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

NCT01893411 | Completed Phase 3 Results DMC

• 2 other identifiers: MRZ60201_3070_12012-005054-30
• Study Type: interventional
• Target: 311
• Locations: 13 countries
• Sites: 49

Brief Summary

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) are effective in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Conditions

Lower Limb Spasticity Due to Cerebral Palsy

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in the Ashworth Scale (AS) Score of Plantar Flexors of the Primary Body Side at Day 29 (Week 4) of the First Injection Cycle (1st IC)

  The Ashworth Scale (AS) is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (= no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. "primary body side" was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (LS) mean differences between baseline and Week 4 resulting from MMRM (Mixed Model Repeated Measurement) 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, Week 4

• Co-primary Variable: Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of the Primary Body Side at Day 29 (Week 4) of the First Injection Cycle

  This variable is classified as co-primary to satisfy a Food and Drug Administration (FDA) request. The GICS-PF scale is a 7-Point Likert Scale for the assessment of the functional change due to treatment of plantar flexor spasticity only. Ranges from +3 (very much improved function) to -3 (very much worse function). For participants with bilateral pes equinus, the body side for primary efficacy analysis i.e. "primary body side" was decided by investigator at screening and was kept throughout the entire study. For participants with unilateral treatment, the treated body side was kept throughout the entire study. Values represent least square (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.

  Baseline, Week 4

Secondary Outcomes (17)

• Change From Baseline in the AS Score of Plantar Flexors of the Nonprimary Body Side in Participants With Bilateral Treatment at Day 29 (Week 4) of the First (1st) and Second Injection Cycle (2nd IC)

  Baseline, Week 4 of 1st IC and Week 16-40 of 2nd IC

• Change From Baseline in the AS Score of Plantar Flexors of the Primary Body Side at Day 29 (Week 4) of the Second Injection Cycle

  Baseline to Week 4 of 2nd IC (Week 16-40)

• Changes From Baseline in AS Score of Plantar Flexors of the Primary Body Side at Day 57 (Week 8) and Day 85 (Week 12) of the First and of the Second Injection Cycle

  Baseline to Week 8 and 12 of 1st IC and 2nd IC (Week 20-44 and 24-48)

• Changes From Baseline in AS Score of Knee Flexors or Thigh Adductors in Participants With Unilateral Treatment at Day 29 (Week 4) of the First and of the Second Injection Cycle

  Baseline to Week 4 of 1st IC and 2nd IC (Week 16-40)

• Changes From Baseline in Modified Tardieu Scale [MTS] of Plantar Flexors of Primary Body Side at Day 29 (Week 4), Day 57 (Week 8), and Day 85 (Week 12) of the First and of the Second Injection Cycle

  Baseline to Week 4, 8, and 12 of 1st IC and 2nd IC (Week 16-40, 20-44 and 24-48)

Study Arms (3)

16 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

Drug: IncobotulinumtoxinA (16 Units per kg body weight)

12 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

Drug: IncobotulinumtoxinA (12 Units per kg body weight)

4 Units per kg body weight incobotulinumtoxinA (Xeomin)

EXPERIMENTAL

Drug: IncobotulinumtoxinA (4 Units per kg body weight)

Interventions

IncobotulinumtoxinA (16 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); Total volume 8.0 mL; 400 units; Mode of administration: intramuscular injection into spastic muscles.

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

16 Units per kg body weight incobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA (12 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); Total volume 8.0 mL; 300 units; Mode of administration: intramuscular injection into spastic muscles.

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

12 Units per kg body weight incobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA (4 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); Total volume 8.0 mL; 100 units; Mode of administration: intramuscular injection into spastic muscles.

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

4 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 with clinical need for uni- or bilateral LL injections with BoNT for the treatment of spasticity.
• Ashworth Scale \[AS\] score ≥2 in plantar flexors (at least unilaterally).
• Clinical need for a total dose of 16 U/kg BW NT 201 (maximum of 400 U) for the treatment of LL spasticity according to the clinical judgment of the investigator.

You may not qualify if:

• Fixed contracture defined as severe restriction of the range of joint movement on passive stretch or predominant forms of muscle hypertonia other than spasticity (e.g., dystonia) in the target limb(s).
• Surgery on pes equinus on side(s) intended to be treated with BoNT injections in this study within 12 months prior to Screening Visit (V1), in the screening period or planned for the time of participation in this study.
• Hip flexion requiring BoNT injection.

Sponsors & Collaborators

• Merz Pharmaceuticals GmbH: lead

Study Sites (53)

Merz Investigational Site #043037

Graz, 8036, Austria

Location

Merz Investigational Site #043036

Vienna, 1100, Austria

Location

Merz Investigational Site #420029

Brno, 65691, Czechia

Location

Merz Investigational Site #420028

Olomouc, 77520, Czechia

Location

Merz Investigational Site #372001

Tallinn, 13419, Estonia

Location

Merz Investigational Site #372002

Tartu, 51014, Estonia

Location

Merz Investigational Site #033056

Amiens, 80054, France

Location

Merz Investigational Site #033052

Bron, 69677, France

Location

Merz Investigational Site #033054

La Tronche, 38700, France

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Merz Investigational Site #033055

Palavas-les-Flots, 34250, France

Location

Merz Investigational Site #049328

Bochum, 44791, Germany

Location

Merz Investigational Site #049330

Marburg, 35043, Germany

Location

Merz Investigational Site #049327

Munich, 80337, Germany

Location

Merz Investigational Site #049329

Münster, 48149, Germany

Location

Merz Investigational Site #049326

Vogtareuth, 83569, Germany

Location

Merz Investigational Site #972003

Jerusalem, 91240, Israel

Location

Merz Investigational Site #972001

Tel Aviv, 6423906, Israel

Location

Merz Investigational Site #972002

Tel Aviv, 6423906, Israel

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

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Merz Investigational Site #048084

Lublin, 20-828, Poland

Location

Merz Investigational Site #048072

Luboń, 62-030, Poland

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Merz Investigational Site #048075

Sandomierz, 27-600, Poland

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Merz Investigational Site #048061

Warsaw, 02-315, Poland

Location

Merz Investigational Site #040003

Bucharest, 041408, Romania

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Merz Investigational Site #040001

Bucharest, 041914, Romania

Location

Merz Investigational Site #040002

Iași, 700309, Romania

Location

Merz Investigational Site #007014

Kazan', 420097, Russia

Location

Merz Investigational Site #007015

Khabarovsk, 680038, Russia

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Merz Investigational Site #007018

Novosibirsk, 630091, Russia

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Merz Investigational Site #007017

Saint Petersburg, 194100, Russia

Location

Merz Investigational Site #007013

Smolensk, 214029, Russia

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Merz Investigational Site #007019

Stavropol, 355029, Russia

Location

Merz Investigational Site #421003

Banská Bystrica, 97409, Slovakia

Location

Merz Investigational Site #421008

Bratislava, 82108, Slovakia

Location

Merz Investigational Site #421006

Krompachy, 05342, Slovakia

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Merz Investigational Site #421004

Levoča, 05401, Slovakia

Location

Merz Investigational Site #082019

Goyang, 410-773, South Korea

Location

Merz Investigational Site #082021

Incheon, 400-711, South Korea

Location

Merz Investigational Site #082018

Seongnam-si, 463-712, South Korea

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Merz Investigational Site #082020

Seoul, 135-710, South Korea

Location

Merz Investigational Site #034031

Granada, 18013, Spain

Location

Merz Investigational Site #034032

Manresa, 08243, Spain

Location

Merz Investigational Site #034030

Seville, 41013, Spain

Location

Merz Investigational Site #034026

Seville, 41071, Spain

Location

Merz Investigational Site #090005

Elâzığ, 23119, Turkey (Türkiye)

Location

Merz Investigational Site #090003

Izmir, 35100, Turkey (Türkiye)

Location

Merz Investigational Site #090002

İzmit, 41380, Turkey (Türkiye)

Location

Merz Investigational Site #380001

Dnipropetrovsk, 49027, Ukraine

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Merz Investigational Site #380005

Kharkiv, 61068, Ukraine

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Merz Investigational Site #380002

Kiev, 04209, Ukraine

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Merz Investigational Site #380003

Odesa, 65012, Ukraine

Location

Related Publications (2)

• Heinen F, Kanovsky P, Schroeder AS, Chambers HG, Dabrowski E, Geister TL, Hanschmann A, Martinez-Torres FJ, Pulte I, Banach M, Gaebler-Spira D. IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study. J Pediatr Rehabil Med. 2021;14(2):183-197. doi: 10.3233/PRM-210040.

  PMID: 34092664 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

Interventions

incobotulinumtoxinA; Botulinum Toxins, Type A

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.de

+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: July 2, 2013
• First Posted: July 9, 2013
• Study Start: June 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: May 1, 2016
• Last Updated: August 5, 2021
• Results First Posted: May 12, 2017

Record last verified: 2017-08

Locations

SL (4); RU (6); ES (2); TU (3); AU (2); FR (4); UA (4); RO (3); PL (7); IL (3); DE (5); KR (4); CZ (2)