Transcript Extracellular matrix changes in Inflammatory Bowel Disease

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
Disease Distribution at Presentation
n = 1116
37%
46%
17%
25%
Farmer RG, et al. Dig Dis Sci. 1993;38(6):1137-1146.
Suggested Treatment Algorithm
Rectal 5ASA
1gm nocte
Other options
Suboptimal response
Rectal 5ASA combined with
Oral 5ASA
Suboptimal response
Rectal 5ASA combined with
Rectal steroids
Or
Rectal 5ASA more frequently
Cummin
Arsenic
Ecabet sodium
Suboptimal response
add in Oral steroids
Infliximab
Cyclosporin
Tacrolimus
Surgery
add in AZA/6MP
Suboptimal response
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 520ug/L)
The higher the trough level the more likely a patient will suffer an adverse effect
Rectal tacrolimus
Systemic absorption
Van Dieren et.al Inflamm Bowel Dis 2009
Lawrance et.al Alimen Pharm Therap 2008
Rectal Tacrolimus
Disease Activity Index
Clinical Response
Suppositories
Enemas
Lawrance et.al Alimen Pharm Therap 2008
Van Dieren et.al Inflamm Bowel Dis 2009
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:
1. Remission rates after 8 weeks of rectal tacrolimus.
2. Effect of rectal tacrolimus on mucosal healing.
3. Changes in the modified Mayo Score between tacrolimus and control
groups.
4. Changes in quality of life by the IBDQ.
5. Safety and tolerability.
6. Changes in cytokine expression in mucosal biopsies
Investigation sites
Sites
01. The Centre 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).
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.
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.
Tacrolimus Study
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.