@article{d96646490c48480d877f6291b029d1f8,
title = "Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)",
abstract = " Background: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. Aims: To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. Design: In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10 8 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. Results: Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). Conclusions: Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity. ",
author = "Friedman, {A. B.} and Brown, {S. J.} and P. Bampton and Barclay, {M. L.} and A. Chung and Macrae, {F. A.} and J. McKenzie and J. Reynolds and Gibson, {P. R.} and Hanauer, {S. B.} and Sparrow, {M. P.}",
note = "Funding Information: Declaration of personal interests: Dr Antony B. Friedman has received speaker fees from AbbVie, Janssen-Cilag, Shire and Takeda. He has received research funding for investigator-driven studies from Abb-Vie. Dr Steven J. Brown has received speaker fees from AbbVie to Janssen-Cilag. A/Prof Peter Bampton has served as a served as consultant or advisory board member for AbbVie. He has received research grants for investigator-driven studies from National Health and Medical Research Council Australia and the Beat Cancer Project (South Australia). Prof Murray L. Barclay has no interests to declare. Dr Alvin Chung has no interests to declare. Prof Finlay A. Macrae has served as a served as consultant or advisory board member for Pfizer. He has received research funding from Cancer Australia, NSW Cancer Council (Aus), National Institute of Health (USA), Cancer Research UK, multiple pharmaceutical trials for study coordinator support and the World Cancer Research Fund. Ms Jo McKenzie has no interests to declare. A/Prof John Reynolds has received research funding from AbbVie, Novartis, Celgene, Janssen-Cilag, Bristol-Myers Squibb, Takeda, National Health and Medical Research Council Australia, Victorian Cancer Agency, Leukemia & Lymphoma Society (USA). He owns stocks in Novartis AG. Professor Peter R. Gibson has served as consultant or advisory board member for AbbVie, Ferring, Janssen, Merck Sharp & Dohme, Nestle Health Science, Danone, Allergan, Pfizer, Celgene and Takeda. His institution has received speaking honoraria from AbbVie, Janssen, Ferring, Takeda, Mylan, Danone and Pfizer. He has received research grants for investigator-driven studies from AbbVie, Janssen, Danone and A2 Milk Company. His Department financially benefits from the sales of a digital application and booklets on the low FODMAP diet. He has published an educational/recipe book on diet. Prof Stephen B. Hanauer has received consulting fees from Prometheus Laboratories Inc prior to 2014. A/Prof Miles P. Sparrow has received speaker fees from Janssen, AbbVie, Ferring, Takeda and Hospira. He has served as consultant or advisory board member for Janssen, Takeda, Pfizer, Celgene, AbbVie and Merck Sharp & Dohme. Funding Information: Declaration of funding interests: The study was funded by a grant from the Broad Medical Research Program (Los Angeles, USA), Award ID: IBD-0245-2. The study sponsor had no oversight or influence regarding study design, in the collection, analysis, and interpretation of data or drafting of the manuscript.",
year = "2018",
month = apr,
doi = "10.1111/apt.14571",
language = "English (US)",
volume = "47",
pages = "1092--1102",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell",
number = "8",
}