Clinical Trials Register

Summary
EudraCT Number:	2010-019069-28
Sponsor's Protocol Code Number:	Y-52-52120-145
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-01-05
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-019069-28

A.3

Full title of the trial

A phase III, multicentre, prospective, double blind, randomised, placebo controlled study, assessing the efficacy and safety of Dysport intramuscular injections used for the treatment of upper limb spasticity in adult subjects with spastic hemiparesis due to stroke or traumatic brain injury.

Studio di fase III, multicentrico, prospettico, in doppio cieco, randomizzato, controllato contro placebo, per valutare l'efficacia e la sicurezza di iniezioni intramuscolo di Dysport nel trattamento della spasticita' dell'arto superiore in soggetti adulti affetti da emiparesi spastica secondaria a ictus o a lesione cerebrale traumatica.

A.3.1

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

A.4.1

Sponsor's protocol code number

Y-52-52120-145

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	IPSEN PHARMA SAS
B.1.3.4	Country	France
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	IPSEN INNOVATION
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ipsen Innovation
B.5.2	Functional name of contact point	Co-ordinating and Monitoring office
B.5.3	Address:
B.5.3.1	Street Address	5 Avenue du Canada
B.5.3.2	Town/ city	Les Ulis-Cedex
B.5.3.3	Post code	91940
B.5.3.4	Country	France
B.5.4	Telephone number	+33 (0) 160 92 94 38
B.5.5	Fax number	+33 (0) 160 92 94 61
B.5.6	E-mail	ct-application@ipsen.com

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	DYSPORT for Injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Ipsen Biopharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	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.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	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	Yes
D.3.11.13.1	Other medicinal product type	tossina

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	Powder for 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

Arm Spasticity

Spasticità arti superiori

E.1.1.1

Medical condition in easily understood language

Arm Spasticity

Spasticità arti superiori

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 primary study objective is to assess the efficacy of Dysport compared to placebo in reducing upper limb muscle tone in hemiparetic subjects with upper limb spasticity due to stroke or traumatic brain injury. The primary study objective will be assessed by comparing between treatment groups at Week 4 the change from baseline in muscle tone (using the Modified Ashworth Scale (MAS)) in the primary targeted muscle group

L'obiettivo primario dello studio consiste nella valutazione dell'efficacia di Dysport rispetto al placebo nella riduzione del tono muscolare dell'arto superiore in soggetti emiparetici affetti da spasticità dell'arto superiore secondaria a ictus o a lesione cerebrale traumatica. L'obiettivo primario dello studio sarà valutato confrontando la variazione rispetto al basale alla settimana 4 del tono muscolare (mediante la scala MAS, Modified Ashworth Scale) del principale gruppo muscolare bersaglio tra i gruppi di trattamento

E.2.2

Secondary objectives of the trial

The secondary study objectives include assessments of the efficacy of Dysport compared to placebo on: • The Physician’s Global Assessment (PGA) of treatment response. • The upper limb passive function using the Principal Target of Treatment (PTT) of the Disability Assessment Scale (DAS)

Gli obiettivi secondari dello studio includono le valutazioni dell'efficacia di Dysport rispetto al placebo per:
• la valutazione globale del medico (PGA) della risposta al trattamento;
• la funzionalità passiva dell'arto superiore usando il target principale del trattamento (PTT) della scala di valutazione della disabilità (DAS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Provision of written informed consent prior to any study related procedures. • Between 18 and 80 years of age, inclusive. • Only one clinically defined stroke episode (as defined by the World Health Organization criteria) or one traumatic brain injury. • At least 6 months post-stroke or post traumatic brain injury. • Modified Ashworth Scale (MAS) score ≥2 in the primary targeted muscle group for toxin naïve subjects or MAS score ≥3 in the primary targeted muscle group for toxin non naïve subjects at least 4 months after the last BTX injection, of any serotype. • Disability Assessment Scale (DAS) score ≥2 on the PTT. • Spasticity angle (measured on the TS) >10° in the primary targeted muscle group. • Modified Frenchay Scale (MFS) overall score (average of all task scores) between 1 and 8 (including limit values).

Per essere eleggibili allo studio, i soggetti dovranno soddisfare i seguenti criteri di inclusione:
• Dovranno aver firmato il consenso informato scritto prima di qualsiasi procedura correlata allo studio.
• Dovranno avere un'età compresa tra 18 e 80 anni.
• Dovranno avere avuto un solo episodio di ictus definito clinicamente (come definito dai criteri dell'OMS) o di una sola lesione cerebrale traumatica.
• Dovranno essere trascorsi almeno 6 mesi dall'ictus o dalla lesione cerebrale traumatica.
• Dovranno avere un punteggio della scala MAS (Modified Ashworth Scale) ≥2 del principale gruppo di muscoli nel caso di soggetti naïve per la tossina o un punteggio della scala MAS ≥3 del principale gruppo di muscoli nel caso di soggetti non naïve per la tossina almeno 4 mesi dopo l'ultima iniezione di BTX di qualsiasi sierotipo.• Dovranno avere un punteggio DAS (Disability Assessment Scale) ≥2 per il PTT.
• Dovranno avere un angolo di spasticità (misurato con la scala TS) >10° nel principale gruppo di muscoli bersaglio.
• Dovranno avere un punteggio totale (media di tutti i punteggi delle attività) secondo la scala MFS (Modified Frenchay Scale) compreso tra 1 e 8 (compresi i valori limite).

E.4

Principal exclusion criteria

Major limitation in the passive ROM at the affected elbow, wrist and fingers, as defined by: o Maximum passive elbow extension <150° (0° corresponding to the minimal stretch of the elbow flexors, which corresponds to a fully flexed elbow position), o Maximum passive wrist extension <70° (0° corresponding to the minimal stretch of the wrist flexors, which corresponds to a fully flexed wrist position), o Maximum passive finger extension <70° (0° corresponding to the minimal stretch of the extrinsic finger flexors, which corresponds to a formed fist with the second phalanx parallel to the metacarpal). • Physiotherapy initiated less than 4 weeks before entry or expected to be initiated during the study. • Previous treatment with BTX of any type within 4 months prior to study entry for any condition. • Subjects likely to be treated with BTX of any type in the lower limb during the course of this double blind study. • Previous primary or secondary non response to any BTXs for the targeted condition. • Previous surgery on the affected muscles and ligaments, tendons, nerve trunks, or bones of the treated upper limb. • Previous treatment with phenol and/or alcohol in the treated upper limb anytime before the study. • Any medical condition (including severe dysphagia or airway disease) that may increase, in the opinion of the Investigator, the likelihood of adverse events (AEs) related to BTX treatment. • Major neurological impairment other than spastic paresis (including major proprioceptive ataxia or apraxia on the paretic side) that could negatively impact on the functional performance of the subject. • Known disease of the neuromuscular junction (such as Lambert-Eaton myasthenic syndrome or myasthenia gravis). • Inability to understand protocol procedures and requirements, which, in the opinion of the Investigator, could negatively impact on protocol compliance. • Known sensitivity to BTX or any excipient of Dysport. • Infection at the injection site(s). • Unwillingness or inability to comply with the protocol. • Current or planned treatment with any drug that interferes either directly or indirectly with neuromuscular function (i.e. aminoglycosides) within the last 4 weeks prior to study treatment. • Pregnant women, or premenopausal women not willing to use contraceptive measures throughout the duration of the study. • Treatment with a new investigational drug in the 4 weeks prior to enrolment into the study or scheduled to receive such a drug during the study period. • Any underlying disease (not associated with the stroke or traumatic brain injury) likely to affect upper limb function and/or muscle tone and/or spasticity. • Any medical condition (or laboratory finding) which, in the opinion of the Investigator may compromise compliance with the objectives and/or procedures of this protocol or preclude the administration of BTX

• Limitazione maggiore nel ROM passivo del gomito, del polso e della dita interessate, come definito da:
o estensione passiva massima del gomito <150° (0° corrisponde alla distensione minima dei flessori del gomito, cioè alla posizione del gomito completamente flesso),
o estensione passiva massima del polso <70° (0° corrisponde alla distensione minima dei flessori del polso, cioè alla posizione del polso completamente flesso),
o estensione passiva massima del dito <70° (0° corrisponde alla distensione minima dei flessori estrinseci delle dita, cioè alla posizione del pugno formato con la seconda falange parallela al metacarpale),
• Fisioterapia iniziata nei 4 mesi precedenti l'inizio dello studio o programmata durante lo studio.
• Precedente trattamento con BTX di qualsiasi tipo nei 4 mesi precedenti l'entrata nello studio per qualsiasi condizione.
• Probabile trattamento con BTX di qualsiasi tipo dell'arto inferiore durante questo studio in doppio cieco.
• Pregressa non risposta primaria o secondaria a qualsiasi BTX per la condizione in analisi.
• Intervento chirurgico pregresso ai muscoli e ai legamenti interessati, ai tendini, ai tronchi nervosi o alle ossa dell'arto superiore trattato.
• Trattamento pregresso con fenolo e/o alcool dell'arto superiore trattato in qualsiasi momento prima dello studio.
• Qualsiasi condizione medica (tra cui disfagia grave o malattia respiratoria) che, secondo l'opinione dello sperimentatore, può aumentare la probabilità di eventi indesiderati (AE) correlati al trattamento con BTX.
• Insufficienza neurologica maggiore, diversa dalla paresi spastica (tra cui atassia propriocettiva maggiore o aprassia sul lato paretico) che potrebbe influire negativamente sulla prestazione funzionale del soggetto.
• Nota patologia delle giunzioni neuromuscolari (come la sindrome miastenica di Lambert-Eaton o la miastenia gravis).
• Incapacità di comprendere le procedure e le richieste del protocollo, che, secondo l'opinione dello sperimentatore, potrebbe influire negativamente sulla compliance al protocollo.
• Sensibilità nota alla BTX o a qualsiasi eccipiente di Dysport.
• Infezione al(i) sito(i) di iniezione.
• Non volontà o incapacità di attenersi al protocollo.
• Trattamento in corso o pianificato con qualsiasi farmaco che interferisce direttamente o indirettamente con la funzione neuromuscolare (cioè, le aminoglicosidi) nelle ultime quattro settimane che precedono il trattamento dello studio.
• Donne in gravidanza o in premenopausa, che non intendono usare misure anticoncezionali durante lo studio.
• Trattamento con un nuovo farmaco sperimentale nelle quattro settimane che precedono l'arruolamento nello studio o un trattamento programmato con tale farmaco durante lo studio.
• Qualsiasi malattia sottostante (non associata all'ictus o alla lesione cerebrale traumatica) che potrebbe influire sulla funzionalità dell'arto superiore e/o sul tono muscolare e/o sulla spasticità.
• Qualsiasi condizione medica (o risultato di laboratorio) che, secondo il giudizio dello sperimentatore, possa compromettere la compliance con gli obiettivi e/o le procedure di questo protocollo o precludere la somministrazione della BTX.

E.5 End points

E.5.1

Primary end point(s)

Modified Ashworth Scale (MAS) for rating muscle tone in the primary targeted muscle group.

Variabile di efficacia primaria
• Scala MAS (Modified Ashworth Scale) per la classificazione del tono muscolare del principale gruppo di muscoli bersaglio.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks

4 settimane

E.5.2

Secondary end point(s)

• Mean PGA Score
• Mean change from baseline in the PTT of the DAS

• Valutazione globale del medico (PGA) della risposta al trattamento.
• Target principale del trattamento (PTT) della scala DAS per la misurazione della funzionalità passiva dell'arto superiore.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Mean PGA Score at Week 4.
• Mean change from baseline in the PTT of the DAS at Week 4.

. PGA: 4 settimane
. Target principale del trattamento (PTT) della scala DAS per la misurazione della funzionalità passiva dell'arto superiore: 4 settimane

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

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Russian Federation

United States

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

Number of subjects for this age range:

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:

125

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

103

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects with a legally acceptable representative. The language in the ICF will be such that it is understood by the subject caregiver

pazienti con un legale rappresentante. il linguaggio del foglio informativo è tale da essere compreso dalla persona che si prende cura del paziente.

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

104

F.4.2.2

In the whole clinical trial

228

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)

Subjects who have completed the Week 12, Week 16, Week 20 or Week 24 follow up visit will be offered entry into the open label extension study

Ai soggetti che avranno completato lo studio alla settimana 12 o 16 o 20 o 24 verrà proposto di partecipare allo studio di estensione in aperto

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

2011-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-30

P. End of Trial
P.	End of Trial Status	Completed

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