None listed
Conditions
Brief summary
Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic incurable inflammatory disorders of the gastrointestinal tract that cause a global health burden. A major advance in the management was the development of biological therapies to treat IBD. This class of drugs, in the form of monoclonal antibodies, target the proinflammatory cytokine tumor necrosis factor (TNF). Several randomised controlled trials (RCT) have shown that infliximab, adalimumab, certolizumab pegol are efficacious in inducing and maintaining clinical remission in moderate-to-severe Crohn’s disease, and for ulcerative colitis, infliximab, adalimumab, and golimumab are effective in inducing and maintaining clinical remission in patients with moderate-to-severe disease activity in whom conventional therapy has failed. Despite the high effectiveness, rates of primary non-response to TNF-a inhibitors in RCTs range between 20 and 40%. Moreover, up to 40% of patients initially responding to TNF-a inhibitors develop intolerable side-effects or lose response overtime. Thus new treatment strategies are needed. The concept of leucocyte migration into inflamed intestinal tissue has been the target for the development of new biologic therapies. a4ß7-integrin is an adhesion molecule expressed on the surface of gut-specific lymphocytes; by binding to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) on intestinal venules it plays a critical role in the mediation of leukocyte trafficking to the gut. Vedolizumab selectively binds to the a4ß7 integrin. The efficacy and safety of vedolizumab in UC and CD has been demonstrated in three pivotal phase III RCTs (GEMINI 1, GEMINI 2 and GEMINI 3) evaluating patients with moderate-to-severe UC or CD who had previously failed at least one prior therapy (e.g. corticosteroids, immunomodulators, TNF-a inhibitors). The combination of an immunosuppressive agent (e.g. azathioprine or its metabolite, 6-mercaptopurine ) with TNF-a inhibitors has proven to be more effective than monotherapy with an immunosuppressive agent or monotherapy with the TNF-a inhibitors. The main role of concomitant immunosuppressive agents is to suppress antibody formation to biological therapies and maintain adequate circulating drug levels. Because of concerns on adverse effects (infections, skin cancers and lymphomas), safety and costs of combination therapy, clinicians always consider withdrawal of therapy once remission is achieved. A recent systematic review on de-escalation of an immunomodulator from combination therapy in IBD showed that in patients discontinued an immunomodulator after combination therapy in CD the rates of relapse did not differ from those of patients who continued taking the drug (55%–60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Although no difference in efficacy
Interventions
Intervention 1 = halving the dose of the current dose of ORAL thiopurine TABLETS (optimally titrated to therapeutic drug monitoring with thioguanine nucleotide of 235-450mg/L) on patient recruitment for 48 weeks
Intervention 2 = complete withdrawal of the ORAL thiopurine TABLETS (= 0 mg dose) for 48 weeks
Adherence is monitored according to thioguanine nucleotide levels on therapeutic drug monitoring.
Sponsors
Concord Repatriation General Hospital
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
• Diagnosis of ulcerative colitis. • Male or female, age 18 years or above • Currently treated with a combination therapy with vedolizumab and dose-optimised thiopurine immunomodulators for ulcerative colitis for at least 6 months • Scheduled administration of vedolizumab 300 mg every 8 weeks over the last 6 months. • Appropriate dose of immunomodulators is defined for azathioprine as a maintenance dose of 2–2.5 mg/kg/day or the maximally tolerated dose, or 6 TGN level within therapeutic range; for 6-mercaptopurine as a maintenance dose of 1-1.5 mg/kg/day or the maximally tolerated dose, or TGN level within therapeutic range (235-450 pmol/8 x 10^8 red blood cells) • Patients in steroid free clinical remission for at least 6 months according to clinical assessment • Mayo score 0 or 1 at baseline or recent past. • Use of contraceptive during the whole study for childbearing potential female patients. • Patients able to understand the information provided to them in English and to give written informed consent for the study
Exclusion criteria
• Patients who have presented a severe acute or delayed reaction to vedolizumab. • Active perianal/abdominal fistulae at time of inclusion, defined by active drainage • Patients with prior colectomy, ostomy or ileoanal pouch or expected to need surgery • Irresectable colorectal dysplasia, history of colorectal cancer or a non-skin cancer (except for cured-cervical cancer) • Pregnancy, breast-feeding or planned pregnancy during the study • Inability to follow study procedures as judged by the investigator • Non-compliant subjects. • Participation in another therapeutic study • Steroid use within 6 months of screening • Currently receiving steroids, non-thiopurine immunomodulators (such as cycloporin, tacrolimus, methotrexate), biological agent treatment (other than vedolizumab), thalidomide, or experimental clinical trial drug (within 5 half-lives of that drug)
Outcome results
None listed