Clinical Trials Register

Summary
EudraCT Number:	2008-005994-36
Sponsor's Protocol Code Number:	BUG-1/LMC
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-11-04
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2008-005994-36

A.3

Full title of the trial

Double-blind, double-dummy, randomised, placebo-controlled, multi-centre phase III study on the efficacy and tolerability of a 8-week treatment with 9 mg budesonide vs. 3 g mesalazine vs. placebo in patients with lymphocytic colitis

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.3.2

Name or abbreviated title of the trial where available

9 mg budesonide vs. 3 g mesalazine vs. placebo in lymphocytic colitis

A.4.1

Sponsor's protocol code number

BUG-1/LMC

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Dr. Falk Pharma GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Dr. Falk Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dr. Falk Pharma GmbH
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Leinenweberstr 5
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79108
B.5.3.4	Country	Germany
B.5.4	Telephone number	00497611514187
B.5.5	Fax number	00497611514377
B.5.6	E-mail	nacak@drfalkpharma.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Salofalk® Granu-Stix® 1,5 g
D.2.1.1.2	Name of the Marketing Authorisation holder	Dr. Falk Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Gastro-resistant granules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MESALAZINE
D.3.9.1	CAS number	89-57-6
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Budenofalk 9 mg gastro-resistant granules
D.3.2	Product code	9 mg Budesonide
D.3.4	Pharmaceutical form	Gastro-resistant granules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUDESONIDE
D.3.9.1	CAS number	51333-22-3
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gastro-resistant granules
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gastro-resistant granules
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Induction of remission in lymphocytic colitis

E.1.1.1

Medical condition in easily understood language

Improvement od the symptoms of lymphocytic colitis

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10025268
E.1.2	Term	Lymphocytic colitis
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the trial is to compare the efficacy of 9 mg budesonide/day and 3 g mesalazine/day compared to placebo for the induction of remission in lymphocytic colitis

E.2.2

Secondary objectives of the trial

- To compare the efficacy of 3 g mesalazine/day vs. 9 mg budesonide/day for the induction of remission in lymphocytic colitis,
- To study safety and tolerability of 9 mg budesonide/day and 3 g mesalazine/day vs. placebo in the form of adverse events and laboratory parameters,
- To assess patients’ quality of life

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent,
2. Man or woman >/= 18 years to ≤ 90 years,
3. History of non-bloody, watery diarrhoea for at least 12 weeks prior to randomisation in patients with newly diagnosed lymphocytic colitis, or history of clinical relapse for more than 1 week prior to 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 screening,
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 µm) sub-epithelial collagen layer on well-orientated sections,
7. 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, sexual abstinence or vasectomised partner. The investigator is responsible for determining whether the subject has adequate birth control for study participation.

E.4

Principal 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.
27. Live vaccination within the last 4 weeks before the baseline visit
28. Diagnosis of chickenpox, herpes zoster or measles within the last 3 months before the baseline visit

E.5 End points

E.5.1

Primary end point(s)

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)

E.5.1.1

Timepoint(s) of evaluation of this end point

Patient Visit V5 after 8 weeks of treatment

E.5.2

Secondary end point(s)

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)
• Change of disease activity from baseline to week 8 /LOCF)

Open-label phase:
• Number (%) of patients experiencing clinical remission, defined as a maximum of 21 stools, thereof not more than 6 watery stools in the last 7 days prior to the visit at week 4 (LOCF) of the open-label phase,
• Change of disease activity from start to open-label phase to week 4 /LOCF)
• Change of quality of life (by GIQLI, SHS) from start of open-label phase to week 4 (LOCF)
• Physician's Global Assessment (PGA)

E.5.2.1

Timepoint(s) of evaluation of this end point

Each visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

double-dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Both MP are to be compared to placebo

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study end is defined as “last patient out” (LPO)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Treatment after study end is left to investigator’s discretion

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-01-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-01-16

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