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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] 283692 0
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 290657 0
Condition category
Condition code
Oral and Gastrointestinal 291037 291037 0 0
Inflammatory bowel disease
Inflammatory and Immune System 291062 291062 0 0
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] 288393 0
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] 291022 0
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] 291022 0
Week 26
Secondary outcome [1] 305857 0
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] 305857 0
Week 26
Secondary outcome [2] 305896 0
Mean change in faecal calprotectin concentration at weeks 14 and 26
Timepoint [2] 305896 0
Week 14 and week 26
Secondary outcome [3] 305897 0
Changes in white cell counts (measured by serum full blood counts)
Timepoint [3] 305897 0
Week 26
Secondary outcome [4] 305900 0
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] 305900 0
Week 26
Secondary outcome [5] 349385 0
Mean change in HBI or SCCAI scores. This is a composite outcome.
Timepoint [5] 349385 0
Weeks 14 and 26
Secondary outcome [6] 349386 0
Mean change in serum CRP
Timepoint [6] 349386 0
Week 14 and 26
Secondary outcome [7] 349387 0
Mean change in total white cell count on blood assay
Timepoint [7] 349387 0
Weeks 14 and 26
Secondary outcome [8] 349388 0
Mean change in alanine transaminase (ALT) on serum analysis
Timepoint [8] 349388 0
Weeks 14 and 26
Secondary outcome [9] 349389 0
Mean change in thiopurine metabolites 6-TGN and 6-MMP on blood assay
Timepoint [9] 349389 0
Weeks 14 and 26
Secondary outcome [10] 349390 0
Incidence of adverse reactions to the treatments based on study specific report forms from medical records
Timepoint [10] 349390 0
Week 26
Secondary outcome [11] 349391 0
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] 349391 0
Week 26
Secondary outcome [12] 349392 0
Remission rate and incidence of adverse reactions on thioguanine based on study specific report forms from medical records
Timepoint [12] 349392 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
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)
VIC
Recruitment hospital [1] 1845 0
Box Hill Hospital - Box Hill
Recruitment hospital [2] 1846 0
Maroondah Hospital - Ringwood East
Recruitment hospital [3] 11438 0
The Alfred - Prahran
Recruitment hospital [4] 11439 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 11440 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 11441 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [7] 11442 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 23448 0
3004 - Prahran
Recruitment postcode(s) [2] 23450 0
3065 - Fitzroy
Recruitment postcode(s) [3] 23452 0
3076 - Epping
Recruitment postcode(s) [4] 23449 0
3084 - Heidelberg
Recruitment postcode(s) [5] 23451 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 288379 0
Charities/Societies/Foundations
Name [1] 288379 0
Gastrenterological Society of Australasia Ferring IBD clinician establishment grant
Address [1] 288379 0
Gastroenterological Society of Australia
PO Box 508
Mulgrave 3170 Victoria, Australia
Country [1] 288379 0
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] 287083 0
None
Name [1] 287083 0
None
Address [1] 287083 0
Country [1] 287083 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290262 0
Alfred Health Ethics Committee
Ethics committee address [1] 290262 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 290262 0
Australia
Date submitted for ethics approval [1] 290262 0
23/06/2016
Approval date [1] 290262 0
29/06/2016
Ethics approval number [1] 290262 0
na

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 44738 0
Dr Daniel van Langenberg
Address 44738 0
Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128
Country 44738 0
Australia
Phone 44738 0
+61 3 90949533
Fax 44738 0
+61 3 9899 9137
Email 44738 0
Daniel.van-Langenberg@monash.edu
Contact person for public queries
Name 44739 0
Ms Nola Parsons
Address 44739 0
Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128
Country 44739 0
Australia
Phone 44739 0
+61 3 9094 9544
Fax 44739 0
+61 3 9899 9137
Email 44739 0
nola.parsons@monash.edu
Contact person for scientific queries
Name 44740 0
Dr Daniel van Langenberg
Address 44740 0
Department of Gastroenterology, Eastern Health
Level 2, 5 Arnold St Box Hill VIC 3128
Country 44740 0
Australia
Phone 44740 0
+61 3 9094 9533
Fax 44740 0
+61 3 9899 9137
Email 44740 0
Daniel.van-Langenberg@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results