Clinical Trials Register

Summary
EudraCT Number:	2014-001013-81
Sponsor's Protocol Code Number:	ProBaBle
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-07-03
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Portugal - INFARMED

A.2

EudraCT number

2014-001013-81

A.3

Full title of the trial

Treatment of Bladder Pain Syndrome with Onabotulinum toxin A

A.3.1

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

Treatment of Bladder Pain Syndrome with Onabotulinum toxin A

A.4.1

Sponsor's protocol code number

ProBaBle

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	Centro Hospitalar de São João, EPE
B.1.3.4	Country	Portugal
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	Centro Hospitalar de São João, EPE
B.4.2	Country	Portugal
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centro Hospitalar de São João, EPE
B.5.2	Functional name of contact point	Prof. Francisco Cruz
B.5.3	Address:
B.5.3.1	Street Address	Alameda Professor Hernâni Monteiro
B.5.3.2	Town/ city	Porto
B.5.3.3	Post code	4200–319
B.5.3.4	Country	Portugal
B.5.4	Telephone number	+35122551 21 00
B.5.5	Fax number	+35122502 57 66
B.5.6	E-mail	cruzfjmr@med.up.pt

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 Pharmaceuticals Ireland
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	BOTOX®
D.3.2	Product code	9060X
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Botulinum Toxin Type A
D.3.9.1	CAS number	93384-43-1
D.3.9.3	Other descriptive name	BOTULINUM TOXIN TYPE A
D.3.9.4	EV Substance Code	SUB13117MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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.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	Solution for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Bladder Pain Syndrome

E.1.1.1

Medical condition in easily understood language

Bladder Pain Syndrome

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10071166
E.1.2	Term	Bladder pain syndrome
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

To assess the efficacy of OnabotA 100 U trigonal injections versus saline in controlling bladder pain, the main symptom referred by patients with BPS/IC, 12 weeks after treatment.

E.2.2

Secondary objectives of the trial

- To compare OnabotA versus saline regarding changes in bladder pain intensity at 4 and 8 weeks after treatment.
- To compare OnabotA versus saline regarding changes in day-time and night-time urinary frequency 4, 8 and 12 weeks after treatment.
- To compare OnabotA versus saline regarding changes in mean urinary volume per void 4, 8 and 12 weeks after treatment.
- To compare OnabotA versus saline regarding changes in OLSI scores 4, 8 and 12 weeks after treatment.
- To compare OnabotA versus saline regarding changes in quality of life 4, 8 and 12 weeks after treatment.
- To compare OnabotA versus saline regarding the benefit reported by patients at 12 weeks after treatment.
- To evaluate the safety of OnabotA, for up to 12 weeks after treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Female patients aged between 20 and 60 years.
- Patients must have pain related to bladder filling, referred to bladder, urethra or perineum for at least 6 months with a score of at least 4 in a 0 (no pain) to 10 (maximum pain) visual analogue scale (VAS). Other urinary complaints such as frequency, urgency or nocturia may be present.
- For patients taking oral standard medication for their BPS/IC like PPS, amitriptyline or hydroxyzine must be discontinued at least 15 days prior to screening procedures and a treatment cannot be commenced during the study.
- For patients taking intravesical medication like heparinoids, PPS, chondrotin sulfate or DMSO medication must be discontinued at least 3 months prior to screening procedures and a treatment cannot be commenced during the study.
- Patients who have received Botulinum toxin type A or resiniferatoxin before, a period of at least 12 months must have elapsed prior to screening procedures. None of these two treatments can be concomitantly commenced during the study.
- If the patient is under analgesic medication (which includes paracetamol, non-steroidal anti-inflammatory drugs, gabapentin and pregabalin), she will be allowed at entry. However the dose must remain constant throughout the study duration. If the patient is off analgesic medication no de novo analgesic medication will be allowed during the study. However patients may receive analgesics once they withdraw the study.
- Patients must be able and be willing to use clean intermittent catheterization (CIC) at any time after study treatment, if it is determined to be necessary by the investigator.
- Anticoagulants, antiplatelet medications, or medications with anticoagulant effects (e.g., warfarin and other coumarinic derivatives, aspirin, clopidogrel, etc) will be prohibited prior to the administration of the study treatment within the following conditions stated in the guideline published by Douketis and colleagues (Douketis et al, 2012):
- Vitamin K antagonists will be interrupted for a minimum of 5 days before surgery.
- Antiplatelet/antiaggregant drug will be interrupted for a minimum of 7 days before surgery.
- These medications could be restarted the day following study treatment. If medically indicated, low molecular weight heparins (e.g. enoxaparin) will be permitted up to 24 hours prior to study drug treatment.

E.4

Principal exclusion criteria

- Pregnant or nursing patients
- Patients of childbearing potential that do not use adequate birth control methods (defined in Section 8.2.6)
- Patient has history or evidence of any pelvic or urological abnormalities including but not limited to the following:
- Current or frequent urinary tract infections (UTI) (> 2 in the last 6 months documented by urine culture) or is taking prophylactic antibiotics to prevent chronic UTI.
- History of bladder tumour with or without additional intravesical chemotherapy (mitomycin, BCG).
- History of previous pelvic radiotherapy, urinary tract tuberculosis, or exposure to ketamine.
- Current or previous non-investigated haematuria (patients with investigated haematuria may enter the study if urological/renal pathology has been ruled out to the satisfaction of the investigator).
- Surgery or bladder diseases that may impact bladder function including bladder stones, stress incontinence, endometriosis, uterine prolapse, rectocele, cystocele or any pelvic surgery.
- Estimated creatinine clearance rate (eCCr) lower than 30 ml/min, calculated by the Cockcroft-Gault formula:
eCCr=((140-Age in years)×Mass (in kilograms))/(72×serum creatinine (in mg⁄dl))[×0.85 if female]
- Cardiac, pulmonary and hematologic conditions or other diseases that may preclude a safe general anaesthesia, in the opinion of the investigator.
- Patients at high risk of thrombotic events for whom suspension of antiplatelet or anticoagulant treatment puts patients’ safety at risk.
- Patient with a post void residual (PVR) urine volume of > 100 ml at screening.
- History of neuromuscular transmission disorders including, but not limited to myasthenia gravis and Eaton Lambert Syndrome
- Patients with peripheral motor neuropathic diseases including but not limited to amyotrophic lateral sclerosis.
- Allergy to OnabotA or any of the study treatments' componentes.
- Administration of OnabotA for other reasons than BPS/IC in the previous 12 weeks.

E.5 End points

E.5.1

Primary end point(s)

Absolute variation of pain intensity in pain VAS from visit 1 (screening) to visit 6 (week 12).

E.5.1.1

Timepoint(s) of evaluation of this end point

From visit 1 (screening) to visit 6 (week 12).

E.5.2

Secondary end point(s)

- Absolute variation of pain intensity in pain VAS from visit 1 (screening) to visits 4 and 5 (weeks 4 and 8).
- Absolute variation of day-time and night-time urinary frequency, measured in the 3D bladder diary from visit 1 (screening) to visits 4, 5 and 6 (weeks 4, 8 and 12).
- Absolute variation of mean volume per void, measured in the 3D bladder diary from visit 1 (screening) to visits 4, 5 and 6 (weeks 4, 8 and 12).
- Absolute variation in O’Leary-Sant problems and symptoms scores from visit 1 (screening) to visits 4, 5 and 6 (weeks 4, 8 and 12).
- Absolute variation of QoL from visit 1 (screening) to visits 4, 5 and 6 (weeks 4, 8 and 12).
- Percentage of patients with 50% decrease in pain VAS score at visit 6 (week 12) since visit 1 (screening).
- Treatment Benefit Scale score at visit 6 (week 12).
- Incidence of adverse events and severe adverse events during the study period.
- Incidence of adverse events and severe adverse events whose relationship to the study drug could not be ruled out during the study period.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Absolute variation of pain intensity in pain VAS: from visit 1 (screening) to visits 4 and 5 (weeks 4 and 8)
- day-time and night-time urinary frequency, mean volume per void, O’Leary-Sant score and QoL: from visit 1 (screening) to visits 4, 5 and 6 (weeks 4, 8 and 12)
- Percentage of patients with 50% decrease in pain VAS score: at visit 6 (week 12) since visit 1 (screening).
- Treatment Benefit Scale score: visit 6 (week 12).
- Incidence of adverse events and severe adverse events: during the study period.
- Incidence of adverse events and severe adverse events whose relationship to the study drug could not be ruled out during the study period: after the study period.

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)

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)

E.8.2.2

Placebo

Yes

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.8.5

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

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

LVLS

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)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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.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)

Patients may return to pentosan polysulfate (PPS), Hyaluronic acid, Amitriptyline and painkillers. Some patients may accept to receive Botox in a compaxionate-use regimen authorized by the Local Ethics Committee.

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

2014-08-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-10

P. End of Trial
P.	End of Trial Status	Ongoing

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials