Clinical Trials Register

Summary
EudraCT Number:	2006-004854-26
Sponsor's Protocol Code Number:	ELB245201-06
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2006-12-04
Trial 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

Sweden - MPA

A.2

EudraCT number

2006-004854-26

A.3

Full title of the trial

A multicenter, randomized, double-blind, parallel group, phase II, forced dose titration study to investigate the efficacy and safety of 400mg and 600mg flupirtine (ELB245) given once daily for 12 weeks (8 + 4 weeks) versus placebo and versus 4mg tolterodine given once daily in patients with incontinent overactive bladder (OAB)

A.4.1

Sponsor's protocol code number

ELB245201-06

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	elbion AG
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Trancolong® einmal täglich
D.2.1.1.2	Name of the Marketing Authorisation holder	Dr. Kade Pharmazeutische Fabrik 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.3.1	Product name	Flupirtine maleate
D.3.2	Product code	ELB245
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Flupirtine maleate
D.3.9.1	CAS number	75507-68-5
D.3.9.2	Current sponsor code	ELB245
D.3.9.3	Other descriptive name	Flupirtine maleate
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	200
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Comparator
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	Detrusitol retard® 4mg Hartkapsel
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmacia GmbH, Pfizer Pharma GmbH, Gödecke 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.3.1	Product name	Detrusitol retard, tolterodine tartrate
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Tolterodine tartrate
D.3.9.1	CAS number	124937-52-6
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Capsule, hard
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

Incontinent Overactive Bladder

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Level	LLT
E.1.2	Classification code	10059617
E.1.2	Term	Overactive bladder

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of escalating doses of flupirtine versus placebo based on mean number of micturitions per 24 hours (averaged over 3 consecutive days), when administered to patients with OAB.

To determine the safety and tolerability of escalating doses of flupirtine versus placebo when administered to patients with OAB

E.2.2

Secondary objectives of the trial

To compare the efficacy of escalating doses of flupirtine versus the standard treatment tolterodine based on mean number of micturitions per 24 hours (averaged over 3 consecutive days), when administered to patients with OAB

To compare safety and tolerability versus tolterodine when administered to patients with OAB

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria to enter 2-week placebo run-in phase:
1. Male or female outpatients ≥ 18 years of age
2. Symptoms of OAB for a minimum of 3 consecutive months prior to study entry; severity of OAB (as defined by patient reported symptoms of frequency ≥ 8 micturition per 24 hours, urgency ≥ 3 episodes per 24 hours, and urinary urgency incontinence on average ≥ 1 per day), for a minimum of one month prior to study entry
3. Willing to comply with requirements of the study protocol including the completion of diaries and questionnaires
4. Ability to use a toilet independently and without difficulty
5. No treatment with any medication against OAB during the 4 weeks prior to study entry
6. Written informed consent

Inclusion criteria at randomization
1. Symptoms of OAB based on patient diary entries during the placebo run in phase with
• ≥ 8 micturitions per 24 hours (based on a 3-day average)
• ≥ 3 episodes of urgency (strong desire to void) per 24 hours (based on a 3-day average)
• ≥ 1 episode of incontinence per 24 hours (based on a 3-day average)
2. No treatment with any medication against OAB during the placebo run in phase
3. Inclusion criteria 3 to 6 above have to be fulfilled

E.4

Principal exclusion criteria

Exclusion criteria for 2-week placebo run-in phase:
1. Breastfeeding women, pregnant women or women who intend to become pregnant during the study or women of childbearing potential who are sexually active and not practicing a highly reliable method of birth control (these are methods with a failure quotient of <1% per year like hormonal implants, injectable contraceptives, oral contraceptives of combination type, intra-uterine devices restricted to hormone contraceptive coil or vasectomy of the partner). The pregnancy test on Visit 1 needs to be negative in women of childbearing potential
2. Any local pathology, (e.g. urinary tract infections [symptomatic active or recurrent i.e. four or more urinary tract infections per year], bladder stones and/or tumors, bladder, urethral or rectal fistulae, diagnosis of interstitial cystitis) that might cause the bladder symptoms
3. Significant stress urinary incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the investigator (for female patients confirmed by cough provocation test), as well as post-operative incontinence
4. Any neurological disease affecting bladder function or muscle strength (e.g. Multiple Sclerosis, Parkinson’s Disease, Stroke, Myasthenia Gravis)
5. Patient history of any lower urinary tract surgery (with the exception of periurethral injections performed at least 6 months ago) or previous pelvic irradiation at any time
6. Local administration of botulinum toxin within the last 9 months in the lower urinary tract
7. Start or change of a behavioral bladder training program or of performance of pelvic muscle exercises (biofeedback) in the 3 months prior to and during the study
8. Post voiding residual volumes larger than 250ml or symptoms of clinically relevant bladder outlet obstruction shown within 3 months prior to the clinical study
9. Nocturial polyuria (as defined as > one third of daily volume voided overnight)
10. History of liver disease and/or impaired liver function (alanine aminotransferase > 2 x upper limit of normal range (ULN), gamma glutamyl transferase > 2 x ULN, cholinesterase < 0.8 x lower limit of normal range) or significant hypoalbuminemia (< 32g/l)
11. Hepatic encephalopathy or history of hepatic encephalopathy
12. Cholestasis (alkaline phosphatase > 2 x ULN, bilirubin > 2 x ULN)
13. Chronic alcohol or drug abuse
14. Evidence of significantly impaired renal function (serum creatinine > 2 x ULN, blood urea nitrogen [BUN] > 2 x ULN)
15. Diabetes mellitus (type I or II) with significant peripheral neuropathy and/or polyuria
16. Inflammatory bowel disease such as Crohn’s disease, or ulcerative colitis
17. Uncontrolled narrow angle glaucoma
18. Any significant disease or condition other than OAB which may put the patient at risk because of participation in the study or which may influence the results of the study or the patient’s ability to participate in the study
19. Chronic use of carbamazepine or paracetamol (on more than 5 consecutive days or on more than 5 days per month)
20. Participation in any drug study in the preceding 3 months
21. Established hypersensitivity to flupirtine, tolterodine or the excipients of the study medication
22. Concomitant treatment with strong CYP3A4 inhibitors (such as macrolid antibiotics [e.g. erythromycin] or antifungal agents [e.g. ketoconazol, and itraconazole] and antiproteases), diuretics (except patients on a stable dose for longer than 6 months) and anticholinergic medications
23. History or evidence of relevant cardiovascular or cerebrovascular disorders such as angina pectoris, cardiac infarction, cardiomyopathy, cardiac failure or cardiac arrhythmias, bradycardia or congenital or documented acquired QT prolongation
Additional exclusion criteria at randomization
1. Symptoms of OAB based on patient diary entries during the placebo run in phase with
• Mean volume voided per 24 hours (based on a 3-day average) > 2.5 liters
• Mean nocturial volume voided per 24 hours (based on a 3-day average) >one third of the total daily volume voided
2. Patients to be excluded if compliance during the placebo run-in phase is below 80% with regard to study medication and if diary completion is unreliable in the opinion of the investigator
None of the exclusion criteria at study entry should be fulfilled at the time of randomization.

E.5 End points

E.5.1

Primary end point(s)

The change from baseline in the mean number of micturitions per 24 hours (based on a 3-day average)

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

Information not present in EudraCT

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

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 end of the study is defined by the last visit of the last subject.

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	50
F.4.2	For a multinational trial
F.4.2.1	In the EEA	275
F.4.2.2	In the whole clinical trial	275

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

2007-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-02-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2007-08-03

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