Clinical Trials Register

Summary
EudraCT Number:	2019-003559-12
Sponsor's Protocol Code Number:	INCIPIT
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-10-22
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-003559-12

A.3

Full title of the trial

Prospective, open-label, non-randomized, single-arm, dose titration study to investigate the efficacy and safety of IncobotulinumtoxinA in children deemed to require a total body dose up to 22U/kg (maximum dose 550U) during the study period for the treatment of upper and lower limb spasticity due to cerebral palsy

Studio prospettico, in aperto, non randomizzato, a braccio singolo, dose titration per studiare l'efficacia e la sicurezza di IncobotulinumtoxinA in bambini che richiedono una total body dose fino a 22 U/kg (dose massima 550 U) durante il periodo di studio per il trattamento della spasticità degli arti superiori e inferiori a causa di paralisi cerebrale

A.3.1

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

Prospective study to investigate the efficacy and safety of IncobotulinumtoxinA in children deemed to require a total body dose up to 22U/kg (maximum dose 550U) during the study period for the treatment of upper and lower limb spasticity due to cerebral palsy

Studio prospettico per studiare l'efficacia e la sicurezza di IncobotulinumtoxinA in bambini che richiedono una total body dose fino a 22 U/kg (dose massima 550 U) durante il periodo di studio per il trattamento della spasticità degli arti superiori e inferiori a causa di paralisi cerebrale

A.3.2

Name or abbreviated title of the trial where available

IncobotulinumtoxinA in ChIldren with upper and lower limb spasticity

IncobotulinumtoxinA in bambini con spasticità degli arti superiori e inferiori

A.4.1

Sponsor's protocol code number

INCIPIT

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	AZIENDA OSPEDALIERA UNIVERSITARIA INTEGRATA VERONA
B.1.3.4	Country	Italy
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	MERZ PHARMA ITALIA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliera Universitaria Integrata verona
B.5.2	Functional name of contact point	UOC Neuroriabilitazione
B.5.3	Address:
B.5.3.1	Street Address	Piazzale Ludovico Scuro 10
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37134
B.5.3.4	Country	Italy
B.5.4	Telephone number	0458124573
B.5.5	Fax number	0458124495
B.5.6	E-mail	nicola.smania@univr.it

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 - 100 UNITA' DL50 POLVERE PER SOLUZIONE INIETTABILE 1 FLACONCINO DI VETRO
D.2.1.1.2	Name of the Marketing Authorisation holder	MERZ PHARMACEUTICALS GMBH
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	IncobotulinumtoxinA
D.3.2	Product code	[IncobotulinumtoxinA]
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	TOSSINA BOTULINICA DI CLOSTRIDIUM BOTULINUM TIPO A
D.3.9.1	CAS number	93384-43-1
D.3.9.2	Current sponsor code	IncobotulinumtoxinA
D.3.9.3	Other descriptive name	botulinum toxin type A
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Multifocal spasticity of the upper and lower limb due to cerebral palsy

Spasticità multifocale dell'arto superiore e inferiore dovuta a paralisi cerebrale

E.1.1.1

Medical condition in easily understood language

Spasticity of the upper and lower limb due to cerebral palsy

Spasticità dell'arto superiore e inferiore dovuta a paralisi cerebrale

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028335
E.1.2	Term	Muscle spasticity
E.1.2	System Organ Class	10029205 - Nervous system disorders

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	10033560
E.1.2	Term	Palsy cerebral
E.1.2	System Organ Class	100000004850

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 investigate the efficacy of IncobotulinumtoxinA in the treatment of both BoNT-A naïve and pretreated children for upper and lower limb spasticity using a dose titration approach over three injection cycles, with a flexible observation period after injection of 12 to 20 weeks and a total duration of exposure up to 60 weeks

Studiare l'efficacia di IncobotulinumtoxinA nel trattamento sia di bambini naïve che pretrattati con tossina botulinica per spasticità agli arti superiori e inferiori utilizzando un approccio di dose titration con tre cicli di iniezione, periodo di osservazione da 12 a 20 settimane dopo iniezione e una durata massima di esposizione di 60 settimane

E.2.2

Secondary objectives of the trial

To investigate the safety of IncobotulinumtoxinA in the treatment of both BoNT-A naïve and pretreated children for upper and lower limb spasticity using a dose titration approach over three injection cycles, with a flexible observation period after injection of 12 to 20 weeks and a total duration of exposure up to 60 weeks.

Studiare la sicurezza di IncobotulinumtoxinA nel trattamento sia di bambini naïve che pretrattati con tossina botulinica per spasticità agli arti superiori e inferiori utilizzando un approccio di dose titration con tre cicli di iniezione, periodo di osservazione da 12 a 20 settimane dopo iniezione e una durata massima di esposizione di 60 settimane

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Children (female or male) aged 2 to 17 years
• Patients with upper and lower limb spasticity due to cerebral palsy
• Gross Motor Function Classification System (GMFCS) from Level II to Level V
• Selected target clinical pattern diagnosed by a qualified health care professional (i.e. physiatrist)
• Focal spasticity scored at least 2 points on the Ashworth scale (AS) in the joints associate with the selected target clinical pattern [12]
• Patients deemed by the investigator to require a total body dose up to 22U/kg (maximum 550U) during the study period
• In the case of children pretreated with BoNT-A, time from last injection at least 5 months
• Informed consent signed by parents

• Bambini (femmine o maschi) dai 2 ai 17 anni
• Pazienti con spasticità degli arti superiori e inferiori a causa di paralisi cerebrale
• Gross Motor Function Classification System (GMFCS) dal livello II al livello V
• Diagnosi da parte di un professionista sanitario qualificato (es. Fisiatra)
• Spasticità focale di almeno 2 punti sulla scala di Ashworth (AS) negli arti colpiti
• Pazienti che secondo parere dello sperimentatore richiedono una dose corporea totale fino a 22 U/kg (massimo 550U) durante il periodo di studio
• nel caso di bambini pretrattati con BoNT-A, tempo dall'ultima iniezione almeno 5 mesi
• Consenso informato firmato dai genitori

E.4

Principal exclusion criteria

• Participation in other trials
• BoNT-A treatment contraindicated
• Presence of fixed contractures, or bony deformities of the affected limbs
• Previous treatment of spastic muscles with nerve phenolization
• Other neurological or orthopedic conditions involving the affected limbs
• institutionalized patients
• girls with childbearing potential (defined as females post menarche)

• Partecipazione ad altri trial
• Trattamento con BoNT-A controindicato
• Presenza di contratture fisse o deformità ossee degli arti colpiti
• Trattamento precedente dei muscoli spastici con fenolizzazione dei nervi
• Altre condizioni neurologiche o ortopediche che coinvolgono gli arti colpiti
• pazienti istituzionalizzati
• ragazze in età fertile (definite come femmine post menarca)

E.5 End points

E.5.1

Primary end point(s)

Changes in Ashworth scale values between the injection cycle baseline visits and the control ones of respective injection cycle (single interventional effect).

Variazione degli score della Scala di Ashworth valutati nella visita baseline di ciascun ciclo in cui avviene l’iniezione rispetto alla visita di controllo dello stesso ciclo di iniezione.

E.5.1.1

Timepoint(s) of evaluation of this end point

V2 vs V3,
V5 vs V6,
V8 vs V9
V2 vs V10

E.5.2

Secondary end point(s)

Efficacy endpoint: Ashworth scale; Efficacy endpoints
- REsistance to PAssive movement Scale (REPAS)
- The GMFCS
- The visual analog scale (VAS); Efficacy endpoints
- The Goal Attainment scale (GAS)
- The Global Assessment of Efficacy; Safety endpoints:
Valori di pressione, frequenza cardiaca e frequenza respiratoria; Peso; eventi avversi

Efficacy endpoint: Scala di Ashworth; Efficacy endpoints
- REsistance to PAssive movement Scale (REPAS)
- The GMFCS
- The visual analog scale (VAS); Efficacy endpoints
- The Goal Attainment scale (GAS)
- The Global Assessment of Efficacy; Safety endpoints:
Values of blood pressure, heart rate, and respiratory rate; Values of Body Weight; adverse events

E.5.2.1

Timepoint(s) of evaluation of this end point

V2 vs V6
V2 vs V9
V2 vs V5
V2 vs V8; V2 vs V3,
V5 vs V6,
V8 vs V9
V2 vs V6
V2 vs V9
V2 vs V5
V2 vs V8
V2 vs V10; V5, V8, V10; V1, V2, V3, V4, V5, V6, V7, V8, V9, V10
V2 vs V4
V2 vs V7
V2 vs V10; V1, V2, V5, V8; from V2 and during the study

V2 vs V6
V2 vs V9
V2 vs V5
V2 vs V8; V2 vs V3,
V5 vs V6,
V8 vs V9
V2 vs V6
V2 vs V9
V2 vs V5
V2 vs V8
V2 vs V10; V5, V8, V10; V1, V2, V3, V4, V5, V6, V7, V8, V9, V10
V2 vs V4
V2 vs V7
V2 vs V10; V1, V2, V5, V8; da V2 e per tutta la durata dello studio

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

E.8.1.1

Randomised

E.8.1.2

Open

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

Yes

E.8.1.7.1

Other trial design description

Dose titration

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

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

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.1.1.1

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:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

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 patients

Pazienti minorenni

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

F.4.2.2

In the whole clinical trial

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)

best clinical practice

secondo migliore pratica clinica

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

2020-11-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-27

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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