Clinical trial NCT00261118: Rituximab in Active Ulcerative Colitis
Official title: Phase 3: Randomised Controlled Trial of Rituximab in Active Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Ulcerative Colitis
Keywords: colitis
rituximab
Lead sponsor: Royal Liverpool University Hospital
Sponsor class: OTHER_GOV
Collaborators: name: Hoffmann-La Roche
name: University of Liverpool
First posted: 2005-12-02
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: There is broad support for the hypothesis that Ulcerative colitis is an auto-immune disease. Rituximab is an antibody protein that removes a subgroup of white blood cells (B lymphocytes) from the circulation. These cells have the capacity to generate the auto-antibodies that typify auto-immune disease. Although Rituximab has been mainly used for treating B lymphocyte malignancies (lymphoma) it has also been used with promising results in Rheumatoid arthritis and has an excellent safety record. This is a small placebo-controlled trial to assess its efficacy and safety in patients with steroid-resistant active ulcerative colitis.

Detailed description: 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? Randomization 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.

Eligibility criteria: Inclusion Criteria:

1. Patients over age of 18 years who are capable of providing written informed consent.
2. Confirmed diagnosis of ulcerative colitis by conventional clinical, endoscopic and histological criteria.
3. Failure of response to at least two weeks of oral prednisolone 40mg/day.
4. Active colitis as assessed by a Mayo score \[21\] of 6-12 inclusive (see Appendix 1)

Exclusion Criteria:

1. Patients under 18 or unable to give informed consent.
2. Patients in their first attack of ulcerative colitis.
3. Patients with severe ulcerative colitis as defined by presence of any of: temperature \>37.5oC, pulse rate \>100, focal severe or rebound abdominal tenderness, haemoglobin \< 10.0g/dl, serum albumin \<3.5 g/dl, transverse colon diameter greater than 5.0cms on plain abdominal X ray.
4. Patients who are pregnant, post partum (\<3months) or breast feeding
5. Patients who are at risk of pregnancy and not using a reliable form of contraception (oral contraceptive and barrier or barrier plus spermicide).
6. Patients with a stoma
7. Positive stool culture for pathogens or test for C difficile at screening within 7 days prior to trial entry
8. Patients for whom a baseline Mayo score can not be reliably calculated: frequent use of laxatives (for proximal constipation) or antimotility agents (for control of diarrhoea)
9. Any change to maintenance medication for ulcerative colitis: azathioprine or 6-mercaptopurine within previous 3 months or 5-aminosalicylates within previous one month
10. Any change to rectal therapy for colitis within the previous two weeks.
11. Participation in other trials in the last 3 months.
12. Serious intercurrent infection or other clinically important active disease (including renal and hepatic disease)

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Primary outcomes:
measure: Remission defined as a decrease in Mayo score to ≤ 2 points at week 4
timeFrame: week 4
Secondary outcomes:
measure: Clinical response defined as a decrease in Mayo score by ≥ 3 points at weeks 4, 8 (partial Mayo score) and 12.
timeFrame: Week 4, 8 & 12
measure: Remission at weeks 8 and 12.
timeFrame: week 8 &12
measure: Endoscopic mucosal healing at week 4 and 12
timeFrame: Week 4 & 12
measure: Improvement in Inflammatory Bowel Disease specific Quality of Life Index at weeks 4 and 12
timeFrame: weeks 4 &12
measure: Histological improvement of disease activity at 4 and 12 weeks compared with baseline.
timeFrame: week 4 & 12 weeks
measure: Treatment tolerability as defined by adverse events.
timeFrame: all visits
Other outcomes:
Locations:
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: Merseyside
Study officials:
affiliation: University of Liverpool
name: Jonathan M Rhodes, MD
role: PRINCIPAL_INVESTIGATOR
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