Randomised clinical trial

efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)

A. B. Friedman, S. J. Brown, P. Bampton, M. L. Barclay, A. Chung, F. A. Macrae, J. McKenzie, J. Reynolds, P. R. Gibson, S. B. Hanauer, M. P. Sparrow

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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/8x108RBCs. 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.

Original languageEnglish
Pages (from-to)1092-1102
Number of pages11
JournalAlimentary Pharmacology and Therapeutics
Volume47
Issue number8
DOIs
Publication statusPublished - 1 Apr 2018

Cite this

Friedman, A. B. ; Brown, S. J. ; Bampton, P. ; Barclay, M. L. ; Chung, A. ; Macrae, F. A. ; McKenzie, J. ; Reynolds, J. ; Gibson, P. R. ; Hanauer, S. B. ; Sparrow, M. P. / Randomised clinical trial : efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). In: Alimentary Pharmacology and Therapeutics. 2018 ; Vol. 47, No. 8. pp. 1092-1102.
@article{fceec2986720439da1e42b808276e8ec,
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/8x108RBCs. 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.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1111/apt.14571",
language = "English",
volume = "47",
pages = "1092--1102",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
publisher = "Wiley-Blackwell",
number = "8",

}

Randomised clinical trial : efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). / Friedman, A. B.; Brown, S. J.; Bampton, P.; Barclay, M. L.; Chung, A.; Macrae, F. A.; McKenzie, J.; Reynolds, J.; Gibson, P. R.; Hanauer, S. B.; Sparrow, M. P.

In: Alimentary Pharmacology and Therapeutics, Vol. 47, No. 8, 01.04.2018, p. 1092-1102.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Randomised clinical trial

T2 - efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)

AU - Friedman, A. B.

AU - Brown, S. J.

AU - Bampton, P.

AU - Barclay, M. L.

AU - Chung, A.

AU - Macrae, F. A.

AU - McKenzie, J.

AU - Reynolds, J.

AU - Gibson, P. R.

AU - Hanauer, S. B.

AU - Sparrow, M. P.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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/8x108RBCs. 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.

AB - 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/8x108RBCs. 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.

UR - http://www.scopus.com/inward/record.url?scp=85042270406&partnerID=8YFLogxK

U2 - 10.1111/apt.14571

DO - 10.1111/apt.14571

M3 - Article

VL - 47

SP - 1092

EP - 1102

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 8

ER -