Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy

NCT ID: NCT02002884

Last Updated: 2021-08-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 351 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-28
• Study Completion Date: 2018-08-28

Brief Summary

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both arms alone or in combination with injections into one or both legs are effective and safe in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Conditions

Cerebral Palsy; Spasticity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

8 Units per kg body weight incobotulinumtoxinA (Xeomin)

8 Units per kg body weight (maximum of 200 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 300 Units per injection cycle. Overall maximum dose per injection cycle: 500 Units.

Group Type: EXPERIMENTAL

IncobotulinumtoxinA (8 Units per kg body weight)

Intervention Type: DRUG

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

6 Units per kg body weight incobotulinumtoxinA (Xeomin)

6 Units per kg body weight (maximum of 150 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 225 Units per injection cycle. Overall maximum dose per injection cycle: 375 Units.

Group Type: EXPERIMENTAL

IncobotulinumtoxinA (6 Units per kg body weight)

Intervention Type: DRUG

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

2 Units per kg body weight incobotulinumtoxinA (Xeomin)

2 Units per kg body weight (maximum of 50 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 75 Units per injection cycle. Overall maximum dose per injection cycle: 125 Units.

Group Type: EXPERIMENTAL

IncobotulinumtoxinA (2 Units per kg body weight)

Intervention Type: DRUG

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Interventions

IncobotulinumtoxinA (8 Units per kg body weight)

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Intervention Type: DRUG

IncobotulinumtoxinA (6 Units per kg body weight)

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Intervention Type: DRUG

IncobotulinumtoxinA (2 Units per kg body weight)

Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Intervention Type: DRUG

Other Intervention Names

Xeomin; NT 201; Botulinum toxin type A (150 kiloDalton), free from complexing proteins; Xeomin; NT 201; Botulinum toxin type A (150 kiloDalton), free from complexing proteins; Xeomin; NT 201; Botulinum toxin type A (150 kiloDalton), free from complexing proteins

Eligibility Criteria

Inclusion Criteria

• Female or male subject of 2 to 17 years of age (inclusive).
• Uni- or bilateral Cerebral Palsy (CP) with clinical need for injections with NT 201 for the treatment of upper limb (UL) spasticity at least unilaterally.
• Ashworth Scale (AS) score in the main clinical target patterns in this study:

1. Flexed elbow: AS≥2 in elbow flexors (at least unilaterally). and/or

2. Flexed Wrist: AS≥2 in wrist flexors (at least unilaterally).

• Clinical need according to the judgment of the investigator in one out of five treatment combinations (A-E, as shown below). AS score must be ≥2 for each target pattern chosen for injection at the Baseline Injection Visit V2.

A. UL(s) treatment only (GMFCS I-V):

A1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

or

A2) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

B. Unilateral UL and unilateral lower limb (LL) treatment (GMFCS I-V):

B1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

B2) Ipsilateral unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U). Dose to LL must be distributed to at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe as clinically needed.

C. Unilateral UL and bilateral LL treatment (GMFCS I-III)

C1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

C2) Bilateral treatment of LL spasticity with 12 U/kg BW (maximum of 300 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

D. Unilateral UL and bilateral LL treatment (GMFCS IV and V)

D1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

D2) Bilateral treatment of LL spasticity with 8 U/kg BW (maximum of 200 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

E. Bilateral UL treatment and bilateral LL treatment (GMFCS I-III)

E1) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW) and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

E2) Bilateral treatment of LL spasticity with 4 U/kg BW (maximum of 100 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

Exclusion Criteria

Pre-treated (non-naïve) subjects must not have received BoNT treatment within the last 14 weeks prior to Screening Visit (V1) in any indication.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merz Pharmaceuticals GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Merz Medical Expert

Role: STUDY_DIRECTOR

Merz Pharmaceuticals GmbH

Locations

Merz Investigational Site #001286

Gulf Breeze, Florida, United States

Merz Investigational Site #001284

Loxahatchee Groves, Florida, United States

Merz Investigational Site #001285

Savannah, Georgia, United States

Merz Investigational Site #001186

Chicago, Illinois, United States

Merz Investigational Site No. #001302

Royal Oak, Michigan, United States

Merz Investigational Site #001283

Columbia, Missouri, United States

Merz Investigational Site #054010

Godoy Cruz, Mendoza Province, Argentina

Merz Investigational Site #054005

Caba, , Argentina

Merz Investigational Site #052023

Aguascalientes, , Mexico

Merz Investigational Site #052003

Guadalajara, , Mexico

Merz Investigational Site #052024

Mexico City, , Mexico

Merz Investigational Site #052022

Mexico City, , Mexico

Merz Investigational Site #052027

Monterrey, , Mexico

Merz Investigational Site #052028

Monterrey, , Mexico

Merz Investigational Site #052026

Zapopan, , Mexico

Merz Investigational Site #048089

Bialystok, , Poland

Merz Investigational Site #048063

Gdansk, , Poland

Merz Investigational Site #048059

Krakow, , Poland

Merz Investigational Site #048084

Lublin, , Poland

Merz Investigational Site #048094

Poznan, , Poland

Merz Investigational Site #048075

Sandomierz, , Poland

Merz Investigational Site #048060

Wiązowna, , Poland

Merz Investigational Site #007014

Kazan', , Russia

Merz Investigational Site #007015

Khabarovsk, , Russia

Merz Investigational Site #007018

Novosibirsk, , Russia

Merz Investigational Site #007298

Saint Petersburg, , Russia

Merz Investigational Site #007013

Smolensk, , Russia

Merz Investigational Site #007019

Stavropol, , Russia

Merz Investigational Site #380001

Dnipropetrovsk, , Ukraine

Merz Investigational Site #380005

Kharkiv, , Ukraine

Merz Investigational Site #380002

Kyiv, , Ukraine

Merz Investigational Site #380003

Odesa, , Ukraine

Countries

United States; Argentina; Mexico; Poland; Russia; Ukraine

References

Dabrowski E, Chambers HG, Gaebler-Spira D, Banach M, Kanovsky P, Dersch H, Althaus M, Geister TL, Heinen F. IncobotulinumtoxinA Efficacy/Safety in Upper-Limb Spasticity in Pediatric Cerebral Palsy: Randomized Controlled Trial. Pediatr Neurol. 2021 Oct;123:10-20. doi: 10.1016/j.pediatrneurol.2021.05.014. Epub 2021 May 21.

Reference Type: RESULT

PMID: 34339951 (View on PubMed)

Berweck S, Banach M, Gaebler-Spira D, Chambers HG, Schroeder AS, Geister TL, Althaus M, Hanschmann A, Vacchelli M, Bonfert MV, Heinen F, Dabrowski E. Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis. Toxins (Basel). 2022 Aug 25;14(9):585. doi: 10.3390/toxins14090585.

Reference Type: DERIVED

PMID: 36136523 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2012-005496-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MRZ60201_3072_1

Identifier Type: -

Identifier Source: org_study_id