TNF-α) antagonists.

Exclusion Criteria:

1. Has evidence of abdominal abscess at the initial Screening Visit.
2. Has had extensive colonic resection, subtotal or total colectomy.
3. Has a history of >3 small bowel resections or diagnosis of short bowel syndrome.
4. Has had ileostomy, colostomy, known fixed symptomatic stenosis of the intestine, or evidence of fixed stenosis, or small bowel stenosis with prestenotic dilation.
5. Has had previous exposure to approved or investigational anti-integrins (e.g., natalizumab, efalizumab, etrolizumab, or AMG-181), or MAdCAM-1 antagonists, or rituximab.
6. Has used topical (rectal) treatment with 5-ASA, corticosteroid enemas/suppositories or traditional Chinese medications for CD treatment within 2 weeks of the administration of the first dose of study drug.
7. Requires currently or is anticipated to require surgical intervention for CD during the study.
8. Has a history or evidence of adenomatous colonic polyps that have not been removed.
9. Has a history or evidence of colonic mucosal dysplasia including low or high-grade dysplasia, as well as indeterminate for dysplasia.
10. Has a suspected or confirmed diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, and radiation colitis.
11. Has evidence of treatment for C.difficile infection or other intestinal pathogen with 28 days prior to first dose of study drug.
12. Has chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection.
13. Has active or latent tuberculosis.
14. Has any identified congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, human immunodeficiency virus \[HIV\] infection, organ transplantation).
15. Has any history of malignancy, except for the following: (a) adequately-treated nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to randomization; and (c) history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to randomization. Participants with remote history of malignancy (e.g., >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case-by-case basis prior to randomization.
16. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
17. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist at Screening or prior to the administration of the first dose of study drug at Week 0.

Participant flow

Outcome results

• Percentage of Participants With Enhanced Clinical Response in the Induction Phase at Week 10 (Primary), Number, percentage of participants: Induction Phase: Placebo 24.3 (14.8 to 36.0); Induction Phase: Vedolizumab 300 mg 19.4 (13.3 to 26.9) (p =0.347)
• Percentage of Participants With Clinical Remission in the Induction Phase at Week 10 (Secondary), Number, percentage of participants: Induction Phase: Placebo 11.4 (5.1 to 21.3); Induction Phase: Vedolizumab 300 mg 9.0 (4.9 to 14.9) (p =0.531)

Adverse events

Time frame: From first dose of the study drug up to 18 weeks after the last dose (Induction Phase: Up to Week 28; Maintenance Phase: Up to Week 78)

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2019-04-23)
• Statistical Analysis Plan (PDF, 2020-10-05)

• Study Director Clinical Science, Study director, Takeda