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I C Lawrance Centre for Inflammatory Bowel Diseases, Fremantle Hospital

A multi-centre, double blind randomised placebo-controlled study of the use of rectal tacrolimus in the treatment of resistant ulcerative proctitis. I C Lawrance Centre for Inflammatory Bowel Diseases, Fremantle Hospital School of Medicine and Pharmacology, UWA. 25%.

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I C Lawrance Centre for Inflammatory Bowel Diseases, Fremantle Hospital

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  1. A multi-centre, double blind randomised placebo-controlled study of the use of rectal tacrolimus in the treatment of resistant ulcerative proctitis I C Lawrance Centre for Inflammatory Bowel Diseases, Fremantle Hospital School of Medicine and Pharmacology, UWA

  2. 25% Disease Distribution at Presentation n = 1116 37% 46% 17% Farmer RG, et al. Dig Dis Sci. 1993;38(6):1137-1146.

  3. Suboptimal response Rectal 5ASA combined with Oral 5ASA Suboptimal response Rectal 5ASA combined with Rectal steroids Or Rectal 5ASA more frequently Suboptimal response add in Oral steroids add in AZA/6MP Suboptimal response Suggested Treatment Algorithm Rectal 5ASA 1gm nocte Other options Infliximab Cyclosporin Tacrolimus Cummin Arsenic Ecabet sodium Surgery

  4. Tacrolimus • Macrolide lactone that inhibits the formation of cytotoxic lymphocytes • Suppresses T and B cell proliferation Clinical trials Prevents allogenic transplant rejection Medical use Prophylaxis of liver, kidney allograft rejection Adverse Reactions Cardiomyopathy, HT, Renal dysfunction, Infection, Seizures Neoplasia Open labelled studies of oral therapy in CD and UC Suggest that the blood trough level should be at least 10ug/L (therapeutic range 5- 20ug/L) The higher the trough level the more likely a patient will suffer an adverse effect

  5. Van Dieren et.al Inflamm Bowel Dis 2009 Rectal tacrolimus Systemic absorption Lawrance et.al Alimen Pharm Therap 2008

  6. Disease Activity Index Suppositories Enemas Lawrance et.al Alimen Pharm Therap 2008 Rectal Tacrolimus Clinical Response Van Dierenet.alInflamm Bowel Dis 2009

  7. Tacrolimus Study • HYPOTHESIS • That the rectal preparation of tacrolimus is safe, well tolerated and efficacious in the treatment of resistant ulcerative proctitis. • Primary end point: • Clinical response (Mayo Score) of resistant ulcerative proctitis after 8 weeks of rectal tacrolimus therapy Secondary end points: Remission rates after 8 weeks of rectal tacrolimus. Effect of rectal tacrolimus on mucosal healing. Changes in the modified Mayo Score between tacrolimus and control groups. Changes in quality of life by the IBDQ. Safety and tolerability. Changes in cytokine expression in mucosal biopsies

  8. Investigation sites • Sites • 01. TheCentre for IBD, Fremantle Hospital, Perth, WA (Prof I.C. Lawrance); • 02. St Vincent’s Hospital, Melbourne, Vic (Prof M. Kamm, Dr S Brown); • 03. Royal Brisbane and Women Hospital, Brisbane, Qld (A/Prof G. Radford-Smith); • 04. Mater Adult Hospital, Brisbane, Qld (Prof T. Florin); • 05.Princess Alexandra Hospital, Brisbane, Qld (Dr D. Burger); • 06. Flinders Medical Centre, Adelaide, SA (A/Prof P. Bampton); • 07. Royal Adelaide Hospital, Adelaide, SA (A/Prof J. Andrews); • 08. Canberra Hospital Canberra, ACT (A/Prof P Pavli); • 09. Liverpool Hospital, Sydney, NSW (Dr S Connor); • 10. Concord Repatriation General Hospital, Sydney, NSW (A/Prof R Leong).

  9. Inclusion Criteria • Is over the age of 18 years • Has a diagnosis of ulcerative colitis of over 3 months • Has inflammation limited to 25cm proximal to the anal verge • Has failed to achieve remission with, or be intolerant of, the use of conventional therapy defined as oral and/or rectal 5-Aminosalicylates, and/or oral and rectal steroids • Has symptoms of active UC with a Mayo score of between 6 and12 • Medications: • Oral 5ASA: used them continuously for 4 weeks and has been on a stable dose for 2 weeks prior to the screening visit. • Oral Corticosteroids: used them continuously for 4 weeks and has been on a stable dose for 2 weeks prior to the screening visit at a dose of <30mg. • Oral Azathioprine/6MP or Methotrexate: used them for a minimum of 12 weeks and has been on a stable dose for 4 weeks prior to screening.

  10. Inclusion Criteria • Does not have unstable, or poorly controlled, hypertension • Rectal Preparations; 5-Aminosalicylates and corticosteroids: All rectal preparations have been ceased at least one week prior to week 0. • Has normal renal function defined as a Glomerular Filtration Rate (GFR) >60ml/min. • Has a normal serum potassium levels defined as 3.4-5mmol/L.

  11. Tacrolimus Study

  12. First 5 patients Clinical response decrease of ≥3 points and ≥30 percent, with an accompanying decrease for rectal bleeding of at least 1 point or rectal bleeding of 0 or 1.

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