To evaluate the efficacy of 9mg budesonide/day and 3g mesalazine/day compared to placebo for the induction of remission in lymphocitic colitis.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Rate of clinical remission, defined as a maximum of 21 stools, thereof not more
than 6 watery stools in the last 7 days prior the visit at week 8 (LOCF).
Secondary outcome
Double-blinded phase:
* Number (%) of patients with a maximum of 21 stools, thereof not more than 6
watery stools in the last 7 days prior the visit at week 2, 4, 6 and 8,
* Number (%) of patients with a maximum of 21 stools in the last 7 days prior
the visit at week 2, 4, 6, 8, and 8 (LOCF),
* Number (%) of patients with a maximum of 6 watery stools in the last 7 days
prior the visit at week 2, 4, 6, 8, and 8 (LOCF),
* Number (%) of patients with baseline mean of > 3 stools/day, who have a mean
of * 3 stools/day AND a reduction of at least 1 stool from baseline in the last
7 days prior the visit at week 2, 4, 6, 6 (LOCF), 8, and 8 (LOCF),
* Times to resolution of symptoms defined as the first of 7 consecutive days
with:
o 3 stools/day on average, or
o < 1 watery stool/day on average, or
o 3 stools/day on average, thereof < 1 watery stool/day on average
* Impact on stool consistency (watery/soft/solid),
* Impact on abdominal pain,
* Impact on patient*s general well-being,
* Proportion of patients being in histological remission at week 8 (LOCF)
defined as * 20 IELs/100 epithelial cells AND a reduction in lamina propria
inflammation,
* Proportion of patients with histological improvement at week 8 (LOCF) defined
as a reduction of more than 50% of the number of IELs/100 epithelial cells
compared to baseline and/or a reduction in lamina propria inflammation,
* Proportion of patients with histological non-response (no significant change
in IEL numbers, no change in lamina propria inflammation) at week 8 (LOCF),
* Changes from baseline in histological parameters,
* Severity of diarrhoea,
* Number of days with diarrhoea (> 3 stools/day) in each week,
* Number of days in each week with watery, soft, soft or solid, or solid stool
consistency, respectively,
* Average frequency of stools/day in each week,
* Quality of life (by GIQLI, SHS)
* Physician*s Global Assessment (PGA).
Open-label phase:
* Number (%) of primary non-responders experiencing clinical remission, defined
as a maximum of 21 stools, thereof not more than 6 watery stools in the last 7
days prior the visit at week 4 (LOCF) of the open-label phase,
* Number (%) of patients with clinical relapse experiencing clinical remission,
defined as a maximum of 21 stools, thereof not more than 6 watery stools in the
last 7 days prior the visit at week 4 (LOCF) of the open-label phase,
* Quality of life (by GIQLI, SHS).
Telephone-based follow-up phase:
* Number (%) of primary responders maintaining clinical remission at wk 16, 24
and 24 (LOCF), with remission defined as a maximum of 21 stools, thereof not
more than 6 watery stools in the last 7 days prior the visit,
* Number (%) of primary responders who experienced a relapse at wk 16, 24, and
24 (LOCF), defined as having at least 28 stools within the last 7 days prior to
the visit, thereof at least 20 watery/soft stools,
* Time to relapse,
* Time to failure (relapse, not anymore in remission, or withdrawal due to lack
of efficacy or adverse drug reaction),
* Time to withdrawal,
* Time in study
Safety
* Adverse Events (AEs),
* Vital signs (blood pressure, heart rate) and body weight,
* Haematology, blood chemistry, urine analysis,
* Serum cortisol,
* Assessment of tolerability by investigator and patient.
Background summary
Lymphocytic colitis (LMC) is a distinct form of microscopic colitis,
characterised by chronic or re-current non-bloody, watery diarrhoea, normal
radiological and endoscopic findings, and microscopic abnormalities in the
colon. In addition to LMC, entity microscopic colitis includes collagenous
colitic (COC). Both diseases cannnot be distuinguished clinically and differ
only by specific histopathological features of the colon mucose. Recently it
has been shown in the first randomised, double-blind, placebo-controlled study
that 9 mg budesonide (Budenofalk® 3mg capsules)/day is superior to placebo in
LMC. However, these promising results have to be confirmed in a second trial.
Budesonide is currently the best-documented treatment in COC and significantly
improves the patient*s clinical symptoms and quality of life. Mesalazine have
been extensively used in microscopic colitis but never strictly evaluated in
randomised-controlled trials. Retrospective assessment of mesalazine has
reported effect in 50% of the patients with COC.
Study objective
To evaluate the efficacy of 9mg budesonide/day and 3g mesalazine/day compared
to placebo for the induction of remission in lymphocitic colitis.
Study design
The study is designed as a double-blind, double-dummy, randomised,
placebo-controlled, parallel-group, 3-arm, multicentre, 8-weeks induction of
remission trial, followed by a 16-weeks follow-up period, and with an optional
4-week open-label treatment with budesonide for non-responder in the
double-blind period or for primary responder who have relapsed during the
16-weeks follow-up period. The study will be performed according to a two-stage
group-sequential adaptive design with possible sample size adjustment after the
planned interim analysis.
Screening phase:
1-week screening period prior randomisation.
Double-blind, randomised induction of remission phase:
Patients will be randomised to receive a 8-week, double-blind, double-dummy
treatment with:
Group A: 9 mg budesonide (1 x Budenofalk® 9 mg granules once daily [OD]) and
mesalazine placebo (2 x mesalazine placebo granules OD)
Group B: budesonide placebo (1 x budesonide placebo granules OD) and 3 g
mesalazine (2 x Salofalk® 1.5g granules OD)
Group C: budesonide placebo (1 x budesonide placebo granules OD) and mesalazine
placebo (2 x mesalazine placebo granules OD)
Follow-up phase:
Patients will be followed up by telephone interviews until 24 weeks after
randomisation.
Open-label phase:
Non-responder during or at the end of the double-blind phase as well as
responder who relapsed during the telephone-based follow-up phase, will receive
a 4-week, open-label treatment with:
9 mg budesonide (1 x Budenofalk® 9 mg granules OD)
Intervention
8 weeks of treatment with either Budenofalk, Salofalk or placebo, taken orally
and once daily
Study burden and risks
Patients randomised to one of the verum groups of this clinical trial will be
treated with well-known drugs, both shown to be safe and efficient for the
treatment of inflammatory bowel disease. With the proven effectiveness of
budesonide in at least three placebo-controlled trial in COC and one in LMC,
and preliminary positive results for mesalazine, it is expected that both drugs
will be efficacious also in LMC.
Using a placebo arm in this clinical trial is ethically justified since the use
of a placebo group is appropriate as there is not yet a fully accepted standard
treatment for LMC. The risk for the patient is minimized by performing a
treatment failure assessment at each interim visit. This treatment failure
assessment makes sure that a possible deterioration of the disease would be
identified at the earliest moment. Such a patient would be regarded as
treatment failure and can be withdrawn from double-blind treatment phase and
would be offered to receive open-label 9 mg budesonide the trial.
Leinenweberstr. 5
Freiburg 79108
DE
Leinenweberstr. 5
Freiburg 79108
DE
Listed location countries
Age
Inclusion criteria
1. Signed informed consent,
2. Man or woman * 18 to * 90 years,
3. History of non-bloody, watery diarrhoea for at least 12 weeks prior randomisation in patients with newly diagnosed lymphocytic colitis, or history of clinical relapse for more than 1 week prior randomisation in patients with previously established lymphocytic colitis,
4. At least 28 stools within the last 7 days prior to baseline, thereof at least 20 watery/soft stools,
5. Complete colonoscopy (or proctosigmoidoscopy) within the last 12 weeks before baseline,
6. Histologically confirmed diagnosis of lymphocytic colitis: a. > 20 intraepithelial lymphocytes (IELs)/100 epithelial cells, b. Signs of inflammation of the lamina propria, c. Normal (i.e., < 10 *m) sub-epithelial collagen layer on well-orientated sections,
7. Women of child-bearing potential have to apply during the enteric duration of the highly effective method of birth control, which is defined as those which result in alow failure rate( i. e. less than 1 % per year) when used constantly and correctly such as implants, injectables, combined oral contraceptive method, sexual abstinence or vasectomised partner. The investigator is responsible for determining whether the subject has adequate birth control for study participation.
Exclusion criteria
1. Evidence of infectious diarrhoea (i.e., pathogenic bacteria in stool culture or rectal biopsies),
2. Diarrhoea as a result of the presence of other symptomatic organic disease(s) of the gastrointestinal tract or endoscopic-histological findings (i.e., collagenous colitis, ulcerative colitis, ischemic colitis, radiation colitis, Crohn*s disease, tumours, polyps > 2 cm),
3. Celiac disease (blood tests and/or oesophagogastroduodenoscopy with histological examination to be performed),
4. Suspicion of drug-induced lymphocytic colitis,
5. History of significant bowel resection,
6. History of radiation therapy towards the abdominal or pelvic region,
7. Post-diverticulitis stenosis,
8. Known hereditary problems of galactose or fructose intolerance, glucose-galactose malabsorption, sucrase-isomaltase insufficiency, Lapp lactase deficiency, or congenital lactase deficiency,
9. History of cancer in the last five years,
10. Severe co-morbidity substantially reducing life expectancy,
11. Abnormal hepatic function (ALT or ALP > 2.5 x upper limit of normal [ULN]), liver cirrhosis, or portal hypertension,
12. Abnormal renal function (Cystatin C > ULN),
13. Local intestinal infection,
14. Known established cataract,
15. Hemorrhagic diathesis,
16. Active peptic ulcer disease,
17. Asthma, diabetes mellitus, infection, osteoporosis, glaucoma, tuberculosis, or hypertension if careful medical monitoring is not ensured,
18. Any severe concomitant cardiovascular, renal, endocrine, or psychiatric disorder,
19. Known intolerance/hypersensitivity to study drugs or drugs of similar chemical structure or pharmacological profile,
20. Treatment with anti-diarrhoeals (e.g. loperamide), Boswellia serrata extract, cholestyramine. or bulking agents within the last 14 days before baseline,
21. Treatment with immunomodulators (e.g. azathioprine, 6-mercaptopurine, thioguanine or methotrexate) within 3 months before baseline,
22. Treatment with budesonide, mesalazine, steroids, or oral antibiotics within 4 weeks before baseline,
23. Treatment with ketoconazole or other CYP3A inhibitors within the last 3 weeks before baseline,
24. Doubt about the patient*s cooperation, e.g. because of addiction to alcohol or drugs,
25. Existing or intended pregnancy or breast-feeding,
26. 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 | EUCTR2008-005994-36-NL |
| ClinicalTrials.gov | NCT01209208 |
| CCMO | NL46785.029.14 |