To assess to efficacy of locally applied tacrolimus suppositories compared to beclomethason suppositories in patients with recurrent or refactory ulcerative proctitis.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-The primary end point will be the proportion of patients with clinical
response at day 28 after treatment with tacrolimus suppositories compared to
beclomethasone suppositories. Clinical response is defined as an absolute
decrease in Mayo score of >=3 from baseline and a relative decrease from
baseline of >=30% with accompanying decrease in the rectal bleeding subscore of
>=1 point or absolute rectal bleeding subscore of 0 or 1.
Secondary outcome
-Proportion of patients in clinical and endoscopic remission. Clinical
remission is defined as a Mayo score <= 2 and no individual subscore >1, and
endoscopic remission is defined as no visible inflammation (i.e. mayo sub-score
0-1).
- Proportion of patients with endoscopic response, defined as a decrease in
Mayo sub-score of >= 1 and/or a decrease in extent of inflammation of >= 5 cm
from baseline.
-Safety and tolerability of tacrolimus suppositories and beclomethasone
suppositories.
-Quality of life (IBDQ).
-Changes in histopathology from biopsies taken before and after treatment
(grading scale (0 _ structural changes only, 1_ chronic inflammation, 2 _
lamina propria neutrophils, 3_ neutrophils in epithelium, 4 _ crypt
destruction, 5 _ erosions or ulcers)).
Background summary
The pathogenesis of ulcerative colitis (UC) is partly understood. Inflammatory
bowel disease (IBD) is a multifactorial disease with probable genetic
heterogeneity. In addition, several environmental risk factors contribute to
the pathogenesis. The incidence rates for UC vary from 0.5 to 24.5 per 100,000
person-years worldwide [1]. Ulcerative proctitis (UP) is a subset of disease
limited to the rectum. Similar etiological factors are likely to precipitate
distal and extensive colitis. An increasing number of newly diagnosed UC cases
in adults presents with disease limited to the distal or descending colon
(L-UC), and the subset of UP may encompass up to one-third of all UC cases
[2,3].The course of UP varies and most patients experience symptoms in
remission-relapse cycles. During the initial work-up, the prevalence of
proctitis may be as high as 44- 60% of all patients [4]. Long-term
epidemiological studies have revealed that UP often extends to more proximal
and even to total colitis. In a study by Moum et al. [5] 22% of proctitis cases
progressed in extent within 12- 24 months of initial diagnosis despite medical
treatment. Two long-term epidemiological studies [2, 6] showed that 32 and 41%
of initial proctitis cases, respectively, progressed within 10 years. The
progression was up to the left flexure in half of the patients, to the right
flexure in 21%, and there was inflammation beyond the right flexure in 29%. In
a recent study by the IBSEN group [7] proximal extension in UP was seen in 28%
of patients in five years, with 10% progressing to extensive colitis. Thus, the
recognition of UP and L-UC may not be important only because distal disease can
generally be treated by topical agents, but also because it has been suggested
that treatment may prevent or delay proximal spread of rectal inflammation
[8].The first step in UP treatment is 5-ASA administered as suppository.
Topical aminosalicylates (5-ASA) induced remission inactive proctitis and
distal colitis in 31- 80% of subjects (median 67%) compared to 7- 11% of those
given placebo in a meta-analysis of 11 trials in 778 patients [9]. Despite the
significant benefits of rectally administered aminosalicylates, some patients
with UP fail to improve and require additional medical therapy. In a step up
design the following drugs are used for the treatment of recurrent UP:
corticosteroids locally or systemic, azathioprine, methotrexate and infliximab.
The efficacy of most of the drugs used in refractory or recurrent UP is based
on data of patients with a more extended UC (except for infliximab). Overall,
these results remain difficult to interpret in the efficacy for specifically
recurrent UP. According to the Dutch CBO-guidelines for the treatment of IBD,
local applied corticosteroids are the preferred drugs when 5-ASA suppositories
fails, however in a meta-analysis the response to this strategy is around 40%
[10]. Furthermore although locally applied patients do experience the
side-effects of corticosteroid therapy. We earlier demonstrated that locally
applied tacrolimus 2 mg suppositories are effective in approximately 80% of the
patients with refractory proctitis and and this strategy also proved to be safe
[11]. Others also demonstrated the effect of local tacrolimus, with similar
efficacy percentages [12]. With this study we aim to demonstrate the
effectiveness of tacrolimus suppositories and we anticipate that these
suppositories can be used as second line therapy after failure of 5-asa
suppositories in patients with UP.
REFERENCES
1. Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of inflammatory
bowel disease across Europe: is there a difference between north and south?
Results of the European collaborative study on inflammatory bowel disease
(EC-IBD). Gut1996;39:690-7
2. Jess T, Riis L, Vind I, et al. Changes in clinical characteristics, course,
and prognosis of inflammatory bowel disease during the last 5 decades: a
population-based study from Copenhagen, Denmark. Inflamm Bowel Dis2007;13:481-9
3. Ayres RC, Gillen CD, Walmsley RS, et al. Progression of ulcerative
proctosigmoiditis: incidence and factors influencing progression. Eur J
Gastroenterol Hepatol 1996; 8: 555Ð8.
4. Meucci G, Vecchi M, Astegiano M, et al. The natural history of ulcerative
proctitis: a multicenter, retrospective study. Gruppo di Studio per le Malattie
Infiammatorie Intestinali (GSMII). Am J Gastroenterol 2000; 95: 469Ð73.
5. Moum B, Ekbom A, Vatn MH, et al. Change in extent of colonoscopic and
histological involvement in ulcerative colitis over time. Am J Gastroenterol
1999;94:1564-9
6. Langholz E, Munkholm P, Davidsen M, et al. Changes in extent of ulcerative
colitis. Scand J Gastroenterol1996;31:260-6
7. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical
course: results of a 5-year population-based follow-up study (the IBSEN study).
Inflamm Bowel Dis2006;12:543-50
8. Pica R, Paoluzi OA, Iacopini F, et al. Oral mesalazine (5-ASA) treatment may
protect against proximal extension of mucosal inflammation in ulcerative
proctitis. Inflamm Bowel Dis2004;10:731-6
9. Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for distal ulcerative
colitis: a meta-analysis. Aliment Pharmacol Ther1995;9:293-300
10. Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative
treatments in ulcerative colitis: a meta-analysis. Gut 1997; 40: 775-781.
11. Dieren JM, Van Bodegraven AA, Kuipers EJ, et al. Local application of
tacrolimus in distal colitis: feasible and safe. Inflamm Bowel Dis 2009; 15:
193Ð8.
12. Lawrance IC, Copeland TS. Rectal tacrolimus in the treatment of resistant
ulcerative proctitis. Aliment Pharmacol Ther 2008; 28: 1214Ð20.
Study objective
To assess to efficacy of locally applied tacrolimus suppositories compared to
beclomethason suppositories in patients with recurrent or refactory ulcerative
proctitis.
Study design
3.1 Setting
Principal center:
Department of Gastroenterology & Hepatology, Erasmus MC Rotterdam, The
Netherlands.
Others:
Multiple centers in The Netherlands will participate in this study.
3.2 Number of patients
88 patients will be included, with 44 patients in each treatment group.
3.3 Design (type of trial)
Multicenter, randomized, contolled study with two arms.
3.4 Medication, dosage and duration
Group A receives tacrolimus suppositories 2 mg for 28 days.
Group B receives beclomethason suppositories 3 mg for 28 days.
Intervention
Group A receives tacrolimus suppositories 2 mg for 28 days.
Group B receives beclomethason suppositories 3 mg for 28 days.
Study burden and risks
Burden: an additional of 3 visits is necessary for this study. Furthermore
patients have to undergo a maximum of 2 addtional lower endoscopies with
biopsies.
From the suppositories only a mild anal irritation is expected. Infrequently
beclomethason suppositories do have systemic side effects such as weight gain
and emtional instability, no major safety issues are anticipated.
Benifit: remission of the proctitis.
s Gravendijkwal 230
Rotterdam 3015 CE
NL
s Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
Endoscopically or histologically proven ulcerative proctitis at least 3 months before randomization.
Proctitis is defined as: disease activity to 20 cm beyond the anal verge.
Refractory proctitis defined as a failure to at least the use of 5-asa suppositories of a maximum of 1 gram for at least 21 days and recurrent proctitis is defined as relapse within 3 months after stopping of local adequate 5-asa treatment.
Endoscopy may have been performed up to 3 weeks before screening, if
the endoscopy was well documented and biopsies were taken.
Age: 18-70 years and written informed consent.
Permitted concomitant therapy: oral aminosalicylates, azathioprine, 6-mercatopurine and methotrexate at stable dose for 12 weeks.
Exclusion criteria
Use of enemas within 14 days prior to randomization
Treatment with tacrolimus prior to randomization
Treatment with any investigational drug in another trial within 12 weeks of randomization
Treatment with any form of corticosteroids within 4 weeks of randomization
Abnormal renal function (eGFR < 30 mL/min)
Presence of toxins or other signs of infectious agents in stool sample (i.e. clostridium, salmonella, shigella, yersinia or campylobacter).
Pre-existent leucopenia or thrombopenia (leucocyte count < 2,000/mm3 or platelets < 90,000/mm3)
Liver function tests abnormalities (>2 ULN).
Other significant medical illness that might interfere with this study:
Current malignancy, immunodeficiency syndromes.
Any known pre-existing medical condition that could interfere with the patient's participation in and completion of the study such as:
- Pre-existing psychiatric condition, especially depression, or a history of severe psychiatric disorder, such as major psychoses, suicidal ideation and/or suicidal attempt are excluded. Severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions. Subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject*s mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient*s mental status during the study
- CNS trauma or active seizure disorders requiring medication
- Significant cardiovascular dysfunction within the past 6 months (e.g. angina, congestive heart failure, recent myocardial infarction, severe hypertension or significant arrhythmia).
- Poorly controlled diabetes mellitus
- Significant pulmonary dysfunction/chronic disease (e.g. chronic obstructive pulmonary disease)
- Renal insufficiency (elevated serum creatinine)
- Pregnancy, lactation
- Substance abuse, such as alcohol (80 gram/day), I.V. drugs and inhaled drugs. If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years. Subjects receiving methadone within the past 2 years are also excluded
- Positive stool culture for enteric pathogens
- Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001259-11-NL |
| CCMO | NL44200.078.13 |