Crohn Disease
Conditions
Brief summary
This multi-centre open label study will involve a minimum of 260 patients in 2 cohorts: 86 patients with 'early CD' defined as disease duration \< 24 months and no other treatments than corticosteroids and/or thiopurines and 174 patients with 'late CD' defined as active disease despite treatment with immunosuppressives and anti-TNF. Patients with intolerance to IS and anti-TNF will also be allowed in the latter group. Participants will be treated with 12 months of open label vedolizumab (study medication followed by commercial medication once reimbursement is available) and undergo monitoring of endoscopic, histological and clinical disease parameters. No randomization or blinding will be performed but the study management will ensure that recruitment in either study group is comparable for number and profile of patients (on/off steroids).
Detailed description
Crohn's disease (CD) is a chronic inflammatory disease of the small bowel and colon. Symptoms commonly include bloody diarrhea, abdominal pain, weight loss, and fever. There is no known cause or cure for CD. The aim of current CD treatments is to induce and maintain remission, to reduce the need of corticosteroids and avoid resections and fistulas. Treatment options include systemic and/or topical corticosteroids, purine analogues (6-mercaptopurine and azathioprine), anti-TNF antibodies and surgery. In 2013, results from the GEMINI II, phase 3, randomized controlled trial demonstrated the efficacy of vedolizumab (VDZ) in inducing and maintaining remission in adult patients with active CD. VDZ (MLN0002, or MLN02), inhibits the interaction between α4β7 integrin on memory T and B cells and mucosal addressin cell adhesion molecule-1 expressed on the vascular endothelium of the gut and has been shown to be effective in both inducing and maintaining clinical remission in ulcerative colitis. The ideal positioning of vedolizumab in the therapeutic armamentarium for CD remains unknown. With other (anti-TNF) biologics, outcomes have usually been better if the treatment was started earlier in the disease course and if the patients had not been exposed to prior antibody treatments. Therefore, it appears appropriate and desirable to test the potency of vedolizumab in an earlier phase of CD. Indeed, also with vedolizumab patients previously exposed to biologics appear to have lower success rates with vedolizumab, so a position earlier in the disease course would most likely lead to better outcomes. This is an investigator-initiated open label study of VDZ therapy in 2 distinct populations of CD patients with active disease: 1. patients who have been diagnosed \< 2 years ago and who only been exposed to aminosalicylates and corticosteroids and 2. patients who have been exposed to immunomodulators and/or anti-TNF agents in addition to steroids and aminosalicylates.
Interventions
DRUGvedolizumab
Sponsors
Takeda
Geert D'Haens
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements. 2. The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Age 18 to 80 4. Male or non-pregnant, non-lactating females. Females of child bearing potential must have a negative serum pregnancy test prior to randomization, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or post-menopausal \[defined as a minimum of one year since the last menstrual period\]). 5. Established diagnosis of ileal, ileocolonic or colonic Crohn's disease with histopathological confirmation available in the record of the patient. 6. Moderately to severely active CD (CDAI 220-450) with objective evidence of ulcerations visualized on endoscopy. 7. Anti-TNF discontinued for at least 4 weeks prior to baseline. GROUP 1 (EARLY CD): 8. Diagnosis of CD \< 24 months prior to enrollment 9. Demonstrated failure to respond to topical or systemic corticosteroids or intolerance to corticosteroids or: need for \> 2 courses of steroids since diagnosis or: steroid dependency at any dose since diagnosis and additionally, but not mandatory, lack of efficacy of thiopurines or intolerance to thiopurines (any duration). Patients who are using thiopurines at screening must have used them for \> 3 months (last 4 weeks at stable dose). GROUP 2 (LATE CD) 10. Demonstrated failure to respond to at least 3 months of thiopurines or intolerance to thiopurines and: failure to respond to at least 1 anti-TNF or intolerance to anti-TNF or loss of response to at least 1 anti-TNF.
Exclusion criteria
1. Previous exposure to any anti-integrin antibodies including- vedolizumab ; α4β7 anti-bodies ; β7 antibodies ; anti- MADCAM-1 2. Contraindication for endoscopy. 3. History of colonic dysplasia/cancer 4. Presence of stoma 5. Received other biologics within the last 4 weeks of baseline 6. Use of 5-aminosalicylic acid (5-ASA) or corticosteroid enemas/suppositories within 2 weeks of enrollment 7. Chronic hepatitis B or C infection 8. Evidence of or treatment for C. difficile infection or other intestinal pathogen at screening within 4 weeks prior to enrollment 9. Active or latent tuberculosis 10. Conditions which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedures. 11. Received any investigational drug in the past 30 days or 5 half-lives, whichever is longer. 12. Positive progressive multifocal leukoencephalopathy ( PML) subjective symptom checklist before enrollment. 13. Subjects with known allergy or hyposensitivity to vedolizumab or its components
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of patients with clinical and endoscopic remission at Week 26 | week 26 | Crohns disease activity index (CDAI) of 150 or lower and Simple endoscopic score for Crohn's disease (SES-CD) \< 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with 25% and 75% reduction of SES-CD at Weeks 26 and 52 | 26 and 52 weeks | SES-CD reduction |
| Proportion of patients with clinical response | 52 weeks | CDAI decrease of ≥ 70 points from baseline |
| Proportion of patients with clinical remission | 52 weeks | (CDAI \<=150) at all time other points |
| Proportion of patients with corticosteroid- free clinical remission | 52 weeks | (CDAI \<=150) at all other time points |
| Proportion of patients with normalized serum C-reactive protein (CRP) at all time points | 52 weeks | CRP |
| Proportion of patients with no granulocytes in the biopsies at Weeks 26 and 52. | Week 26 and week 52 | No granulocytes |
| Proportion of patients with 25%, 50% and 75% reduction in the Geboes histology score at Weeks 26 and 52 | Week 26 and week 52 | Geboes score |
| Proportion of patients with endoscopic response at Weeks 26 and 52 | 26 and 52 weeks | SES-CD reduction by ≥ 50 % |
| Proportion of patients with sustained clinical remission | After week 10 | (remission at all time points after week 10) |
| Proportion of patients with draining fistulas | 52 weeks | Fistula |
| Proportion of patients that need to be hospitalized | 52 weeks | — |
| Quality of life measured by Inflammatory Bowel Disease Questionnaire ( IBDQ) | Screening, week 10, week 26 and week 52 | Questionnaire |
| Work productivity Index | Screening, week 10, week 26 and week 52 | Questionnaire |
| Serum concentrations of vedolizumab and antibodies to vedolizumab before every infusion | 52 weeks | through concentration |
| Quality of life measured by Euroqol (EQ-5D) | Screening, week 10, week 26 and week 52 | Questionnaire |
| Proportion of patients with sustained clinical response (response at all time points after week 10) | After week 10 | Geboes score reduction |
Countries
Belgium, Hungary, Netherlands
Outcome results
None listed