Vedolizumab 4006

Principal Investigator: John  Valentine
Keywords: Crohns , Vedolizumab , 4006 , Triple combination therapy Department: Gastroenterology
IRB Number: 00094798 Co Investigator:  
Specialty: Gastroenterology, Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis
Recruitment Status: Recruiting

Contact Information

Julie Will

Brief Summary


The aim of the current study is to evaluate the efficacy and safety of triple combination therapy of
vedolizumab, adalimumab, and methotrexate in the induction of clinical remission and endoscopic
healing and remission as a measure of mucosal healing of subjects with newly diagnosed CD at
higher risk for complications due to aggressive disease followed by efficacy and safety of
vedolizumab monotherapy to maintain remission. Therapeutic goals for CD have evolved from
control of symptoms to mucosal healing. Achieving clinical remission, biomarker remission, and
mucosal healing has become one of the treatment goals for subjects with CD and is associated with
better outcomes of steroid-free remission and decreased risk of surgery and hospitalization.
Complete mucosal healing, however, is only achieved by a minority of subjects in clinical practice
and trials. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the SES-CD are
robust, validated, endoscopic indices that show high reproducibility among central readers.
The absence of validated score thresholds associated with specific prognostic values or with
endoscopic healing, however, represents a weakness of both the CDEIS and the SES-CD. While
most thresholds for remission in trials have been chosen arbitrarily by investigators, specialists in
the field of IBD recently agreed on a SES-CD of 0–2 for the definition of endoscopic remission.
Endoscopic response as a >50% decrease in SES-CD was also proposed.
There are different treatment agents and combinations used currently in clinical practice to achieve
the goal of endoscopic and clinical remission. Combination therapy for CD appears to lead to
significantly improved efficacy; however, many subjects treated with combined TNF-antagonist
and immunomodulator therapy do not achieve mucosal healing. Vedolizumab has a unique,
gut-selective, immunomodulatory mechanism of action that provides the basis for its development
as a treatment for CD. In a pivotal phase 3 clinical trial, vedolizumab IV was effective for
induction and maintenance therapy in subjects with CD. The goal of adding vedolizumab,
which has a different mechanism of action, to a TNF antagonist and immunomodulator, is to safely
and effectively improve remission rates in CD patients. Coadministration of the 2 biologics
infliximab and natalizumab was previously studied for 10 weeks in 52 CD subjects and was well
tolerated without increased adverse events compared to monotherapy with infliximab alone [41].
The primary endpoint evaluated in this study will be endoscopic remission at Week 26. Based on
a post hoc analysis of the SONIC trial, 26 weeks is the minimum time for the majority of patients
to achieve deep remission with combination therapy. CD patients treated early in their course
of disease with combination therapy have reduced chances of hospitalization, complications, and
surgeries. Our understanding of which patients with CD are at higher risk for aggressive
disease course has improved. Risk factors continue to be identified and the PROSPECT predictive
tool has been developed by Siegel et al. to stratify which subjects are at higher risk for developing
complications. Because CD is a progressive disease with long-term structural complications,
the proposed duration of this study is 102 weeks, in order to provide long-term efficacy data of
vedolizumab maintenance therapy following triple combination induction therapy. Secondary
endpoints will include achieving and maintaining clinical remission and maintaining endoscopic
remission, and additional endpoints will include PROs and AEs. All subjects will receive
vedolizumab IV 300 mg on Day 1, Weeks 2 and 6, and Q8W thereafter until Week 102;
adalimumab 160 mg SC on Day 2, 80 mg SC at Week 2, and 40 mg SC every 2 weeks thereafter
until Week 26; and oral methotrexate 15 mg weekly until Week 34. The initial dosing
recommendations in the dosing regimen for both vedolizumab IV and adalimumab SC follow the
approved labels. 


Primary Objective:The primary objective is to determine the effect of triple combination therapy with an anti-integrin(vedolizumab IV), a TNF antagonist (adalimumab SC), and an immunomodulator (oral methotrexate) on endoscopic remission at Week 26.

Secondary Objectives:
 To evaluate the effect of vedolizumab IV monotherapy on endoscopic remission at Week 102
following triple combination therapy.
 To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on
endoscopic healing at Weeks 26 and 102.
 To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on
endoscopic response at Weeks 26 and 102.
 To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on
deep remission at Weeks 26 and 102.
 To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on
clinical remission by CDAI at Weeks 10, 26, 52, 78, and 102.
 To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on
clinical response by CDAI at Weeks 10, 26, 52, 78, and 102
Additional Objectives:
Additional objectives include:
 To evaluate the PK of vedolizumab and adalimumab in CD subjects at higher risk for
complications at Week 26.
 To assess immunogenicity to vedolizumab and adalimumab over the follow-up period.
 To evaluate C-reactive protein (CRP) levels at Weeks 10 and 26.
 To evaluate fecal calprotectin at Weeks 10, 26, 52, 78, and 102.
 To evaluate the impact of triple combination therapy on health-related quality-of-life
(HRQOL) using the Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity
and Activity Impairment - Crohn’s Disease (WPAI-CD), and the Inflammatory Bowel Disease
Disability Index (IBD-DI).
Safety Objective:
The safety objective is to evaluate the safety of triple combination therapy with an anti-integrin, a
TNF antagonist, and an immunomodulator over a 26-week period, followed by 76 weeks of
monotherapy with an anti-integrin.


Inclusion Criteria

1. In the opinion of the investigator, the subject is capable of understanding and complying with
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative has signed and
dated a written, informed consent form and any required privacy authorization prior to the
initiation of any study procedures.
3. The subject is male or non-pregnant, non-breast-feeding female and aged 18 to 65 years,
inclusive at time of Screening.
4. The subject has an initial diagnosis of CD established within 24 months prior to screening
with involvement of the ileum and/or colon that can be assessed by ileocolonoscopy.
5. The subject has moderate to severely active CD during Screening defined by:
a. CDAI score ≥ 220 within 14 days prior to enrollment, AND
b. Centrally assessed SES-CD score ≥7 (or ≥ 4 if isolated ileal disease) during
Screening, AND
c. Elevated biomarker of inflammation (CRP > 5 mg/L OR fecal calprotectin level
>250 μg/g stool) during Screening.
6. By investigator judgement, the subject is assessed as having CD at moderate-high risk for
complications. Investigator judgement may include clinical assessment, the PROSPECT tool,
or criteria defined by the 2014 AGA CD Clinical Care Pathway.
7. The subject may be receiving a stable therapeutic dose of conventional therapies for CD listed
in the permitted medications and treatments below.
8. If the subject is on corticosteroids, they must be on a stable dose of oral corticosteroids up to
30 mg of prednisone daily or 9 mg of budesonide daily for at least 7 days prior to enrollment.
9. If the subject is on corticosteroids, they must be willing to follow a mandatory taper of
prednisone or budesonide within 60 days after enrollment.
10. The subject must be willing to stop treatment with 5-aminosalicylate (5-ASA), antibiotics, and
probiotics for luminal CD at enrollment.
11. [Previous criterion 11 deleted in amendment number 1].
12. A male subject who is nonsterilized* and sexually active with a female partner of childbearing
potential* agrees to use adequate contraception* from signing of informed consent throughout
the duration of the study and for 18 weeks after last dose.
13. A female subject of childbearing potential* who is sexually active with a nonsterilized* male
partner agrees to use routinely adequate contraception* from signing of informed consent
throughout the duration of the study and for 18 weeks after last dose.
14. Subjects with a family history of colorectal cancer, personal history of increased colorectal
cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer
surveillance (may be performed during Screening as standard of care).

Exclusion Criteria

Gastrointestinal Exclusion Criteria
1. The subject has a diagnosis of UC or indeterminate colitis.
2. [Previous criterion 2 deleted in amendment number 1].
3. The subject has clinical evidence of abdominal abscess or a history of prior abdominal abscess.
4. The subject has a known perianal fistula with abscess. (The subject may have a perianal fistula
without abscess.)
5. The subject has a known fistula (other than perianal fistula).
6. The subject had abdominal surgery within 6 months prior to enrollment.
7. The subject has any prior CD-related surgery OR CD complication requiring surgery during
the study period (other than seton placement for perianal fistula without abscess).
8. The subject has a history of 2 or more small bowel resections or diagnosis of short bowel
9. The subject has extensive colonic resection, ie, subtotal or total colectomy with <15 cm colon
10. The subject has an ileostomy, colostomy, or known fixed symptomatic stricture or stenosis of
the intestine.
11. The subject has a history or evidence of adenomatous colonic polyps that have not been
12. The subject has a history or evidence of colonic mucosal dysplasia.
13. The subject has intolerance or contraindication to undergo ileocolonoscopy.
14. The subject has known fixed stricture or stenosis of the intestine.
Infectious Disease Exclusion Criteria
15. The subject has any identified congenital or acquired immunodeficiency (eg, common variable
immunodeficiency, human immunodeficiency virus [HIV] infection).
16. Subject has undergone organ transplantation.
17. The subject has evidence of an active infection during Screening.
18. Infections requiring treatment with oral (PO) or IV antibiotics, antivirals, or antifungals within
28 days of enrollment.
19. The subject has active or latent TB, regardless of treatment history, as evidenced by any of the
a. History of TB.
b. A diagnostic TB test performed during Screening that is positive, as defined by:
i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON
tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the
equivalent of >15 mg/day prednisone)
20. The subject has a history of listeria, histoplasmosis, coccidioidomycosis, blastomycosis,
candidiasis, aspergillosis, legionella, or pneumocystosis.
21. The subject has a history of any bacterial, viral, and other infection due to opportunistic
22. The subject has chronic hepatitis B virus* (HBV) or hepatitis C virus (HCV) infection. *HBV
immune subjects (ie, being hepatitis B surface antigen negative and hepatitis B surface
antibody positive), may however, be included.
23. The subject has evidence of active Clostridium difficile infection or is having treatment for C.
difficile infection or other intestinal pathogens during Screening.
24. The subject has received any live vaccinations within 28 days prior to enrollment.
General Exclusion Criteria
25. The subject has other inflammatory or rheumatic diseases (eg, psoriasis, rheumatoid arthritis,
ankylosing spondylitis).
26. The subject had a surgical procedure requiring general anesthesia within 60 days prior to
Screening or is planning to undergo major surgery during the study period.
27. The subject is required to take any excluded medications.
28. The subject has received either approved or investigational biologic or nonbiologic agents for
the treatment of IBD in an investigational protocol.
29. The subject has had prior exposure to any TNF antagonist including infliximab, certolizumab
pegol, golimumab, adalimumab, or biosimilar TNF antagonist agents.
30. The subject has had prior exposure to approved or investigational anti-integrin antibodies (eg,
vedolizumab, natalizumab, efalizumab, etrolizumab, AMG 181, anti-MAdCAM-1 antibodies,
or rituximab).
31. The subject has received either approved or investigational biologic agents for the treatment of
non-IBD conditions, other than localized injections (eg, intraocular injections for wet macular
32. The subject has a history of hypersensitivity or allergies to methotrexate, vedolizumab,
adalimumab, or their components.
33. The subject has a medical history that contraindicates the use of vedolizumab, adalimumab, or
methotrexate as per each drug’s package insert.
34. The subject has conditions which, in the opinion of the investigator, may interfere with the
subject’s ability to comply with the study procedures.
35. The subject has a history of any lymphoma or lymphoproliferative disease.
36. The subject has a history of congestive heart failure (New York Heart Association class III/IV)
or unstable angina.
37. The subject has renal insufficiency, ascites, or pleural effusion and underlying liver disease.
38. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI,
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic,
or other medical disorder that, in the opinion of the investigator, would confound the study
results or compromise subject safety.
39. The subject has had gastric bypass surgery.
40. The subject has symptoms of shortness of breath and cough and a diagnosis of clinically
significant lung disease.
41. The subject has a history of malignancy, except for the following: adequately-treated
nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately
treated and that has not recurred for at least 1 year prior to Screening; and history of cervical
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years
prior to Screening. Subjects with a remote history of malignancy (eg, >10 years since
completion of curative therapy without recurrence) will be considered based on the nature of
the malignancy and the therapy received; this must be discussed with the sponsor on a
case-by-case basis prior to enrollment.
42. The subject has a history of any major neurological disorders, including stroke, central nervous
system demyelinating disease, brain tumor, or neurodegenerative disease.
43. The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective
symptom checklist during Screening or prior to the administration of study drug on Day 1.
44. The subject has a history of pre-existing blood dyscrasias, such as bone marrow hypoplasia,
leukopenia (WBC count <3 × 109/L), thrombocytopenia (platelet count <100 × 109/L), or
significant anemia (hemoglobin level <8 g/dL).
45. The subject has rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or
glucose-galactose malabsorption.
46. The subject has any of the following laboratory abnormalities during the Screening period:
a) Hemoglobin level <8 g/dL.
b) WBC count <3 x 109/L.
c) Lymphocyte count <0.5 x 109/L.
d) Platelet count <100 x 109/L or >1200 x 109/L.
e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 the upper limit
of normal (ULN).
f) Alkaline phosphatase >1.5 x ULN.
g) Renal dysfunction (serum creatinine concentration greater than 1.5 mg per deciliter [133
μmol per liter]) or estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 at
Note: Retesting laboratory values during the screening interval may be considered with
consultation from the Medical Monitor.
47. The subject has a history of high alcohol consumption (more than 7 drinks per week), a history
of prior alcohol abuse within 5 years prior to enrollment, has alcoholic liver disease, has
withdrawal symptoms, or a history of illicit drug use.
48. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere
with compliance with study procedures.
49. The subject is unable to attend all the study visits or comply with study procedures.
50. The subject is an immediate family member, study site employee, or is in a dependent
relationship with a study site employee who is involved in conduct of this study (eg, spouse,
parent, child, sibling) or may consent under duress.
51. The subject’s body mass index is >37.
52. If female, the subject is pregnant or lactating or intending to become pregnant before, during,
or within 6 months after participating in this study; or intending to donate ova during such time
53. If male, the subject intends to father a child or donate sperm during the course of this study or
for 6 months thereafter.