Clinical Trials Register

Summary
EudraCT Number:	2011-005375-16
Sponsor's Protocol Code Number:	A-99-52120-162
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-01-03
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

Finland - Fimea

A.2

EudraCT number

2011-005375-16

A.3

Full title of the trial

A PHASE III PROSPECTIVE, MULTI-CENTER, RANDOMISED, EVALUATOR-BLINDED STUDY TO COMPARE NEUROMUSCULAR JUNCTION (NMJ) TARGETED TECHNIQUE FOR DYSPORT INJECTIONS IN UPPER LIMB SPASTICITY POST STROKE OR TRAUMATIC BRAIN INJURY TO THE TECHNIQUE USED IN CURRENT CLINICAL PRACTICE

Faasi III, prospektiivinen, satunnaistettu, arvioijan osalta sokkoutettu monikeskustutkimus, jossa verrataan Dysport pistosten hermo-lihasliitospistostekniikkaa nykyiseen vakiintuneeseen hoitokäytäntöön aivoinfarktin, verenvuodon tai vakavan aivoruhjeen jälkeisen yläraaja spastisuuden hoidossa (A-99-5210-162 NMJ-tutkimus)

A.3.1

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

Study to compare the effect of two different injection techniques used for Dysport treatment of patients with upper limb spasticity post stroke or traumatic brain injury

A.3.2

Name or abbreviated title of the trial where available

The NMJ Study

A.4.1

Sponsor's protocol code number

A-99-52120-162

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01682148

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	Institut Produits Synthèse (IPSEN) AB
B.1.3.4	Country	Sweden
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 AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut Produits Synthèse (IPSEN) AB
B.5.2	Functional name of contact point	Medical Department
B.5.3	Address:
B.5.3.1	Street Address	Kista Science Tower, 15th floor, Färögatan 33
B.5.3.2	Town/ city	Kista
B.5.3.3	Post code	164 51
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46084516083
B.5.5	Fax number	+46084516002
B.5.6	E-mail	kia.bengtsson@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
D.2.1.1.2	Name of the Marketing Authorisation holder	Institut Produits Synthese (IPSEN)AB
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Dysport
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	Clostridium Botulinum Toxin Type A-Hemagglutinin Complex
D.3.9.3	Other descriptive name	CLOSTRIDIUM BOTULINUM NEUROTOXIN TYPE A (150KD), FREE OF COMPLEXING PROTEINS
D.3.9.4	EV Substance Code	SUB26174
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	300
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	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Upper limb spasticity post stroke or traumatic brain injury.

E.1.1.1

Medical condition in easily understood language

Patients suffering from spasticity in their arm as a consequence to a previous stroke or traumatic brain injury.

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10048970
E.1.2	Term	Arm spasticity
E.1.2	System Organ Class	100000004852

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 objective is to compare Dysport treatment results after current clinical practice technique and 300U/mL dilution (high-concentration, Group 1) to the neuromascular junction (NMJ) targeted technique and 100U/mL dilution (low-concentration, Group 2), in the elbow joint assessed by Modified Ashworth Scale (MAS, Appendix 3) 4 weeks post treatment.

E.2.2

Secondary objectives of the trial

• Elbow joint, assessed by MAS, 12 weeks post treatment
• Pain associated with spasticity, assessed by VAS, at visit 1(baseline, day 1), 4 and 12 weeks post treatment
• Pain associated with injection technique, assessed by VAS, at visit 1
• GAS responder rate, as defined by the achievement of the primary goal related to the elbow flexion from the GAS, 4 or 12 weeks post treatment depending on the time point defined at the baseline visit
• Subject global evaluation of the treatment effect, at the end of the study (visit 3 or 4) compared to previous treatment cycle
• Safety, based on treatment emergent adverse event
- Investigator global preference of current clinical practice vs. the NMJ targeted injection technique when all subjects at the site have completed the study (LPLV of each site).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

o Provision of written informed consent prior to any study related procedures,
o Subjects male or female, aged 18 or older,
o Upper limb spasticity post stroke or traumatic brain injury,
o Spasticity position pattern type 1, 3 or 4,
o Elbow flexor muscles spasticity MAS 2 to 3,
o At least 2 consecutive previous treatment cycles of BoNT-A for current diagnosis,
o The latest treatment cycle demonstrating good treatment efficacy where the Dysport dose administered was considered to be adequate according to Investigator judgement,
oNeed of the same treatment modality in m. brachialis, m. biceps brachii, m. brachioradialis, m. flex. carpi ulnaris, m. flex. carpi radialis as the previous treatment cycle,
o Last BoNT-A treatment 12-24 weeks ago

E.4

Principal exclusion criteria

Subjects will not be included in the study if they meet any or the following criteria:
• Poor response to BoNT-A treatment, according to Investigator,
• Need of Dysport doses >800U in the upper limb,
• Concomitant treatment with BoNT-A for other indications than spasticity,
• Any elbow flexor contracture prohibiting MAS evaluation and/or elbow flexion improvement of at least 1 step on the MAS
• Cutaneous or joint inflammation in the affected upper limb,
• Is likely to start other spasticity treatment during the study,
• Is likely to start physiotherapy treatment during the study,
• Other ongoing neurological disorder (e.g., myasthenia gravis),
• History of dysphagia or aspiration,
• Use of agents interfering with neuromuscular transmission (e.g., aminoglycosides),
• Treated with an investigational medicinal product within 30 days before start of the study,
• Known sensitivity to BoNT-A or any components of Dysport,
• Is at risk of pregnancy or is lactating. Females of childbearing potential must provide a negative pregnancy test (U-hCG) at visit 1 and must be using adequate contraception. Non childbearing potential is defined as post-menopause for at least one year, surgical sterilisation or hysterectomy at least three months before the start of the study,
• Has a history of, or known current, problems with alcohol or drug abuse,
• Has a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude,
• Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.

E.5 End points

E.5.1

Primary end point(s)

MAS of elbow flexors at 4 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks post treatment

E.5.2

Secondary end point(s)

• MAS of elbow flexors at 12 weeks
Change from baseline to week 12 for elbow flexors muscle tone as measured by the MAS.

• Spasticity pain measured by VAS.
Mean change from baseline to week 4 and 12 of spasticity related pain, assessed by the subject. The VAS ruler used in this study will be a straight 10 cm horizontal line with anchor points of No pain (score 0) and Worst pain imaginable (score 10).

• Injection pain measured by VAS.
Subject perceived injection site pain at day 1. The VAS ruler used in this study will be a straight 10 cm horizontal line with anchor points of No pain (score 0) and Worst pain imaginable (score 10).

• Achievement of the primary goal measured by GAS.
At baseline, the investigator will interview the subject to identify the main problem area and establish an agreed primary goal related to elbow flexion to be followed up at week 4 or 12 depending on the time point defined at the baseline visit.

• Subject global evaluation of treatment effect. Comparison of treatment effect between previous (pre study) and study treatment cycles assessed by the subject at the end of study (visit 3 or 4) Categorised as follows: Much worse / Worse / Same / Better / Much better.

• Investigator preference of injection technique.
When all subjects at the site have completed the study (Last Patient Last Visit, LPLV) a global assessment of the preference of injection technique will be made by the Investigator.

Safety Endpoints and Evaluations:
• Adverse Events (AEs)
Adverse events will be monitored from the subject gives informed consent (visit 1, day 1) to the time when the subject’s participation in the study has ended (visit 3 or 4). AEs will be elicited by direct, non-leading questioning at each clinic visit or by spontaneous reports.

E.5.2.1

Timepoint(s) of evaluation of this end point

4, 12 and 13-24 weeks.

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

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

Yes

E.8.1.7.1

Other trial design description

Evaluator blinded

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Same medicinal product but injected using a different technique.

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

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

Last patient, last visit.

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:

180

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

272

F.4.2.2

In the whole clinical trial

272

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)

Not applicable. Expected to go back to normal treatment.

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

2012-02-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-31

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