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Trial registered on ANZCTR

Registration number

ACTRN12612001107819

Ethics application status

Approved

Date submitted

15/10/2012

Date registered

17/10/2012

Date last updated

17/10/2012

Type of registration

Prospectively registered

Titles & IDs

Public title

Febuxostat-thiopurine combination therapy in patients with moderately severe inflammatory bowel disease

Scientific title

Febuxostat-thiopurine combination therapy in patients with moderately severe inflammatory bowel disease (IBD): a pilot study of a novel drug combination that may influence thiopurine bioavailability

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1135-8358

Trial acronym

Febuxostat-thiopurine bioavailability trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

inflammatory bowel disease

Condition category

Condition code

Oral and Gastrointestinal

Inflammatory bowel disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

To use the combination of febuxostat and 6-mercaptopurine over 4 weeks. 40mg febuxostat will be taken orally once daily together with 6-mercaptopurine at a dose of 1/3 that based on thiopurine methyl transferase activity (TPMT) prediction. (The rule of thumb of 1/3 dosing is based on our published experience with the other xanthine oxidase inhibitor (allopurinol)-thiopurine combination

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

not applicable - will be monitoring drug levels with the combination treatment

Control group

Uncontrolled

Outcomes

Primary outcome [1]

therapeutic drug monitoring of drug efficacy using concurrent monitoring of total 6-thioguanine (6TG) methyl 6-mercaptopurine (me6MMP) in red blood cells (method of Dervieux and Bouleau)
together with the ratio of mean red blood cell volume : white blood cell count in peripheral venous blood

Timepoint [1]

1,2,4 weeks

Secondary outcome [1]

drug combination efficacy by -

clinical measures of disease activity: Harvey Bradshaw for Crohn's or Simple severity of colitis index for ulcerative colitis as appropriate, together with C-reactive protein and requirement for and dose of steroid

Timepoint [1]

1,2,4 weeks

Eligibility

Key inclusion criteria

i) moderately severe IBD
ii) patients who accumulate methylated thiopurine metabolites

Minimum age

18 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

i) allergic reaction to 6-mercaptopurine
ii) not so severe as to fit PBS criteria for anti-TNFa treatments
iii) TPMT < 0.3

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Single site, pilot study

STUDY SETTING/LOCATION
Single site, Mater Adults Hospital, Gastroenterology department

STUDY DURATION
One year from patient recruitment to write up

STUDY POPULATION
Patients with moderately severe IBD
Recruitment Process
Patients will be recruited at their routine clinic visit.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

not applicable

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

nil

Phase

Phase 1

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/11/2012

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)

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

Australia

Primary sponsor type

Individual

Name

Prof Tim Florin

Address

Dept Gastroenterology, Mater Health Services, Raymond Terrace, South Brisbane, QLD 4101

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Mater Health Services HREC

Ethics committee address [1]

Quarters Building, Raymond Terrace, South Brisbane, QLD 4101

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

04/10/2012

Ethics approval number [1]

1926A

Summary

Brief summary

1. BACKGROUND 
Febuxostat is a novel xanthine oxidase inhibitor licensed in USA, Europe and Japan for treatment of gout and other hyperuricemic disorders. There has been no attempt to license it in Australia because the market is considered too small.  In Australia, the only xanthine oxidase inhibitor on the market is allopurinol. Allopurinol is an analogue of xanthine, which competitively binds xanthine oxidase. Febuxostat is not a xanthine analogue and so works by a different mechanism to competitively inhibit xanthine oxidase. 
The cornerstone of treatment of patients with moderately severe IBD is thiopurine therapy. Thiopurines are cytotoxic and immunosuppressive therapies originally designed for treatment of acute childhood leukemias and for organ transplantation. Patients have regular monitoring of treatment response as well as blood tests (FBC = full blood count) to ensure that there is no over-immunosuppression and that there is no excessive build-up of methylated metabolites which are hepatotoxic (therapeutic drug monitoring of thiopurine metabolites).
Prof Florin and others have pioneered the combination of allopurinol – thiopurine co-therapy in IBD. The advantages of this therapy are that there the thiopurine requires a considerably lower dose (about 1/3 normal dose) to achieve a beneficial treatment outcome and there are less of its toxic methylated metabolites. Currently, there is debate about why allopurinol can result in less methylated metabolites because allopurinol has no known action on methylating enzymes. Some people think that a metabolite of allopurinol inhibits the methylation enzyme but this has not been proven. 
Allopurinol is generally well tolerated but there are known severe adverse drug reactions including hepatitis, fever, severe skin rash, eosinophilia and renal failure which occurs especially in Asian populations. Febuxostat is a good alternative therapy to allopurinol, but its therapeutic action when combined with thiopurines is unknown. We wish to investigate whether febuxostat – thiopurine co-therapy also works for IBD patients.

2.	AIM(S) OF STUDY
A pilot experiment with highly motivated patients who accumulate increased methylated metabolites on thiopurine monotreatment.

3	HYPOTHESES
3.1  The combination of thiopurine – febuxostat will allow us to use less thiopurine to effect immunosuppressive and therapeutic success.		
3.2 Febuxostat will cause a reduction in methylated metabolites of thiopurines.

Trial website

nil

Trial related presentations / publications

nil

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Prof Tim Florin

Address

Mater Health Services, Raymond Terrace, South Brisbane, QLD 4101

Country

Australia

Phone

+61412764379

Fax

+61731631548

t.florin@uq.edu.au

Contact person for scientific queries

Name

Tim Florin

Address

Mater Health Services
Qld 4101

Country

Australia

Phone

+61412764379

Fax

+61412764379

t.florin@uq.edu.au

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

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

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