Scientific Abstract
Proposal No. IBD-0245
Principal Investigator: Miles Patrick Sparrow, MBBS
Applicant Organization: Alfred Health (Melbourne, Australia)
Project Title: Use of adjunctive allopurinol in azathioprine/6-mercaptopurine non-responders to optimize 6-thioguanine nucleotide production and improve clinical outcomes
Period of Award: April 1, 2010 – August 31, 2012
The thiopurine immunomodulators azathioprine (AZA) and 6-mercaptopurine (6-MP) are well established in inflammatory bowel disease treatment algorithms as induction, maintenance and steroid-sparing agents. The thiopurines are metabolized to produce the active nucleotide metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), with 6-TGN being the active metabolite responsible for therapeutic efficacy, while 6-MMP is instead associated with hepatotoxicity when elevated. A significant subgroup of patients, perhaps 15-30%, preferentially produce 6-MMP instead of 6-TGN on thiopurine dose-escalation, minimizing the likelihood of drug efficacy and increasing the risk of hepatotoxicity. Two small open-label studies have shown that the addition of low doses of allopurinol to this subgroup of patients otherwise producing 6-MMP can safely switch metabolism towards 6-TGN production and produce the resultant expected clinical benefits. The aim of this study is to prospectively demonstrate the safety and efficacy of this therapeutic maneuver in a multi-center, dose-ranging, randomized clinical trial.
A prospective, multi-center, dose-ranging, parallel group, randomized trial is proposed. Eligible subjects will be thiopurine-treated IBD patients who are unable to enter or maintain a steroid-free remission due to preferential metabolism of thiopurines towards production of 6-MMP instead of 6-TGN. Subjects will be randomized into two groups; Group A will receive allopurinol 100 mg daily for 24 weeks and Group B allopurinol 50 mg daily for 24 weeks, in addition to an equal reduction in thiopurine dose in both groups. The primary endpoint will be the proportion of patients in each group in a steroid-free remission at 24 weeks.
We anticipate that adjunctive allopurinol will allow this subgroup of patients, who otherwise preferentially produce the inefficacious 6-MMP metabolite, to tolerate and respond to these drugs. This will allow clinicians to more completely optimize thiopurine therapy before otherwise switching to alternate agents such as methotrexate or infliximab.
This novel therapeutic combination has never before been prospectively studied in inflammatory bowel disease. If proven safe and efficacious the combination has the potential to be a practical, simple and cost-effective alternative to clinicians that could be applied immediately in clinical practice. Given the unquestionable benefits of immunomodulators in inflammatory bowel disease, if 15-30% more patients were able to tolerate and respond to these agents this would represent a very significant advance in the medical treatment of these diseases.
The thiopurine immunomodulators azathioprine (AZA) and 6-mercaptopurine (6-MP) are well established in inflammatory bowel disease treatment algorithms as induction, maintenance and steroid-sparing agents. The thiopurines are metabolized to produce the active nucleotide metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), with 6-TGN being the active metabolite responsible for therapeutic efficacy, while 6-MMP is instead associated with hepatotoxicity when elevated. A significant subgroup of patients, perhaps 15-30%, preferentially produce 6-MMP instead of 6-TGN on thiopurine dose-escalation, minimizing the likelihood of drug efficacy and increasing the risk of hepatotoxicity. Two small open-label studies have shown that the addition of low doses of allopurinol to this subgroup of patients otherwise producing 6-MMP can safely switch metabolism towards 6-TGN production and produce the resultant expected clinical benefits. The aim of this study is to prospectively demonstrate the safety and efficacy of this therapeutic maneuver in a multi-center, dose-ranging, randomized clinical trial.
A prospective, multi-center, dose-ranging, parallel group, randomized trial is proposed. Eligible subjects will be thiopurine-treated IBD patients who are unable to enter or maintain a steroid-free remission due to preferential metabolism of thiopurines towards production of 6-MMP instead of 6-TGN. Subjects will be randomized into two groups; Group A will receive allopurinol 100 mg daily for 24 weeks and Group B allopurinol 50 mg daily for 24 weeks, in addition to an equal reduction in thiopurine dose in both groups. The primary endpoint will be the proportion of patients in each group in a steroid-free remission at 24 weeks.
We anticipate that adjunctive allopurinol will allow this subgroup of patients, who otherwise preferentially produce the inefficacious 6-MMP metabolite, to tolerate and respond to these drugs. This will allow clinicians to more completely optimize thiopurine therapy before otherwise switching to alternate agents such as methotrexate or infliximab.
This novel therapeutic combination has never before been prospectively studied in inflammatory bowel disease. If proven safe and efficacious the combination has the potential to be a practical, simple and cost-effective alternative to clinicians that could be applied immediately in clinical practice. Given the unquestionable benefits of immunomodulators in inflammatory bowel disease, if 15-30% more patients were able to tolerate and respond to these agents this would represent a very significant advance in the medical treatment of these diseases.