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

NCT02002884 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: MRZ60201_3072_12012-005496-14
• Study Type: interventional
• Target: 351
• Locations: 6 countries
• Sites: 32

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

Keywords

Upper limb spasticity; lower limb spasticity; combined upper and lower limb spasticity

Outcome Measures

Primary Outcomes (2)

• MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4

  The AS categorizes severity of spasticity by judging resistance to passive movement. Spasticity was assessed by using the 5-point AS with:0 (no increase in tone); 1 (slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2 (more marked increase in tone, but limb easily flexed); 3 (considerable increase in tone -passive movements difficult); 4 (limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and Week 4 resulting from Mixed Model Repeated Measurement (MMRM) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.

  Baseline and Week 4

• Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4

  The GICS was used to measure independently the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). Values represent LS mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.

  Week 4

Secondary Outcomes (13)

• MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4

  Baseline and Week 4

• MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4

  Baseline and Week 4

• MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4

  Baseline up to Week 4

• MP: Change From Baseline in Scores of Pain Intensity (From Participants) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain Caused by Spasticity (QPS)'

  Baseline, Weeks 4, 8, and 14

• MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4

  Week 4

Study Arms (3)

8 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

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.

Drug: IncobotulinumtoxinA (8 Units per kg body weight)

6 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

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.

Drug: IncobotulinumtoxinA (6 Units per kg body weight)

2 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

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.

Drug: IncobotulinumtoxinA (2 Units per kg body weight)

Interventions

IncobotulinumtoxinA (8 Units per kg body weight) 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.

Also known as: Xeomin, NT 201, Botulinum toxin type A (150 kiloDalton), free from complexing proteins

8 Units per kg body weight incobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA (6 Units per kg body weight) 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.

Also known as: Xeomin, NT 201, Botulinum toxin type A (150 kiloDalton), free from complexing proteins

6 Units per kg body weight incobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA (2 Units per kg body weight) 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.

Also known as: Xeomin, NT 201, Botulinum toxin type A (150 kiloDalton), free from complexing proteins

2 Units per kg body weight incobotulinumtoxinA (Xeomin)

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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:
• Flexed elbow: AS≥2 in elbow flexors (at least unilaterally). and/or
• 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:
• At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).
• and
• 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.
• 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:
• At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).
• and
• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Merz Pharmaceuticals GmbH: lead

Study Sites (32)

Merz Investigational Site #001286

Gulf Breeze, Florida, 32561, United States

Location

Merz Investigational Site #001284

Loxahatchee Groves, Florida, 33470, United States

Location

Merz Investigational Site #001285

Savannah, Georgia, 31405, United States

Location

Merz Investigational Site #001186

Chicago, Illinois, 60611, United States

Location

Merz Investigational Site No. #001302

Royal Oak, Michigan, 48073, United States

Location

Merz Investigational Site #001283

Columbia, Missouri, 65212, United States

Location

Merz Investigational Site #054010

Godoy Cruz, Mendoza Province, M5501, Argentina

Location

Merz Investigational Site #054005

Caba, CP 1428, Argentina

Location

Merz Investigational Site #052023

Aguascalientes, 20127, Mexico

Location

Merz Investigational Site #052003

Guadalajara, 44280, Mexico

Location

Merz Investigational Site #052024

Mexico City, 04530, Mexico

Location

Merz Investigational Site #052022

Mexico City, 06700, Mexico

Location

Merz Investigational Site #052027

Monterrey, 64060, Mexico

Location

Merz Investigational Site #052028

Monterrey, 64710, Mexico

Location

Merz Investigational Site #052026

Zapopan, 45030, Mexico

Location

Merz Investigational Site #048089

Bialystok, 15-274, Poland

Location

Merz Investigational Site #048063

Gdansk, 80-389, Poland

Location

Merz Investigational Site #048059

Krakow, 30-539, Poland

Location

Merz Investigational Site #048084

Lublin, 20-828, Poland

Location

Merz Investigational Site #048094

Poznan, 60-480, Poland

Location

Merz Investigational Site #048075

Sandomierz, 27-600, Poland

Location

Merz Investigational Site #048060

Wiązowna, 05-462, Poland

Location

Merz Investigational Site #007014

Kazan', 420097, Russia

Location

Merz Investigational Site #007015

Khabarovsk, 680038, Russia

Location

Merz Investigational Site #007018

Novosibirsk, 630091, Russia

Location

Merz Investigational Site #007298

Saint Petersburg, 192148, Russia

Location

Merz Investigational Site #007013

Smolensk, 214019, Russia

Location

Merz Investigational Site #007019

Stavropol, 355029, Russia

Location

Merz Investigational Site #380001

Dnipropetrovsk, 49000, Ukraine

Location

Merz Investigational Site #380005

Kharkiv, 61068, Ukraine

Location

Merz Investigational Site #380002

Kyiv, 04209, Ukraine

Location

Merz Investigational Site #380003

Odesa, 65012, Ukraine

Location

Related Publications (2)

• 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.

  PMID: 34339951 RESULT

• 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.

  PMID: 36136523 DERIVED

MeSH Terms

Conditions

Cerebral Palsy; Muscle Spasticity

Interventions

incobotulinumtoxinA; Botulinum Toxins, Type A

Condition Hierarchy (Ancestors)

Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Results Point of Contact

• Title: Public Disclosure Manager
• Organization: Merz Pharmaceuticals GmbH

clinicaltrials@merz.com

+49 69 1503 1

Study Officials

• Merz Medical Expert

  Merz Pharmaceuticals GmbH

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2013
• First Posted: December 6, 2013
• Study Start: March 28, 2014
• Primary Completion: July 4, 2017
• Study Completion: August 28, 2018
• Last Updated: August 5, 2021
• Results First Posted: August 3, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

RU (6); PL (7); UA (4); AR (2); ME (7); US (6)