Study to Compare the Efficacy and Safety of NT 201 (Botulinum Toxin) With Placebo for the Treatment of Lower Limb Spasticity Caused by Stroke or Traumatic Brain Injury

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a single treatment with administration of 400 Units NT 201 (botulinum toxin) is superior to placebo (no medicine) for the treatment of lower limb spasticity caused by stroke or traumatic brain injury (Main Period). Participants will be assigned to the treatment groups by chance and neither the participants nor the research staff who interact with them will know the allocation. The following 4 to 5 treatment cycles will investigate the safety and tolerability of treatment with NT 201 (botulinum toxin) when administered in doses between 400 and 800 Units (Open Label Extension Period). All participants will receive the treatment and the dose will depend on whether only lower limb spasticity or combined upper and lower limb spasticity are treated.

Official Title
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Prospective, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Investigate the Efficacy and Safety of NT 201 in the Treatment of Lower Limb Spasticity Caused by Stroke or Traumatic Brain Injury in Adult Subjects, Followed by an Open Label Extension With or Without Combined Upper Limb Treatment

Conditions
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Lower Limb or Combined Lower Limb and Upper Limb Spasticity Due to Stroke or Traumatic Brain Injury

Intervention / Treatment
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* Drug: NT 201
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male subject ≥ 18 years and ≤ 85 years at screening Diagnosis of lower limb spasticity with or without upper limb spasticity of the same body side caused by stroke or traumatic brain injury Disabling ankle flexor spasticity presenting as pes equinus or pes equinovarus Modified Ashworth Scale-Bohannon [MAS] score of 2 or 3 points in the ankle plantar flexor of the target lower limb (supine position, knee extended) Minimum passive range of motion in ankle of the target lower limb (supine position, knee extended): 10°dorsiflexion and 20°plantarflexion At least 4 months since last botulinum neurotoxin [BoNT] injection for treatment of spasticity or any other condition For subjects receiving anticoagulation therapy, the investigator confirms and documents that the subject has an: Activated partial thromboplastin time [aPTT] ≤ 80 seconds (subjects on dabigatran or other direct thrombin inhibitors) or International normalized ratio [INR] value of ≤ 2.5 (subjects on coumarins or other anticoagulants monitored by INR) Exclusion Criteria: Generalized disorders of muscle activity (e.g. myasthenia gravis, Lambert Eaton syndrome, amyotrophic lateral sclerosis) or any other significant peripheral neuromuscular dysfunction which might interfere with the study Bilateral lower limb paresis/paralysis/spasticity or tetraparesis/paralysis/spasticity Body weight < 50 kg Severe atrophy of the target limb muscles Previous, ongoing or planned treatments of spasticity with intrathecal baclofen Previous, ongoing, or planned treatments of spasticity in the target lower limb with any of the following procedures: Surgical Intervention; Alcohol or phenol block; Muscle afferent block Physiotherapy or use of orthoses or splints at the target limb initiated less than 4 weeks before screening or expected to change during the double blind phase of the study Current or planned treatment with parenterally administered drugs that interfere with neuromuscular transmission (e.g. intrathecal baclofen, tubocurarine type muscle relaxants used in anesthesia), or local anesthetics in the treated region within 2 weeks prior to screening Infection or inflammation at the injection sites Subjects with presence or history of aspiration pneumonia, recurrent lower respiratory tract infections, or compromised respiratory function as per investigator's clinical judgment Pregnancy (as verified by a positive pregnancy test) or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NT 201 (IncobotulinumtoxinA, Xeomin)<br>Main Period (1 treatment cycle): subjects to receive intramuscular injection of NT 201 (400 units) into muscles of the lower limb. Open Label Extension Period (4-5 treatment cycles): subjects to receive intramuscular injection of NT 201 (up to 800 units) into muscles of the lower limb and upper limb, if indicated. | Drug: NT 201<br>* 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).<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Placebo Comparator: Placebo<br>Main Period (1 treatment cycle): subjects to receive intramuscular placebo injection into muscles of the lower limb. Open Label Extension Period (4-5 treatment cycles): subjects to receive intramuscular injection of NT 201 (up to 800 units) into muscles of the lower limb and upper limb, if indicated. | Drug: NT 201<br>* 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).<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;Drug: Placebo<br>* Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in derived Modified Ashworth Scale-Bohannon (MAS) ankle score (knee extended) at weeks 4 to 6 | The MAS is a 6-grade scale | Baseline to week 4-6 | 
| Co-Primary: Global Impression of Change Scale (GICS) assessed by physician at Week 4 to 6 | The GICS s a 9-grade scale | Week 4-6 | 
| Occurrence of treatment emergent adverse events [TEAEs] in the Main Period |  | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Study Baseline in Goal Attainment Scale [GAS] at Week 6 | The GAS is a 6-grade scale | Baseline to week 6 | 
| Global Impression of Change Scale (GICS) assessed by the study subject at Week 4 to 6 | The GICS s a 9-grade scale | Week 4-6 | 
| Global Impression of Change Scale (GICS) assessed by the caregiver at Week 4 to 6 | The GICS s a 9-grade scale | Week 4-6 |