* To demonstrate efficacy of budesonide (9 mg budesonide/d) vs. placebo for induction of remission in active incomplete microscopic colitis after 8 weeks of treatment* To study the maintenance of remission after end of treatment* To study safety and…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Rate of clinical remission at final/withdrawal visit (clinical remission
defined as a mean of < 3 stools/day and a mean of < 1 watery stool/day during
the week prior to the visit)
Secondary outcome
Double-blind phase:
* Rate of clinical remission at V2 and V3
* Time to remission
* Total number of stools in the week prior to V2, V3, V4/withdrawal and change
from baseline
* Number of formed stools in the week prior to V2, V3, V4/withdrawal and change
from baseline
* Number of soft stools in the week prior to V2, V3, V4/withdrawal and change
from baseline
* Number of watery stools in the week prior to V2, V3, V4/withdrawal and change
from baseline
* Number of days with abdominal pain in the week prior to V2, V3, V4/withdrawal
and change from baseline
* Number of urgent stools in the week prior to V2, V3, V4/withdrawal and change
from baseline
* Number of stools with urgency grade 3 (have to go immediately to the
toilette) in the week prior to V2, V3, V4/withdrawal and change from
baseline
* Number of stools with difficulties staying continent in the week prior to V2,
V3, V4/withdrawal and change from baseline
* Number of days with bloating in the week prior to V2, V3, V4/withdrawal and
change from baseline
* Changes from baseline of histological signs (inflammation of the lamina
propria, thickness of the subepithelial collagen band, number of IELs in the
surface epithelium, degeneration of the surface epithelium) at V4/withdrawal
* Rate of histological remission as defined in 6.4.7 at V4/withdrawal
* Rate of histological improvement/no change/aggravation as defined in 6.4.7 at
V4/withdrawal
* Physician*s Global Assessment (PGA) at V4/withdrawal
* Short Health Scale (SHS) dimensions symptom burden, social function,
disease-related worry and general well-being at V2, V3, V4/withdrawal and
change from baseline
Follow-up phase:
* Rate of responders maintaining clinical remission at FU1 and FU2
* Rate of patients with relapse at FU1 and FU2 (relapse defined as a mean of *
3 stools/day and thereof a mean of * 1 watery stool/day during at least one
week)
* Time to relapse
Safety variables
* Incidence and type of Adverse Events (AEs)
* Vital signs (blood pressure, heart rate) at V2, V3, V4/withdrawal and change
from baseline, body weight at V4/withdrawal and change from
baseline
* Haematology, blood chemistry, urinalysis
* Assessment of tolerability by investigator and patient
Background summary
Microscopic colitis (MC) is a leading cause of repetitive periods of chronic
non-bloody diarrhoea, in particular in the elderly, with a profound negative
impact on quality of life.
For the individual patient, the clinical symptoms associated with both MC
subtypes * collagenous colitis and lymphocytic colitis - cannot be
distinguished from other causes of watery diarrhoea including drug induced
diarrhoea, irritable bowel syndrome and bile acid diarrhoea. As the colonic
mucosa at colonoscopy appears macroscopically normal or nearly normal, the
diagnosis MC rests on strict, albeit controversial histopathological findings
in colonic biopsies taken from the rectum to the proximal colon, including the
caecum.
Abnormal chronic inflammation in the lamina propria is a typical characteristic
but does not help to distinguish between the subtypes of MC. Collagenous
colitis (CC) is characterised by a thickened subepithelial collagen band, i.e.,
> 10 *m in well oriented biopsies cut perpendicularly to the surface, and
lymphocytic colitis (LC) is characterised by an increased number of
intraepithelial lymphocytes (IEL), i.e., * 20 IEL per 100 epithelial cells.
Colonic biopsies are regarded normal when the lamina propria is without chronic
inflammation, the number of surface epithelial cells is * 5 IEL/100, and the
collagen band is * 5 micrometers. Warren et al. found the original definitions
of limited use for routine diagnosis. The terms MC *not otherwise
specified* (MC nos) and *paucicellular* lymphocytic colitis have been used to
describe a subgroup of patients with chronic
diarrhoea and an increased cellular infiltrate in the lamina propria.
Recent results indicate that the present diagnostic criteria may not ensure
that all patients with MC receive effective treatment. Histological findings in
the individual patient are inconsistent over time, as findings of MC
interchange with chronic (non-specific) inflammation or incomplete signs of MC
at prior or repeat colonoscopy, and the overlap between CC and LC is
significant. Even more important, a large group of patients with chronic
diarrhoea, symptoms and findings indistinguishable from those with CC and LC,
but with incomplete histological signs of MC appear to have an effect of
budesonide treatment similar to that of patients with MC. Furthermore, there is
no correlation between symptoms
and neither the thickness of the subepithelial collagenous layer nor the number
of intraepithelial lymphocytes. The histological interchange between MC
subtypes and the incomplete identification of some patients have led to the
introduction of the term incomplete MC (MCi) for this third MC subtype.
The histological criteria for MCi are an abnormally thickened collagenous band
(> 5 and < 10 *m), and /or an increased number of intraepithelial lymphocytes
(> 5 and < 20 per 100 epithelial cells) without reaching the thickness or
number required for the diagnosis of CC or LC.
Controlled trials of interventions to induce remission in patients with MC are
few and largely performed with budesonide. Progress has been hampered by
restricting most trials to one subtype only (CC or LC). Budesonide has proven
consistently effective, although a single definition of remission has yet to be
agreed on and validated.
Recently, MCi was proposed as a third subgroup of MC. Patients with MCi display
a wider variety of gastrointestinal symptoms and a higher incidence of bile
acid malabsorption and lactose malabsorption than cases with CC or LC
indicating a more heterogenic group. In addition, a significant subgroup of
patients with MCi had in fact LC or CC when subjected to a pathological
re-examination or to a new endoscopy with biopsies. Finally, the clinical
effect of budesonide in the MCi-group was apparently similar to that of the
other MC subtypes in which efficacy was identical to that of controlled trials
and independent of coexisting bile acid diarrhoea. Due to the lack of
controlled data, prospective therapeutic trials of patients with MCi are needed.
Traditionally, the primary efficacy parameter, clinical remission, has been
determined after 4 to 8 weeks of double-blind treatment. However, several
studies indicate that the effect is evident already after 2 weeks. To allow for
direct comparison with previous studies the primary efficacy parameter will be
determined after 8 weeks of treatment and early efficacy will be a secondary
efficacy parameter, anticipating that shorter treatment periods will be
feasible in future studies.
Study objective
* To demonstrate efficacy of budesonide (9 mg budesonide/d) vs. placebo for
induction of remission in active incomplete microscopic colitis after 8 weeks
of treatment
* To study the maintenance of remission after end of treatment
* To study safety and tolerability of budesonide
* To assess patients* health related quality of life
* To assess the proportion of patients that fulfil the criteria for irritable
bowel syndrome (ROME III criteria)
Study design
The trial is designed as a prospective, double-blind, randomised,
placebo-controlled, parallelgroup, multi-centre, multi-national, comparative
phase III trial. The trial will be conducted with two arms in the form of a
parallel group comparison and will serve to compare oral budesonide and placebo
for induction of remission in patients with incomplete microscopic colitis. The
trial is subdivided in 3 phases:
- Screening phase, lasting up to two weeks:
Patients considered suitable for entry into the trial will be recorded on a
registration log and then informed about the trial, both verbally and by
reviewing the patient informed consent.
Once written consent is obtained, patients will be screened for their
suitability for entry into
the trial, using the selection criteria.
- 8-weeks treatment phase:
Eligible patients will be randomised in one of the two following treatment
groups in conformity with a randomisation list:
A Budenofalk® 9 mg gastro-resistant granules OD
B Placebo granules OD
After randomisation patients will undergo visits at week 2, week 4 and 8 post
randomisation, to assess efficacy and safety of the treatment.
It is planned to randomise 53 patients in each group, i.e., a total of 106
patients.
- 24-weeks follow-up phase:
Responders (patients in clinical remission) will be followed up by telephone at
week 20 and 32 post randomisation, to assess the maintenance of clinical
remission after the treatment phase.
Intervention
8 weeks treatment with either budesonide or placebo. Medication is taken orally
and once daily.
Study burden and risks
Microscopic Colitis is a condition associated with chronic watery diarrhoea,
abdominal pain, weight loss and a high impact on health related quality of life
and social life. As a first step, drugs suspected of being able to cause MC
(e.g., NSAIDS or proton-pump inhibitor) should be tried to stop. Also, generic
anti-diarrhoeal drugs can be given. If these measures are unsuccessful, more
specific medical treatment is indicated.
Budesonide is currently the best-documented treatment in CC and LC and seems to
be effective also in MCi. Budesonide is a well-known, highly potent
non-halogenated glucocorticosteroid. Its highly anti-inflammatory action makes
it ideal for the treatment of asthma and gastrointestinal disorders. Budesonide
is licensed since 1998 and clinical experiences are abundant for various
indications and also for diverse preparation forms.
A daily dose of 9 mg OD was chosen, because in four previous placebo-controlled
trials in CC and in one trial in LC this dosage turned out to be effective and
safe. Due to its rapid inactivation by biotransformation in the liver,
budesonide has a very low bioavailability when absorbed through mucosal
surfaces. This minimises systemic side effects and leads to a high ratio of
topical versus systemic activity. The steroid action of budesonide is mainly
restricted to the target organs, so that even low dosing leads to a good
therapeutic outcome and long term treatment is well tolerated.
Patients randomised to the verum group of this clinical trial will be treated
with a well-known drug, shown to be safe and efficient for the treatment of
inflammatory bowel disease. With the proven effectiveness of budesonide in CC
and LC (see above), it is expected that the drug will be efficacious also in
MCi.
Leinenweberstr. 5
Freiburg 79108
DE
Leinenweberstr. 5
Freiburg 79108
DE
Listed location countries
Age
Inclusion criteria
1. Signed informed consent,
2. Man or woman between 18 and 80 years of age,
3. Histologically established diagnosis of incomplete microscopic colitis (MCi) defined as the following findings in at least two segments of the colon:
* increased lymphoplasmacellular infiltrate in the lamina propria and
* thickened subepithelial collagenous band > 5 *m and < 10 *m and/or
* abnormal intraepithelial lymphocytes > 5 and < 20 per 100 epithelial cells,
4. History of chronic non-bloody, watery diarrhoea for at least 4 weeks,
5. Clinically active disease (defined as a mean of * 3 stools/day, thereof a mean of * 1 watery stool/day during the week prior to randomisation),
6. Women of child-bearing potential have to apply during the entire duration of the study a highly effective method of birth control, which is defined as those which result in a low failure rate (i.e., less than 1% per year) when used constantly and correctly such as implants, injectables, combined oral contraceptive method, some IUDs, sexual abstinence or vasectomised
partner. The investigator is responsible for determining whether the patient uses adequate birth control for study participation.
Exclusion criteria
1. Other significant abnormalities in colonoscopy that may have been the cause of diarrhoea except for colonic diverticulosis and non-dysplastic polyps < 2 cm,
2. Infectious cause of diarrhoea (local routine stool samples, Clostridium difficile included) or history of infectious diarrhoea within the last 3 months prior inclusion or local intestinal infection,
3. Clinical suspicion of drug-induced diarrhoea,
4. Prior and present MC (i.e., all histological criteria for collagenous colitis or lymphocytic colitis fulfilled),
5. History of bowel resection,
6. Radiation therapy of the abdominal or pelvic region,
7. Positive antibody titres for celiac disease (tGT IgA + serum IgA),
8. Untreated active thyroid dysfunction,
9. Any severe concomitant cardiovascular, renal, endocrine, or psychiatric disorder reducing life expectancy,
10. Abnormal hepatic function (ALT or ALP > 2.5 x upper limit of normal [ULN]), liver cirrhosis, or portal hypertension,
11. Tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer disease, glaucoma, cataract, or infection if careful medical monitoring is not ensured,
12. History of colorectal cancer,
13. History of cancer (other than colorectal) in the last 5 years,
14. Therapy with immunomodulators (e.g., azathioprine, 6-mercaptopurine, or methotrexate) within 3 months prior to baseline,
15. Treatment with budesonide or other steroids within 4 weeks prior to baseline,
16. Treatment with antibiotics within 4 weeks prior to baseline,
17. Treatment with anti-diarrhoeal drugs (e.g., loperamide, ispaghula, codeine,
and opium), cholestyramine, bulking agents, and spasmolytics within 2 weeks prior to baseline,
18. Known intolerance/hypersensitivity/resistance to the trial drug or drugs of similar chemical structure or pharmacological profile,
19. Current or intended pregnancy or breast-feeding,
20. Doubt about the patient*s cooperation, e.g. because of addiction to alcohol or drugs,
21. Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial.
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 | EUCTR2013-001912-31-NL |
| CCMO | NL46786.029.14 |