ANZCTR - Registration

Please note the ANZCTR will be unattended from Friday 20 December 2024 for the holidays. The Registry will re-open on Tuesday 7 January 2025. Submissions and updates will not be processed during that time.

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12613001347752

Ethics application status

Approved

Date submitted

4/12/2013

Date registered

9/12/2013

Date last updated

25/02/2020

Date data sharing statement initially provided

25/02/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

De novo combination allopurinol-thiopurine vs standard thiopurine in inflammatory bowel disease (IBD) patients escalating to immunomodulators: a randomized controlled trial

Scientific title

A randomized controlled trial of patients with IBD attending specialist clinics comparing de novo combination allopurinol and thiopurine versus thiopurine and placebo (ie standard practice) in terms of objective and clinical outcomes at six months

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

The DECIDER study

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

Inflammatory and Immune System

Other inflammatory or immune system disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

De novo combination therapy with allopurinol 100mg orally and gradual pre-specified dose increments of azathioprine (or mercaptopurine) starting at 50mg (or 25mg) orally daily as determined by measuring thiopurine metabolite levels at week 14 and the absence of serious side effects. The decision to commence azathioprine or mercaptopurine will be at the discretion of the treating clinician as per their standard practice. Medications will be supplied in sealed non-distinguishable treatment bottles which will be supplied every eight weeks and drug/ packaging will be returned to assess adherence at the relevant study visit(s). The overall duration of study treatment will be six months.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Introduction of placebo with azathioprine (or merpcaptopurine) starting at 50mg and incrementally increasing dose up to 200mg orally daily every two weeks (also with aid of thiopurine metabolite testing at week 14). Medications will be supplied similarly in blank packaging to intervention group. The overall duration of treatment will be six months.

Control group

Active

Outcomes

Primary outcome [1]

The proportion of patients in each group achieving remission as determined by normalization of faecal calprotectin (to <150 µg/g)and improvement in disease activity score to SCCAI<4 (for UC) or HBI<5 (for CD) at 26 weeks. This is a composite outcome.

Timepoint [1]

Week 26

Secondary outcome [1]

The proportion of patients in each group remaining on either thiopurine monotherapy or thiopurine allopurinol co-therapy at week 26 based on study specific report forms from medical records

Timepoint [1]

Week 26

Secondary outcome [2]

Mean change in faecal calprotectin concentration at weeks 14 and 26

Timepoint [2]

Week 14 and week 26

Secondary outcome [3]

Changes in white cell counts (measured by serum full blood counts)

Timepoint [3]

Week 26

Secondary outcome [4]

Incidence of adverse reactions (by type) - compared by proportion of patients in each group reporting or have laboratory testing consistent with one or more episodes of a significant adverse reaction attributable to either thiopurine or allopurinol at one or more study visits with investigator(s). Examples of adverse reactions include nausea, rash, myalgia/ arthralgia, malaise, abdominal pain, serious infection, leukopenia, deranged liver function.

Timepoint [4]

Week 26

Secondary outcome [5]

Mean change in HBI or SCCAI scores. This is a composite outcome.

Timepoint [5]

Weeks 14 and 26

Secondary outcome [6]

Mean change in serum CRP

Timepoint [6]

Week 14 and 26

Secondary outcome [7]

Mean change in total white cell count on blood assay

Timepoint [7]

Weeks 14 and 26

Secondary outcome [8]

Mean change in alanine transaminase (ALT) on serum analysis

Timepoint [8]

Weeks 14 and 26

Secondary outcome [9]

Mean change in thiopurine metabolites 6-TGN and 6-MMP on blood assay

Timepoint [9]

Weeks 14 and 26

Secondary outcome [10]

Incidence of adverse reactions to the treatments based on study specific report forms from medical records

Timepoint [10]

Week 26

Secondary outcome [11]

Incidence of treatment failure as defined by requirement for rescue therapy, surgery and hospitalisations for CD or UC based on study specific report forms from medical records

Timepoint [11]

Week 26

Secondary outcome [12]

Remission rate and incidence of adverse reactions on thioguanine based on study specific report forms from medical records

Timepoint [12]

Week 26

Eligibility

Key inclusion criteria

• Age 18 - 80 years
• Confirmed UC or CD diagnosis
• Evidence for active disease as determined by baseline faecal calprotectin > or = 150µg/g and/or SCCAI > or = 4 (for UC) or HBI > or = 5 (for CD) at baseline screening visit
• Require commencement of thiopurine therapy according to the patient’s treating physician
• Stable doses of other IBD medications (standardized prednisolone weaning schedule only, maintenance biologics only, aminosalicylates at same dose only) for three months prior to enrolment

Minimum age

18 Years

Maximum age

80 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Unable to understand adequate English
• Unable to give informed consent
• Pregnancy or breastfeeding, or planning to become pregnant and breast feed during the study period
• Medical comorbidities including concurrent sepsis, advanced chronic liver disease, malignancy, haematological disorders causing one or more cytopenias, or any other medical condition that the investigators feel would preclude study entry
• Previous serious adverse reaction to a thiopurine or allopurinol
• Low thiopurine methyltransferase (TPMT) activity at baseline visit (<5 U/ml) or TPMT homozygous genotype (TPMTL/ TPMTL) if previously tested
• Unable to tolerate two weeks of either azathioprine 50mg or mercaptopurine 25mg (or half these doses if TPMT intermediate metaboliser or TPMT genotype 1*/3*)
• Stage 4 or worse chronic kidney disease (an eGFR <30mL/min/1.73m2)

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)

Patients will be consecutively enrolled into this study with approval of the treating physician. The patients will be randomised by computer software by the lead site Clinical Trials Pharmacist. Allocation involves contacting the holder of the allocation schedule at the central administration site so that the person enrolling patients is not aware of which group they would be allocated to.

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

Simple randomization via computer software sequence generation with stratification by IBD diagnosis and concurrent anti-TNF maintenance therapy.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people analysing the results/data

Intervention assignment

Parallel

Other design features

Nil

Phase

Phase 3 / Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

This study hypothesises that the treatment effect would be a 25% difference in the proportion of patients with normalisation of stool inflammatory markers in patients treated with the combined allopurinol-thiopurine co-therapy compared to the patients treated with standard thiopurine monotherapy. Assuming a 15% drop out rate, this results in a total sample size of 140 patients or 70 patients in each treatment group to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.8. The Type I error probability associated with this test of this null hypothesis is 0.05. A futility analysis is proposed to occur on all patients recruited up until the 31st of January 2020.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

3/03/2014

Actual

27/10/2016

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

140

Accrual to date

101

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Box Hill Hospital - Box Hill

Recruitment hospital [2]

Maroondah Hospital - Ringwood East

Recruitment hospital [3]

The Alfred - Prahran

Recruitment hospital [4]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [5]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [6]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [7]

The Northern Hospital - Epping

Recruitment postcode(s) [1]

3004 - Prahran

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

3065 - Fitzroy

Recruitment postcode(s) [4]

3220 - Geelong

Recruitment postcode(s) [5]

3076 - Epping

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Gastrenterological Society of Australasia Ferring IBD clinician establishment grant

Address [1]

Gastroenterological Society of Australia
PO Box 508
Mulgrave 3170 Victoria, Australia

Country [1]

Australia

Primary sponsor type

Hospital

Name

Eastern Health

Address

Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128 Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Health Ethics Committee

Ethics committee address [1]

55 Commercial Rd, Melbourne VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

23/06/2016

Approval date [1]

29/06/2016

Ethics approval number [1]

Summary

Brief summary

The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are immune system related conditions where an overactive immune response from the body’s white blood cells causes inflammation and damage to the intestines and in turn the typical symptoms of diarrhoea, abdominal pain and weight loss. Immune-modifying drugs (immunomodulators) like azathioprine (AZA) and 6-mercaptopurine (6MP) dampen down the overactive white blood cells that are the cause of the inflammation. Over 50% of patients who attend an IBD clinic at Eastern Health are on one of these medications. 

In IBD like other immune related conditions, AZA and 6MP have been shown to both get patients well (induce remission), and keep patients well (maintain remission). Importantly, they also reduce the need for cortisone-based medicines such as prednisolone that are associated with many side effects and no long-term benefits. 

We know that AZA and 6MP to produce two chemical end-products (metabolites) that are responsible for the benefits and also side effects of these drugs. These metabolites are known as 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). 6-TGN is the good metabolite that makes these drugs work, while 6-MMP instead can cause side-effects, especially affecting the liver. Therefore it is desirable to have high levels of 6-TGN and low levels of 6-MMP to get the best out of these drugs.

Recent research has shown that by adding another drug called allopurinol to AZA/6MP in almost all cases the 6TGN levels improve and the 6MMP levels greatly reduce. Also, we generally use a much lower dose of the AZA/6MP combined with the allopurinol and thus most patients end up getting a greater benefit but with fewer tablets, with no increase in side effects. It should be noted that the use of allopurinol in combination with azathioprine or 6-mercaptopurine remains experimental, and is not currently approved by the TGA.

In this study we are comparing patients who are commencing on treatment with azathioprine with those who will be started on a combination of azathioprine and allopurinol to see if this combination of drugs is more effective and quicker to work, yet similarly safe, to those taking the standard AZA alone. 

If we are able to show that the combination is better in this study, then this will have major consequences to how azathioprine is used in the treatment of IBD in the future.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Daniel van Langenberg

Address

Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128

Country

Australia

Phone

+61 3 90949533

Fax

+61 3 9899 9137

Daniel.van-Langenberg@monash.edu

Contact person for public queries

Name

Nola Parsons

Address

Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128

Country

Australia

Phone

+61 3 9094 9544

Fax

+61 3 9899 9137

nola.parsons@monash.edu

Contact person for scientific queries

Name

Daniel van Langenberg

Address

Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128

Country

Australia

Phone

+61 3 9094 9533

Fax

+61 3 9899 9137

Daniel.van-Langenberg@monash.edu

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

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

Source	Title	Year of Publication	DOI
Dimensions AI	Editorial: an argument for low-dose thiopurine allopurinol combination use as first-line therapy in inflammatory bowel disease—authors’ reply	2018	https://doi.org/10.1111/apt.14798
Dimensions AI	Editorial: transplantation in the setting of acute-on-chronic liver failure—calculating chances	2018	https://doi.org/10.1111/apt.14679
Embase	Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).	2024	https://dx.doi.org/10.1111/apt.17831

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Registering a new trial?

Documents added manually

Documents added automatically