Clinical Trials Register

Summary
EudraCT Number:	2014-001068-36
Sponsor's Protocol Code Number:	R03465
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-30
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

UK - MHRA

A.2

EudraCT number

2014-001068-36

A.3

Full title of the trial

Onabotulinum toxin-A versus extended release tolterodine in the management of
idiopathic overactive bladder in children: A pilot randomised controlled trial (OVERT)

A.3.1

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

Botox versus extended release tolterodine in the management of
overactive bladder in children

A.3.2

Name or abbreviated title of the trial where available

Botulinum toxin-A versus tolterodine for idiopathic overactive bladder

A.4.1

Sponsor's protocol code number

R03465

A.5.4

Other Identifiers

Name:

RfPB

Number:

PB-PG-0712-28094

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	Central Manchester University Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	National Institute for Health Research
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Central Manchester University Hospitals NHS Foundation Trust
B.5.2	Functional name of contact point	Lynne Webster
B.5.3	Address:
B.5.3.1	Street Address	Oxford Road
B.5.3.2	Town/ city	Manchester
B.5.3.3	Post code	M13 9WL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01612764125
B.5.5	Fax number	01612765766
B.5.6	E-mail	lynne.webster@cmft.nhs.uk

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	Botox
D.2.1.1.2	Name of the Marketing Authorisation holder	Allergan Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Onabotulinum toxin A
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Botulinum toxin type A (from Clostridium botulinum)
D.3.9.4	EV Substance Code	AS4
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5 to 150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	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	Tolterodine XL
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Tolterodine
D.3.2	Product code	Tolterodine XL
D.3.4	Pharmaceutical form	Capsule, hard
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	Tolterodine
D.3.9.3	Other descriptive name	Tolterodine XL
D.3.9.4	EV Substance Code	AS2
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	4 to 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)	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Idiopathic Overactive Bladder

E.1.1.1

Medical condition in easily understood language

Overactive bladder

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10059617
E.1.2	Term	Overactive bladder
E.1.2	System Organ Class	100000004857

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 principle objective of the pilot study is to ensure that a full randomised control trial (RCT) is logistically feasible and acceptable to patients.

The aim of the RCT study will be to compare the effectiveness of Botox® (onaBtA) with extended release tolterodine in children with IOAB aged 7-16 years inclusive. Our hypothesis is that treatment with Botox® will result in significant improvement in the mean number of daytime incontinence episodes per day compared to extended release tolterodine.

We will collect the following information to allow us to plan the main trial:

1. Eligibility rate of the patients screened - how many meet the eligibility criteria.

2. Recruitment rate of the eligible patients - how many consent to take part in the study.

3. Acceptability of randomisation to those patients consenting - how many are actually randomised, and of those randomised how many receive the treatment allocated.

4. Primary outcome data for the power calculation.

5.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Children of both sexes between the age of 7 and 16 years inclusive, with clinical symptoms of IOAB. IOAB clinical symptoms are urgency, wetting episodes, increased frequency of micturition.

2. Symptoms must include episodes of daytime urinary incontinence. Symptomatic patients are defined as those who have symptoms of overactive bladder with at least two episodes of daytime wetting per week despite medication.

3. Incomplete resolution of symptoms after bladder training and at least six months of anticholinergic therapy (or at least four months duration of therapy at study registration). Anticholinergic therapy may comprise of Oxybutynin, Solifenacin or Tolterodine. Incomplete resolution is defined as per ICCS definition as no and partial response (less than 50% and 50 - 90% improvement respectively).

4. Urodynamic studies demonstrating either detrusor over activity and/or reduced bladder compliance and/or reduced bladder capacity.

• Reduced bladder capacity is defined as bladder capacity smaller than 70% of expected capacity.
Expected bladder capacity (mls) is calculated as: (age{in years} +1) X 30

• Reduced bladder compliance is defined as <15mls / cm H2O

Bladder compliance is calculated by dividing the change in bladder volume (V) by the change in detrusor pressure (pdet) during that change in bladder volume: Compliance (ml/cm H20) = V/pdet

Two standard points are taken for calculation of bladder compliance – first is detrusor pressure at start of bladder filling; second is detrusor pressure at cystometric capacity or immediately before the start of any detrusor contraction that causes significant leakage

• Detrusor overactivity is defined as bladder activity involving a rise of detrusor pressure of greater than 5 cm H2O above baseline

5. Ultrasound of the renal tract showing no structural abnormality, which could account for the symptoms.

E.4

Principal exclusion criteria

1. Recurrent urinary tract infection (UTI) (more than two documented episodes in the last three months) not controlled with antibiotic prophylaxis.

2. The presence of a neurological pathology, which could account for incontinence, on physical examination.

3. Evidence of significant dysfunctional voiding.

4. Post-void residuals greater than 20% of predicted bladder capacity.

5. Previous treatment with Botox®

6. Allergy to Botox® or Tolterodine

7. Positive pregnancy test in post menarchal girls

8. Myasthenia gravis

9. Kidney transplant

10. Abnormal liver function (liver function tests > 3 times upper limit of laboratory normal range)

11. Severe ulcerative colitis, toxic megacolon, gastro-intestinal obstruction or intestinal atony.

E.5 End points

E.5.1

Primary end point(s)

We will collect the following information to allow us to plan the main trial:

1. Eligibility rate of the patients screened - how many meet the eligibility criteria.

2. Recruitment rate of the eligible patients - how many consent to take part in the study.

3. Acceptability of randomisation to those patients consenting - how many are actually randomised, and of those randomised how many receive the treatment allocated.

4. Primary outcome data for the power calculation.

5. Loss to follow up rate of the patients randomised - how many children will continue to be willing to participate throughout the study

6. Acceptability and suitability of urodynamic study to assess secondary outcome measures

The pilot study will be conducted with the same protocol as is intended for the full trial. Our primary outcome measure for the proposed RCT will be the mean number of episodes of urinary incontinence per day. This information will be derived from the data recorded in the bladder diary. No bladder diary has been validated for this purpose in the literature although the standardisation committee of the International Children's Continence Society(ICCS) stipulates what data should be collected in a bladder diary and for how long. We will therefore assess whether patients complete the data collection tool (bladder diary) with sufficient detail and accuracy to allow robust reporting of the primary outcome measure.

The secondary outcome measures for the proposed RCT following this pilot/feasibility study will be follows:

Urodynamic study data at six weeks
Bladder diary analysis at six weeks, three and six months
Post-void residual urine volume at 3 and 6 months
Quality of life scores (PedsQL / PinQ) at six weeks, three and six months
Adverse effects

E.5.1.1

Timepoint(s) of evaluation of this end point

22.5 months from commencement of study

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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 end of trial will be the date of the last visit of the last participant. An end of trial notification will be submitted to the REC and Regulatory Authority within 90 days of this date. An end of the trial notification will be submitted to the REC and Regulatory Authority within 15 days if the trial is terminated prematurely.

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

Yes

F.1.1