Clinical Trial: Rectal Tacrolimus in the Treatment of Resistant Ulcerative Proctitis

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Multi-centre Double Blind Randomised Placebo-controlled Study of the Use of Rectal Tacrolimus in the Treatment of Resistant Ulcerative Proctitis

Brief Summary: Ulcerative Colitis (UC) is a life-long incurable disease with remissions and exacerbations. Inflammation confined to the rectum occurs in a quarter of patients and can be extremely hard to treat. Many medications have been tried in order to control the inflammation, but they do not always work. One of the newer medications is the immunosuppressing medication, tacrolimus that has been shown to be effective in UC when taken orally. Unfortunately, the oral use of this medication can have numerous serious side effects. In order to overcome these side effects, the use of topical rectal tacrolimus has been examined. Pilot studies in ulcerative proctitis (inflammation confined to the rectum) resistant to conventional therapies have demonstrated a clinical remission in 75% of patients and although the medication was well absorbed through the lining of the bowel, the levels in the blood were very low and no serious side effects were reported. The findings suggest that this preparation is indeed effective for inflammation in the distal bowel and that the method of administration reduces side effects. Further work, however, now needs to be undertaken to validate the original findings.

Detailed Summary:

The Inflammatory Bowel Diseases (IBDs) are life-long conditions often diagnosed between 15 and 35 years of age that are increasing in frequency. In developed countries, IBD prevalence was about 100-220/100,000 in 2002. More recently the estimated prevalence of CD and UC in the USA are 201 and 238 per 100,000 respectively. This indicates more than 620,000 CD and 730,000 UC patients in the USA alone. It has also been noted that the incidence of IBD has been increasing in the ethnic minorities in American over the last two decades and it is predicted that IBD, which was previously thought of as a 'Caucasian disease', will reach a comparable levels in Asia as in the Western Countries within 10-15 years. One of the major costs in IBD treatment is the need for a hospital admission. These have been falling for CD patients secondary to the increasing use of the biological therapies, however, admissions for UC have doubled over the last 15 years. IBD now costs the Australian economy of 22,000,000 people over $2.7 billion annually and this is comparable throughout the western World.

Tacrolimus and cyclosporin are classical calcineurin inhibitors and are widely used as immunosuppressive medications with promising results in UC. Calcineurin, or protein phosphatase 2B (PP2B), is a ubiquitously expressed cytosolic Ser/Thr protein phosphatase, that is highly conserved in eukaryotes. It has the ability to dephosphorylate a broad range of proteins and can regulate interleukin (IL)-2, IL-4 and interferon (IFN)γ expression, as well as modulating the activity of transcription factors like NF-κB. Enhanced NF-kB activity is well described in CD and UC and induces the proinflammatory cytokine IL-1β, IL-6 and TNFα expression. It is primarily through the reduction in the levels of these cytokines that clinical remission may be achieved.

Clinical response (Mayo Score) of resistant ulcerative proctitis after 8 weeks of rectal tacrolimus therapy