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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 (XARA)

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ClinicalTrials.gov Identifier: NCT02002884
Recruitment Status : Completed
First Posted : December 6, 2013
Results First Posted : August 3, 2020
Last Update Posted : August 3, 2020
Sponsor:
Information provided by (Responsible Party):
Merz Pharmaceuticals GmbH

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.

Condition or disease Intervention/treatment Phase
Cerebral Palsy Spasticity Drug: IncobotulinumtoxinA (8 Units per kg body weight) Drug: IncobotulinumtoxinA (6 Units per kg body weight) Drug: IncobotulinumtoxinA (2 Units per kg body weight) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 351 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Prospective, Multicenter, Randomized, Double-blind, Parallel-group, Dose-response Study of Three Doses Xeomin® (incobotulinumtoxinA, NT 201) for the Treatment of Upper Limb Spasticity Alone or Combined Upper and Lower Limb Spasticity in Children and Adolescents (Age 2 - 17 Years) With Cerebral Palsy
Actual Study Start Date : March 28, 2014
Actual Primary Completion Date : July 4, 2017
Actual Study Completion Date : August 28, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: 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.
Other Names:
  • Xeomin
  • NT 201
  • Botulinum toxin type A (150 kiloDalton), free from complexing proteins

Experimental: 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.
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.
Other Names:
  • Xeomin
  • NT 201
  • Botulinum toxin type A (150 kiloDalton), free from complexing proteins

Experimental: 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.
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.
Other Names:
  • Xeomin
  • NT 201
  • Botulinum toxin type A (150 kiloDalton), free from complexing proteins




Primary Outcome Measures :
  1. MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4 [ Time Frame: Baseline and 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.

  2. Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4 [ Time Frame: 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.


Secondary Outcome Measures :
  1. MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4 [ Time Frame: Baseline and Week 4 ]
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.

  2. MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4 [ Time Frame: Baseline and Week 4 ]
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.

  3. MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4 [ Time Frame: Baseline up to Week 4 ]
    The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 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 LS mean differences between baseline and Week 4 resulting from 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.

  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)' [ Time Frame: Baseline, Weeks 4, 8, and 14 ]
    Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with QPS. The QPS Total Score for pain intensity ranges from 0 ('No Hurt') to 10 ('Hurt Worst'). The QPS Total Score for the observed pain frequency ranges from 0 (Never) to 4 (Always). Values represent LS mean differences between baseline and Week 4 resulting from 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. P/C = Parent/Caregiver.

  5. MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4 [ Time Frame: Week 4 ]
    The GICS was used to measure independently the child's/adolescent's, and parent's or caregiver'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.

  6. Number of Participants With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  7. Number of Participants With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  8. Number of Participants With Occurrence of Serious TEAEs (TESAEs) Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  9. Number of Participants With Occurrence of TEAEs Related to Treatment Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  10. Number of Participants With Occurrence of TEAEs by Worst Intensity Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  11. Number of Participants With Occurrence of TEAEs by Worst Causal Relationship Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  12. Number of Participants With Occurrence of TEAEs by Final Outcome Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]
  13. Number of Participants With Occurrence of TEAEs Leading to Discontinuation Overall and Per Treatment Cycle [ Time Frame: Baseline up to Week 66 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02002884


Locations
Show Show 32 study locations
Sponsors and Collaborators
Merz Pharmaceuticals GmbH
Investigators
Layout table for investigator information
Study Director: Merz Medical Expert Merz Pharmaceuticals GmbH
  Study Documents (Full-Text)

Documents provided by Merz Pharmaceuticals GmbH:
Statistical Analysis Plan  [PDF] October 18, 2018
Study Protocol  [PDF] April 7, 2016

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Responsible Party: Merz Pharmaceuticals GmbH
ClinicalTrials.gov Identifier: NCT02002884    
Other Study ID Numbers: MRZ60201_3072_1
2012-005496-14 ( EudraCT Number )
First Posted: December 6, 2013    Key Record Dates
Results First Posted: August 3, 2020
Last Update Posted: August 3, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merz Pharmaceuticals GmbH:
Upper limb spasticity
lower limb spasticity
combined upper and lower limb spasticity
Additional relevant MeSH terms:
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Muscle Spasticity
Cerebral Palsy
Neurologic Manifestations
Nervous System Diseases
Brain Damage, Chronic
Brain Diseases
Central Nervous System Diseases
Muscular Diseases
Musculoskeletal Diseases
Muscle Hypertonia
Neuromuscular Manifestations
Botulinum Toxins
Botulinum Toxins, Type A
abobotulinumtoxinA
incobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents