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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]

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

Condition category

Condition code

Inflammatory and Immune System

Other inflammatory or immune system disorders

Oral and Gastrointestinal

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]

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]

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]

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]

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]

48 weeks post randomisation

Secondary outcome [2]

Median faecal calprotectin concentration found in patients' stools provided at week 48 post randomisation

Timepoint [2]

48 weeks post randomisation

Secondary outcome [3]

Median C-reactive protein level in the serum measured at week 48 post randomisation

Timepoint [3]

48 weeks post randomisation

Secondary outcome [4]

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]

48 weeks post randomisation

Secondary outcome [5]

Median serum thioguanine nucleotide level

Timepoint [5]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/06/2018

Actual

Date of last participant enrolment

Anticipated

28/12/2018

Actual

Date of last data collection

Anticipated

29/11/2019

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Concord Repatriation Hospital - Concord

Recruitment hospital [2]

Blacktown Hospital - Blacktown

Recruitment hospital [3]

Royal Prince Alfred Hospital - Camperdown

Recruitment postcode(s) [1]

2139 - Concord

Recruitment postcode(s) [2]

2148 - Blacktown

Recruitment postcode(s) [3]

2050 - Camperdown

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Takeda Pharmaceuticals

Address [1]

Chifley Plaza Chifley Tower, 5/2 Chifley Square, Sydney NSW 2000

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Local Health District Human Research Ethics Committee CRGH

Ethics committee address [1]

Concord Hospital
Executive Building, Level 3
1 A Hospital Rd 
Concord Repat Hospital NSW 2139

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

23/02/2017

Approval date [1]

26/05/2017

Ethics approval number [1]

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]

/AnzctrAttachments/375035-VIEWS HREC approval_26.5.17.pdf (Ethics approval)

Attachments [2]

/AnzctrAttachments/375035-Non-oncology IISR Protocol template-guide - FINAL version 171103 tracked3.pdf (Protocol)

Contacts

Principal investigator

Name

Prof Rupert Leong

Address

Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139

Country

Australia

Phone

+61297676111

Fax

[email protected]

Contact person for public queries

Name

Rupert Leong

Address

Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139

Country

Australia

Phone

+61297676111

Fax

[email protected]

Contact person for scientific queries

Name

Rupert Leong

Address

Concord Hospital Level 1 West
Hospital Rd
Concord Repat Hospital
NSW 2139

Country

Australia

Phone

+61297676111

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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