Trial Information

Phase 3: Randomised Controlled Trial of Rituximab in Active Ulcerative Colitis

WHAT IS THE PROBLEM TO BE ADDRESSED ?

Lack of effective cure for Ulcerative colitis.

WHAT IS THE HYPOTHESIS TO BE TESTED?

That rituximab may be effective in active ulcerative colitis.

WHY IS A TRIAL NEEDED NOW?

Rituximab has been used to treat more than 300,000 patients with B lymphocyte malignancies
and has been shown to have an excellent safety record [6-8]. Published pilot studies have
shown excellent results with rituximab in patients with autoimmune diseases such as
immune-mediated thrombocytopaenia, Wegeners granulomatosis, cold agglutinin disease,
myasthenia gravis, rheumatoid arthritis and SLE [11-17]. Together with increasing evidence
to support a pathogenic role for the pANCA associated with ulcerative colitis, a study of
rituximab in ulcerative colitis is timely. Moreover the only significant advance in the
treatment of ulcerative colitis in recent years has been the introduction of cyclosporin
which probably halves the colectomy rate [18,19] but at the risk of considerable side
effects and with a drug-related mortality that has been estimated at 2%.

HAS A SYSTEMATIC REVIEW BEEN CARRIED OUT AND WHAT WERE THE FINDINGS?

A Medline search for “ rituximab and ulcerative colitis” yielded no responses. There has
been a recent report of its use in a single patient with ileocolonic Crohn’s disease who
also had immune-mediated thrombocytopaenia [20]. The thrombocytopaenia improved but the
Crohn’s disease did not. It can be argued though that there is little or no evidence for
autoimmunity in Crohn’s disease which seems in many cases to be due to a defect in phagocyte
function, eg in association with the recently described NOD2/CARD15 genetic alteration.

2.5 HOW WILL THE RESULTS OF THIS TRIAL BE USED? This trial will establish whether rituximab
is effective in achieving remission in patients with ulcerative colitis who are failing to
respond to conventional therapy with corticosteroids. Because there is no background
evidence of its efficacy the initial study will be a small two centre study with placebo
blinding. If the result of this study is promising, these would be used as pilot data for
power calculations for a larger multicentre study.

3.1 WHAT IS THE PROPOSED TRIAL DESIGN? A “placebo-blinded” study with 16 patients receiving
rituximab and 6 patients receiving placebo (0.9% saline).

3.2 WHAT ARE THE PLANNED TRIAL INTERVENTIONS? Patients will receive either (i) rituximab 1g
in 500 mls of 0.9% saline infused into a peripheral vein over four hours (see appended
infusion chart), or (ii) 500 mls of 0.9% saline infused into a peripheral vein over two
hours as placebo. This regimen will be repeated once at 2 weeks. This protocol is based on
the dosing regimen that proved most efficacious for rheumatoid arthritis. All patients will
also receive paracetamol 1g orally and chlorpheniramine (Piriton) 10mg intravenously
immediately prior to each Rituximab/placebo infusion.

All patients will continue to receive oral prednisolone 40mg/day for 2 weeks then 30mg for
two weeks, then 20mgs/day for two weeks, then reduce by 5mg/day every 7 days until off
prednisolone.

3.3 WHAT IS THE PROPOSED DURATION OF THE TREATMENT PERIOD? Two treatments, two weeks apart.

3.4 WHAT ARE THE PROPOSED INCLUSION/EXCLUSION CRITERIA? see earlier

3.5 WHAT ARE THE PROPOSED OUTCOME MEASURES? see earlier 3.6 WILL HEALTH SERVICE RESEARCH
ISSUES BE ADDRESSED? Not Applicable 3.7 WHAT IS THE PROPOSED FREQUENCY/DURATION OF FOLLOW
UP? Patients will be reviewed after one, two and four, eight, twelve and twenty four weeks.
Patients will be monitored thereafter in routine gastroenterology clinic follow up.

3.8 HOW WILL THE OUTCOME MEASURES BE MEASURED AT FOLLOW-UP? Patients will complete a daily
diary with details of bowel frequency, presence of blood in the stool, any change in medical
therapy and any new or worsening symptoms The IBD quality of life questionnaire will be
completed at baseline and at weeks 4 and 12.

Patients will also have a diary card to record the details of any other symptoms noted
during the trial to assess adverse effects of the trial treatment.

3.9 WHAT ARE THE PROPOSED PRACTICAL ARRANGEMENTS FOR ALLOCATING PATIENTS TO TRIAL GROUPS?
Randomisation will be allocated in blocks of five by the pharmacy department of the
hospital.

3.10 WHAT ARE THE PROPOSED METHODS FOR PROTECTING AGAINST OTHER SOURCES OF BIAS? Controls
(known only to the Pharmacy Department) will receive a placebo saline infusion.

3.11 WHAT IS THE PROPOSED SAMPLE SIZE? A “placebo-blinded” study with 16 patients receiving
rituximab and 8 patients receiving placebo (0.9% saline). This will provide 80% power for
excluding an 80% remission rate with active treatment compared with an assumed 25% placebo
response.

3.12 WHAT IS THE PLANNED RECRUITMENT RATE? 1-2 patients per month 3.13 ARE THERE LIKELY TO
BE ANY PROBLEMS WITH COMPLIANCE? No.

3.14 WHAT IS THE LIKELY RATE OF LOSS TO FOLLOW UP? 100% follow up should be achievable. 3.15
HOW MANY CENTRES WILL BE INVOLVED? Two 3.16 WHAT IS THE PROPOSED TYPE OF ANALYSIS? Formal
hypothesis testing of the primary outcome will be compared by chi-square test.

Wilcoxon signed rank test will be used for comparisons against baseline for changes in
secondary quantitative endpoints.

3.17 WHAT IS THE PROPOSED FREQUENCY OF ANALYSIS? Once only on completion. 3.18 ARE THERE ANY
PLANNED SUBGROUP ANALYSES? Subgroup analysis may be performed according to pANCA status.

3.19 WHAT IS THE ESTIMATED RESEARCH COST OF THE TRIAL? Cost of therapy plus £800 pharmacy
fee plus £2200 towards ethics submission/ research nurse time/ cost of pANCA assays to be
provided as an unrestricted educational grant from Roche UK.

3.20 IS THERE AN NHS SERVICE SUPPORT COST OF THIS TRIAL, AND IF SO WHAT IS THE ESTIMATED
COST? The only NHS cost would be modest, involving only the routine testing of full blood
count and SMAC which is current practice in the monitoring of patients with relapses of
inflammatory bowel disease.

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