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Trial registered on ANZCTR


Registration number
ACTRN12618000812291
Ethics application status
Approved
Date submitted
3/05/2018
Date registered
11/05/2018
Date last updated
11/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Vedolizumab blood levels with or without immunomodulators in patients with ulcerative colitis
Scientific title
Vedolizumab trough levels following randomised withdrawal of immunomodulator in ulcerative colitis patients in remission
Secondary ID [1] 294787 0
None
Universal Trial Number (UTN)
U1111-1213-3468
Trial acronym
VIEWS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ulcerative colitis 307714 0
Condition category
Condition code
Inflammatory and Immune System 306768 306768 0 0
Other inflammatory or immune system disorders
Oral and Gastrointestinal 306776 306776 0 0
Inflammatory bowel disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 301097 0
Treatment: Drugs
Comparator / control treatment
Control = continuing the current optimised dose of ORAL thiopurine TABLETS (optimally titrated to therapeutic drug monitoring with thioguanine nucleotide level 235-450mg/L) on patient recruitment for 48 weeks
Adherence is monitored according to thioguanine nucleotide levels on therapeutic drug monitoring.
Control group
Active

Outcomes
Primary outcome [1] 305760 0
Serum trough level of vedolizumab according to a blood test at week 48.
The level will be detected by serological assessment with QPS, an independent laboratory.
Timepoint [1] 305760 0
48 weeks post randomisation is the primary outcome measure.
Serum is collected at week 0, week 8, week 16, week 24, week 26, week 32, week 40, week 48.
Secondary outcome [1] 346389 0
Clinical relapse defined as clinical symptoms of ulcerative colitis requiring treatment escalation (eg commencement of corticosteroids, increased dose of mesalazine, commencement of rectally-administered therapy, need for biological agent, need for surgery) based on prospectively collected clinical information recorded on clinical data notes or electronic medical records.
Timepoint [1] 346389 0
48 weeks post randomisation
Secondary outcome [2] 346390 0
Median faecal calprotectin concentration found in patients' stools provided at week 48 post randomisation
Timepoint [2] 346390 0
48 weeks post randomisation
Secondary outcome [3] 346391 0
Median C-reactive protein level in the serum measured at week 48 post randomisation
Timepoint [3] 346391 0
48 weeks post randomisation
Secondary outcome [4] 346392 0
Mayo endoscopic subscore scale from 0 to 3 with remission defined as a score of 0 or 3. Patients will be assessed for the proportion of subjects in endoscopic remission (either sigmoidoscopy or colonoscopy) or not according to the randomised groupings.
Timepoint [4] 346392 0
48 weeks post randomisation
Secondary outcome [5] 346393 0
Median serum thioguanine nucleotide level
Timepoint [5] 346393 0
48 weeks post-randomisation

Eligibility
Key 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
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Opaque envelope
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random number generator on website
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
Median trough level of vedolizuimab (and interquartile range) as determined by an independent laboratory blinded to the randomisation allocation. Mann Whitney test will be used between control group and the full withdrawal group as primary analysis. Secondary analysis will be use of the Kruskal Wallis test

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 10831 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 10832 0
Blacktown Hospital - Blacktown
Recruitment hospital [3] 10833 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 22576 0
2139 - Concord
Recruitment postcode(s) [2] 22577 0
2148 - Blacktown
Recruitment postcode(s) [3] 22578 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 299395 0
Commercial sector/Industry
Name [1] 299395 0
Takeda Pharmaceuticals
Address [1] 299395 0
Chifley Plaza Chifley Tower, 5/2 Chifley Square, Sydney NSW 2000
Country [1] 299395 0
Australia
Primary sponsor type
Hospital
Name
Concord Repatriation General Hospital
Address
Department of Gastroenterology
Level 1 West
Concord Hospital
Hospital Rd
Concord Repat Hospital NSW 2139
Country
Australia
Secondary sponsor category [1] 298678 0
None
Name [1] 298678 0
Address [1] 298678 0
Country [1] 298678 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300298 0
Sydney Local Health District Human Research Ethics Committee CRGH
Ethics committee address [1] 300298 0
Concord Hospital
Executive Building, Level 3
1 A Hospital Rd
Concord Repat Hospital NSW 2139
Ethics committee country [1] 300298 0
Australia
Date submitted for ethics approval [1] 300298 0
23/02/2017
Approval date [1] 300298 0
26/05/2017
Ethics approval number [1] 300298 0
CH62/6/2017-015

Summary
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
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2659 2659 0 0

Contacts
Principal investigator
Name 83198 0
Prof Rupert Leong
Address 83198 0
Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139
Country 83198 0
Australia
Phone 83198 0
+61297676111
Fax 83198 0
Email 83198 0
rupertleong@hotmail.com
Contact person for public queries
Name 83199 0
Prof Rupert Leong
Address 83199 0
Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139
Country 83199 0
Australia
Phone 83199 0
+61297676111
Fax 83199 0
Email 83199 0
rupertleong@hotmail.com
Contact person for scientific queries
Name 83200 0
Prof Rupert Leong
Address 83200 0
Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139
Country 83200 0
Australia
Phone 83200 0
+61297676111
Fax 83200 0
Email 83200 0
rupertleong@hotmail.com

No information has been provided regarding IPD availability
Summary results
No Results