Clinical Trials Register

Summary
EudraCT Number:	2012-005055-17
Sponsor's Protocol Code Number:	MRZ60201_3071_1
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-04-08
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

Estonia - SAM

A.2

EudraCT number

2012-005055-17

A.3

Full title of the trial

Open-label, non-controlled, multicenter long-term study to investigate the safety and efficacy of Xeomin® (incobotulinumtoxin A, NT 201) for the treatment of spasticity of the lower limb(s) or of combined spasticity of upper and lower limb in children and adolescents (age 2 - 17 years) with cerebral palsy

A.3.1

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

Long-term open-label study of botulinumtoxin type A to treat spasticity of leg(s) or leg(s) and arm in cerebral palsy

A.3.2

Name or abbreviated title of the trial where available

TIMO - Treatment with IncobotulinumtoxinA in Movement Open-Label

A.4.1

Sponsor's protocol code number

MRZ60201_3071_1

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/042/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merz Pharmaceuticals GmbH
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	Merz Pharmaceuticals GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merz Pharmaceuticals GmbH
B.5.2	Functional name of contact point
B.5.6	E-mail	clinicaltrials@merz.de

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	Xeomin
D.2.1.1.2	Name of the Marketing Authorisation holder	Merz Pharmaceuticals 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	NT 201
D.3.2	Product code	NT 201
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	n.a
D.3.9.2	Current sponsor code	NT 101
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	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	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

Lower limb and combined lower limb and upper limb spasticity due to cerebral palsy

E.1.1.1

Medical condition in easily understood language

Lower limb and combined lower limb and upper limb spasticity due to cerebral palsy

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	LLT
E.1.2	Classification code	10058977
E.1.2	Term	Spastic paresis
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 purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) or of leg(s) and one arm are safe in treating children/adolescents (age 2-17 years) long-term with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

E.2.2

Secondary objectives of the trial

n.a

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Main clinical inclusion criteria for completers of study MRZ60201_3070_1:

• Subject with LL spasticity who completed lead-in study MRZ60201_3070_1 in any of the three dose groups with duration of both injection cycles between 12 and 16 weeks.
• Ashworth scale [AS] score ≥2 in plantar flexors (at least unilaterally). For subjects with an AS score of 1, the investigator has to decide on the clinical need for reinjection.
• Clinical need for spasticity treatment with NT 201 according to the clinical judgment of the investigator for:
Unilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into pes equinus
and
need for additional 8 U/kg BW NT 201 (maximum of 200 U) for treatment of clinical pattern flexed knee or adducted thigh (ipsilateral)
or
Bilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into pes equinus on each side.
No treatment of other clinical patterns is allowed.

Main clinical inclusion criteria for subjects who did not participate in MRZ60201_3070_1:

• Female or male subject of 2 to 17 years age (inclusive).
• Uni- or bilateral CP with clinical need for BoNT injection to treat limb spasticity.
• AS score ≥ 2 in plantar flexors (at least unilaterally).
• Clinical need according to the clinical judgment of the investigator in one out of four treatment combinations:

1. For LL(s) treatment only (GMFCS levels I V):
Unilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into pes equinus,
and
8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh
or
Bilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides).

2. For combined unilateral UL and unilateral LL, (GMFCS levels I-III):
Unilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into pes equinus,
and
8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh
plus
Unilateral treatment of UL spasticity with
4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.

3. For combined unilateral UL and unilateral LL (GMFCS level IV-V):
Unilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum 200 U) into pes equinus, and
4 U/kg BW NT201 (maximum 100 U) into flexed knee or adducted thigh
plus
Unilateral treatment of UL spasticity with
4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.

4. For combined unilateral UL and bilateral LL (GMFCS levels I-III):
Bilateral treatment of LL spasticity with
8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides)
plus
Unilateral treatment of UL spasticity with
4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.

E.4

Principal exclusion criteria

Exclusion Criteria for subjects who completed MRZ60201_3070_1:

• Infection and/or inflammation in the area of the planned injection points.
• Pregnancy for female with history of menarche.
• Clinically relevant pathological findings indicating active disease of vital organs.

Exclusion Criteria for subjects who did not participate in MRZ60201_3070_1:

• Fixed contracture defined as severe restriction of the range of joint movement on passive stretch in the target clinical pattern(s) or predominant forms of muscle hypertonia other than spasticity (e.g., dystonia) in the target limb(s).
• Surgery in the pes equinus on side(s) intended to treat with BoNT injections within 12 months prior to Screening Visit (V1), within the screening period or planned for the time of participation in this study.
• Hip flexion requiring BoNT injection.
• Limitation of hip abduction to less than 40° or pre-diagnosed migrational percentage greater than 30
• Vaccination within 2 weeks prior to Screening Visit (V1) and/or within the screening period.
• Non-resolved fractures of the treated limb.
• Ventilator dependency.
• Severe neurological diagnosis and comorbidity outside the spectrum of cerebral palsy.
• Pure dyskinetic CP or mixed CP with predominantly dyskinetic movements.
• Treatment with BoNT (other than IP in this study) for any body region within 14 weeks prior to Screening Visit (V1), within the screening period and/or intended to be administered during the study period.
• Treatment with phenol or alcohol of any muscle within 6 months prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.
• Treatment with
- drugs acting as peripheral muscle relaxants
- intrathecal baclofen, or
- oral anticoagulants
administered within 2 weeks prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.

E.5 End points

E.5.1

Primary end point(s)

Occurrence of treatment emergent adverse events [TEAEs], AEs of special interest [TEAESIs], and serious AEs [TESAEs], overall and per injection cycle.

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall and per injection cycle 1-4

E.5.2

Secondary end point(s)

• Investigator’s Global Assessment of Tolerability at Injection Visits (V5, V7, and V9) and at End of Study Visit (V11) at Day 99 (Week 14) of each injection cycle.
• Changes in the AS score of plantar flexors from baseline (Day 1, V2) to all other visits and from Day 1 of each injection cycle to Control [Ctrl.] Visit at Day 29 (Week 4), Day 57 (Week 8, only 1st cycle), and Day 99 (Week 14) of the respective injection cycle.
• Investigator’s, Child’s/Adolescent’s and Parent’s/Caregiver’s Global Impression of Change Scale [GICS] at Day 29 (Week 4) of all injection cycles.
• Investigator’s Global Impression of Change of Planter Flexor Spasticity Scale [GICS PF] at Day 29 (Week 4) of each respective injection cycle.
• Changes from baseline (Day 1, V2) of modified Tardieu Scale [MTS] of plantar flexors to all other visits and from Day 1 of each injection cycle to Day 29 (Week 4), Day 57 (Week 8, only 1st cycle), and Day 99 (Week 14) of the respective injection cycle.
• Changes from baseline (Day 1, V2) in scores of pain intensity (from subject) and pain frequency (from parent/caregiver) assessed with Questionnaire on Pain caused by Spasticity for subjects with CP [QPS] to all other visits and from Day 1 of each injection cycle to Day 29 (Week 4), Day 57 (Week 8, only 1st cycle), and Day 99 (Week 14) of the respective injection cycle.
• Changes in GMFM-66 score from the 1st Injection Visit (Day 1, V2) to all injection visits of the subsequent injection cycles (V5, V7 and V9) and to the End of Study Visit V11.

E.5.2.1

Timepoint(s) of evaluation of this end point

Between week4 and week 14 of each injection cycle

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Estonia

Germany

Israel

Austria

Poland

Romania

Russian Federation

Ukraine

Czech Republic

Korea, Republic of

Slovakia

Spain

Turkey

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

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

Yes

F.1.1

Number of subjects for this age range:

360

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

230

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

130

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

underage subjects and underage subjects with intellectual disability

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

198

F.4.2.2

In the whole clinical trial

360

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)

None

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

2013-05-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-01-16

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