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
ACTRN12611000363987
Ethics application status
Approved
Date submitted
8/09/2010
Date registered
7/04/2011
Date last updated
10/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Use of Ajunctive Allopurinol in Azathioprine/6-Mercaptopurine Non-responders to Optimize 6-Thioguanine Nucleotide Production and Improve Clinical Outcomes in Patients with Inflammatory Bowel Disease (IBD).
Scientific title
The Triple A (Adjunctive Allopurinol and Azathioprine) Study: Use of Ajunctive Allopurinol in Azathioprine/6-Mercaptopurine Non-responders to Optimize 6-Thioguanine Nucleotide Production and Improve Clinical Outcomes in Patients with Inflammatory Bowel Disease (IBD).
Secondary ID [1] 253097 0
none
Universal Trial Number (UTN)
Trial acronym
IBDBF1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammatory Bowel Disease (IBD) 257934 0
Condition category
Condition code
Oral and Gastrointestinal 258105 258105 0 0
Inflammatory bowel disease
Inflammatory and Immune System 258224 258224 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible IBD patients will be randomly allocated to receive either 100mg or 50mg of allopurinol orally in 1:1 using computer generated list. Patients will continue to take their usual azathioprine or 6-mercaptopurine at reduced doses as determined by the study doctor. The study duration for each individual patient is 24 weeks. Allopurinol will be taken once dail and frequency for usual azathioprine or 6-mercaptopurine treatments remains regular.
Intervention code [1] 256991 0
Treatment: Drugs
Comparator / control treatment
Allopurinol 100mg or Allopurinol 50mg
Control group
Dose comparison

Outcomes
Primary outcome [1] 259048 0
Proportion of patients in each group in a steroid-free remission at 24 weeks. Remission is defind as Harvey Bradshw Index(HBI) < 4, for Crohn's Disease(CD) and Simple Clinical Colitis Activity Index (SCCAI) < 2 for Ulcerative Colitis (UC), without corticosteroid therapy. These diesease activity indices will be assessed clinically. There is no need for any investigations, nor statistics.
Timepoint [1] 259048 0
24 weeks (This means 24 weeks from randomisation)
Secondary outcome [1] 265146 0
Statistical comparison of the following values before and after the addition of allopurinol
-thiopurine metabolite levels
-disease activity indices
-corticosterooid dosages
-white blood cell counts
-liver aminotransferases
-Thiopurine methyltransferase phenotypic activity (TPMT)
Timepoint [1] 265146 0
24 weeks from randomisation.
Secondary outcome [2] 265147 0
Tolerability and safety of allopurinol-thiopurine combination therapy will be assessed clinical (History and Examination) and blood tests.
Timepoint [2] 265147 0
24 weeks from randomisation.
Secondary outcome [3] 265148 0
Comparision of safety and efficacy data between allopurinol 50mg and allopurinol 100mg daily groups.
Timepoint [3] 265148 0
24 weeks from randomisation.
Secondary outcome [4] 265149 0
Proportion of patients in each group in a steroid free remission at 12 weeks. The outcome will be assessed clinical (History and Examination) and blood tests.
Timepoint [4] 265149 0
12 weeks from randomisation.

Eligibility
Key inclusion criteria
Adult inflammatory bowel disease patients (both Crohn’s disease and ulcerative colitis) taking thiopurine immunomodulators (azathioprine or 6- mercaptopurine) and fulfilling all 3 of the following criteria will be eligible:

A) Patient is not in a corticosteroid-free remission. Remission is defined as a Harvey Bradshaw Index (HBI) = 4 for Crohn's Disease (CD) and a Simple Clinical Colitis Activity Index (SCCAI) = 2 for Ulcerative Colitis (UC).

B) Patient is metabolizing thiopurines preferentially to produce 6-MMP instead of 6-TGN, with 6-MMP > 5,000 pmol/8 x 108 Red Blood Count (RBC) and 6-TGN < 235 pmol/8 x 108 Red Blood Count (RBC).

C) Patient has an adequate initial white blood cell count (WBC) to tolerate the anticipated White Blood Count (WBC) reduction after the addition of allopurinol: White Blood Count(WBC) = 4.5 x109/L.

Additionally, patients or their legal guardians must be willing and able to sign the written, informed consent document.

(Patients will be eligible for screening as soon as their metabolite profile identifies them to be shunting towards 6-MMP production, meaning a full 12 week trial of thiopurine therapy is not required prior to screening).
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected or known intolerance or allergy to allopurinol.

2. Concomitant therapy with the following immune modified and biologic agents will not be allowed within the following time intervals from the screening visit:
a. Cyclosporine- 4 weeks
b. Infliximab- 4 weeks
c. Any investigational study drug - 4 weeks.

3. Patients, or legal guardians, unable to give informed consent.
4. Pregnant and breast-feeding patients

5. TPMT heterozygous (TPMTH / TPMTL ) and TPMT homozygous low patients (TPMTL/ TPMTL ).

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 randomly allocated to receive either 100 mg allopurinol or 50 mg allopurinol in a 1:1 ratio, using a computer generated list. An existing telephone Interactive Voice Response System (IVRS) will be used to perform the randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by using a randomisation table created by computer software that is, telephone Interactive Voice Response System (IVRS) will be used to perform the randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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)
SA,VIC
Recruitment postcode(s) [1] 3203 0
3004
Recruitment postcode(s) [2] 3205 0
3128
Recruitment postcode(s) [3] 3204 0
4101
Recruitment postcode(s) [4] 3206 0
5042
Recruitment outside Australia
Country [1] 2817 0
New Zealand
State/province [1] 2817 0
Christchurch

Funding & Sponsors
Funding source category [1] 257510 0
Charities/Societies/Foundations
Name [1] 257510 0
The Eli and Edythe Broad Foundation
Address [1] 257510 0
10900 Wilshire Boulevard,
Twelth Floor
Los Angeles
California
90024
Country [1] 257510 0
United States of America
Primary sponsor type
Hospital
Name
The Alfred Hospital
Address
Department Of Gastroenterology
Level 4
The Alfred Hospital
Commercial Road
Melbourne
VICTORIA
3004
Country
Australia
Secondary sponsor category [1] 256674 0
None
Name [1] 256674 0
Address [1] 256674 0
Country [1] 256674 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259538 0
The Alfred Research and Ethics Unit
Ethics committee address [1] 259538 0
The Alfred Hospital
Commercial Road
Melbourne
VICTORIA
3004
Ethics committee country [1] 259538 0
Australia
Date submitted for ethics approval [1] 259538 0
Approval date [1] 259538 0
03/09/2009
Ethics approval number [1] 259538 0
1/09/0139

Summary
Brief summary
It is understood that the body metabolizes azathioprine (AZA) to produce two chemical end-products: 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP). 6-TGN is the chemical that makes these drugs work, while 6-MMP causes side-effects. Our research group has previously shown that by adding another drug, allopurinol, patients who otherwise made 6-MMP switched to instead produce 6-TGN, thereby increasing their response to these drugs. Our proposal is for a clinical trial that aims to confirm the safety and efficacy of this clinical maneuver.
Trial website
Trial related presentations / publications
1. Sparrow MP, Hande SA, Freidman S et al. Allopurinol Safely and Effectively Optimizes Thioguanine Metabolites in Inflammatory Bowel Disease Patients not Responding to Azathioprine or 6-Mercaptopurine. Alimentary Pharmacology and Therapeutics 2005 Sep 1; 22(5): 441-6.

2. Sparrow MP, Hande SA, Friedman S et al. Effect of Allopurinol on Clinical Outcomes in Inflammatory Bowel Disease Nonresponders to Azathioprine and 6-Mercaptopurine. Clinical Gastroenterology and Hepatology 2007 Feb; 5(2): 209-214.

3. Leung Y, Sparrow MP, Schwartz, M and Hanauer SB. Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. Journal of Crohn’s and Colitis 2009 Sep; 3(3): 162-67.
Public notes

Contacts
Principal investigator
Name 31508 0
Dr Miles Sparrow
Address 31508 0
The Alfred Centre
Gastroenterology Unit
99 commercial Rd
Prahran. VIC 3004
Country 31508 0
Australia
Phone 31508 0
61 3 9076 3332
Fax 31508 0
Email 31508 0
m.sparrow@alfred.org.au
Contact person for public queries
Name 14755 0
Ms Ms Jo Mckenzie
Address 14755 0
Jo Mckenzie
Gastroenterology Unit
99 Commercial Rd. The Alfred Centre
Prahran, VIC 3004
Country 14755 0
Australia
Phone 14755 0
+61 3 9076 3322
Fax 14755 0
+61 3 9076 2757
Email 14755 0
j.mckenzie@alfred.org.au
Contact person for scientific queries
Name 5683 0
Dr Dr Miles Sparrow
Address 5683 0
Department of Gastroenterology
Level 4
The Alfred Hospital
Commercial road
Melbourne
VICTORIA
3004
Country 5683 0
Australia
Phone 5683 0
+61 408 889 551 / +61 3 9591 0466
Fax 5683 0
+61 3 9076 2194
Email 5683 0
m.sparrow@alfred.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary