AAA Study. Dr Antony Friedman IBD Fellow, The Alfred Hospital Melbourne, Australia

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1 AAA Study Use of Adjunctive Allopurinol in Azathioprine / 6-Mercaptopurine Non-Responders to Optimise 6-Thioguanine Nucleotide Production and Improve Clinical Outcomes Dr Antony Friedman IBD Fellow, The Alfred Hospital Melbourne, Australia

2 Background Historically many IBD patients fail thiopurine therapy due to resistance or intolerance Thiopurine remission rates of 30 60% Adjunctive allopurinol optimises thiopurine metabolism when given with reduced dose AZA / 6-MP Increasing 6-TGN levels Reducing 6-MMP levels Small retrospective case series to date 75% of patients achieve clinical remission This would allow > 15% more patients to tolerate and benefit from AZA / 6-MP which would represent a significant advance in IBD treatment

3 Traditional Thiopurine Metabolism 6-MMP 6-MMP 6-MeTIMP TPMT TPMT AZA 2.5mg/kg Glutathione 6-MP 1mg/kg XO 6-TA HPRT IMPDH GMPS 6-TIMP 6-TXMP 6-TIDP ITPase 6-TGN 6-TITP TPMT 6-MeTITP 6-TGMP 6-TGDP 6-TGTP

4 6-TGN Level Meta-Analysis Data Support the Correlation Between 6-TGN Levels and Clinical Response TGN level remission 6-TGN level active disease Odds Ratio remission if 6-TGN > = % C.I , p<0.001 Osterman MT et al. Gastroenterology 2006;130(4):

5 Recent Advances Ansari A et al, APT 2008; 28: TPMT 6-MMP >4,500 TPMT 6-MMP >4,500 6-MeTIMP Smith M et al, APT 2009; 30: Blaker PA et al, DDW 2011, Tu1214 AZA Glutathione 6-MP HPRT IMPDH GMPS 6-TIMP 6-TXMP 6-TGMP Allopurinol XO 6-TIDP ITPase 2-OH-6MP (6-TX) AO 6-TITP TPMT 6-TGN < TGDP 6-TA 6-MeTITP 6-TGTP

6 2-OH-6MP (6-TX) 2-OH-6MP (6-TX) 6-MMP <4,500 6-MMP <4,500 6-MeTIMP Ansari A et al, APT 2008; 28: Smith M et al, APT 2009; 30: Blaker PA et al, DDW 2011, Tu1214 TPMT TPMT AZA Glutathione 6-MP HPRT IMPDH GMPS 6-TIMP 6-TXMP 6-TGMP Allopurinol XO 6-TIDP ITPase 2-OH-6MP (6-TX) AO 6-TITP TPMT 6-TGN > TGDP 6-TA 6-MeTITP 6-TGTP

7 6-MMP pmol/l/hr 6-Thioxanthine Reduces 6-MMP Washed RBC from 8 healthy volunteers incubated with 6MP or 6MP + 6-TX, then lysed and 6-MMP measured p< MP 6MP + 2-OH6MP hours 4 hours Blaker PA et al, DDW 2011, Tu1214

8 TPMT - IU/ml 6-Thioxanthine Inhibits TPMT p=0.03 Blaker PA et al, DDW 2011, Tu1214

9 Aims 1. Prospectively reproduce these results in a clinical trial 2. To demonstrate that adjunctive allopurinol in patients otherwise producing 6-MMP increases the proportion of patients in clinical remission at 24 weeks 3. To demonstrate the safety of allopurinol-thiopurine combination therapy 4. To determine the optimal dose of allopurinol for this manoeuvre

10 Study Design Open to both Crohn s Disease (CD) and Ulcerative Colitis (UC) patients who meet the inclusion criteria Prospective study Double blind (to allopurinol dose) Dose-ranging, parallel group two arms: 50mg allopurinol with 25% of previous thiopurine dose 100mg allopurinol with 25% of previous thiopurine dose Randomised (to allopurinol dose) Interactive, web-based, randomisation schedule

11 Study Design Population: 76 patients (38 in each arm) Study timeline: 24 week study Wk 0, 2, 4, 8, 12 and 24) Safety/follow up visit at week 36 Sites: Melbourne: The Alfred Hospital, Box Hill Hospital, St Vincent s Hospital Adelaide: Flinders Medical Centre Brisbane: Mater Hospital UK: St Thomas s Hospital, London New Zealand: Christchurch Hospital

12 Inclusion Criteria Must fulfil all three of the following criteria: 1. Either steroid dependent OR not in clinical remission 2. Documented thiopurine shunter a. 6TGN < 260 and 6MMP > 4,500 b. 6TGN < 260 and 6MMP:6TGN ratio 20 c. 6TGN < 260 with hepatotoxcity (ALT 2 X ULN) 3. WCC 3.5 Not in clinical remission is defined as: > Harvey-Bradshaw Index (HBI) score 5 for CD > Simple Clinical Colitis Activity Index score 2 for UC

13 Primary Endpoint Steroid-free remission at 24 weeks Remission is defined as: HBI 4 for Crohn s Disease SCCAI 2 for Ulcerative colitis

14 Secondary Endpoints Disease Activity Comparison of the following values before and after the addition of allopurinol: disease activity indices corticosteroid dosages thiopurine metabolite levels TPMT phenotypic activity faecal calprotectin levels white cell count, CRP, LFTs Steroid-free remission at 12 weeks

15 Secondary Endpoints Safety & Tolerability Tolerability &safety of allopurinol-thiopurine combination: Leucopenic events (with/without sepsis) Hepatotoxicity from elevated 6TGN levels > Nodular regenerative hyperplasia and veno-occlusive disease Comparison of safety and efficacy data between allopurinol 50mg and 100 mg daily groups.

16 Study Progress Recruitment opened: April 2011 Total Enrolments: 10 patients Alfred: 7 Flinders: 2 St Vincent s: 1 Total Patients Completed: 2 Initial impressions at Week 12 (n = 5)... Non-analysed descriptive means

17 Allopurinol decreases thiopurine requirements and avoids leucopaenia 6MP Dose (mg) 80 Total WCC Screening Wk Wk 0 Wk 12

18 Allopurinol stops 6MMP production and increases 6TGN levels with decreased thiopurine dose 6TGN levels 6MMP levels Screening Wk Screening Wk 12

19 Combination therapy improves clinical scores for disease activity 6 HBI SCCAI Wk 0 Wk Wk 0 Wk 12

20 Combination therapy improves liver function and decreases inflammatory burden ALT (U/L) CRP Screening Wk 12 Wk0 Wk12

21 Interim Week 12 Biochemically effective: Reverses adverse thiopurine metabolite profile Improves LFTs Clinically effective: 4 of 5 patients in clinical remission Well tolerated: Self limiting mild nausea on initiation of allopurinol Safe: No episodes of leucopaenia No serious adverse events

22 Acknowledgements Broad Foundation AAA Study Sponsor Jo McKenzie Study Co-ordinator, The Alfred Hospital Dr Miles Sparrow & Prof Peter Gibson The Alfred Hospital A/Prof Peter Bamptom Flinders Medical Centre Dr Steven Brown St Vincent s Hospital Dr Alvin Chung Eastern Health Drs Paul Blaker & Jeremy Sanderson St Thomas s Hospital A/Prof Murray Barclay Christchurch Hospital Prof Tim Florin Mater Adult Hospital If anyone would like a copy of the slides or further information, please me at a.friedman@alfred.org.au