Efficacy and Safety Study of MYOBLOC® in the Treatment of Adult Lower Limb Spasticity

Study Overview
=================
Brief Summary
-----------------
Phase 2/3, randomized, double-blind, placebo-controlled, single-treatment, multicenter trial assessing the efficacy and safety of MYOBLOC for the treatment of lower limb spasticity, in adults followed by an open-label extension safety trial.

Detailed Description
-----------------
Phase 2, randomized, double-blind, placebo-controlled, single-treatment, multicenter trial will compare the efficacy and safety of two doses of MYOBLOC versus volume-matched placebo in the treatment of lower limb spasticity in adults. An interim analysis will evaluate all available safety and efficacy data from the Phase 2 double-blind trial in order to recommend which dose will be evaluated in subsequent Phase 3 trial. The Phase 3, randomized, double-blind, placebo-controlled, single-treatment, multicenter trial will compare the efficacy and safety of MYOBLOC versus placebo in the treatment of lower limb spasticity in adults. Subjects who complete either the Phase 2 or Phase 3 trial will continue into an open-label extension where each will receive 5 separate MYOBLOC treatments ( 13 week apart) for lower limb spasticity.

Official Title
-----------------
A Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Treatment Efficacy and Safety Study of MYOBLOC® in the Treatment of Adult Lower Limb Spasticity

Conditions
-----------------
Spasticity

Intervention / Treatment
-----------------
* Drug: Phase 2; Low Dose MYOBLOC
* Drug: Phase 2; High Dose MYOBLOC
* Drug: Phase 2; Placebo
* Drug: Phase 3; MYOBLOC
* Drug: Phase 3; Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to understand the potential risks and benefits, the study requirements, and provide written informed consent before enrollment into the study; or if unable, the subject's Legally Authorized Representative (LAR) may provide written informed consent. Male or female ≥18 to maximum of 80 years of age, inclusive. Lower limb spasticity due to stroke, traumatic brain injury, or spinal cord injury that occurred ≥6 months prior to randomization. Eligible subjects may have lower limb monoplegia or hemiplegia. Subjects with cerebral palsy are eligible for study enrollment. Ambulatory (with or without the use of a walking assistive device). Modified Ashworth Scale (MAS) score ≥2 in the ankle plantar flexors of the affected lower limb at screening and at baseline. In the Investigator's opinion, the subject will be available and able to comply with the study requirements for at least 1 year, based on the subject's overall health and disease prognosis. In the Investigator's opinion, the subject will be willing and able to comply with all requirements of the protocol, including completion of study questionnaires. A caregiver may be designated to assist with the physical completion of questionnaires/scales. Exclusion Criteria: Quadriplegia/tetraplegia, lower limb diplegia or triplegia. Uncontrolled epilepsy or any type of seizure disorder with a seizure(s) within the previous year. Neuromuscular disorders including, but not limited to, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), multiple sclerosis (MS), myasthenia gravis, or muscular dystrophy. History of major joint contracture(s), in which, based on the Investigator's assessment, the contracture(s) significantly contribute(s) to joint immobility in the affected lower limb. Unresolved fracture(s) in the affected lower limb. Severe atrophy in the affected lower limb. Known hypersensitivity to botulinum toxins type A or B or to any MYOBLOC solution components. Concomitant use or exposure within 5 half-lives of randomization of the following: aminoglycoside antibiotics, curare-like agents, or other agents that may interfere with neuromuscular function. Treatment with a neurolytic agent (e.g., phenol, alcohol blocks) to the affected lower limb within 1 year before randomization. Presence of a spinal stimulator or intrathecal baclofen pump that has not been turned off within 30 days before screening. Changes to treatment regimen or any new treatment with oral antispasmodics and/or muscle relaxants within 30 days before randomization. Initiation of physical and/or occupational therapy <30 days before randomization. Subjects receiving physical and/or occupational therapy ≥30 days before randomization must be willing to maintain their therapy regimen through Week 4 of the DBP. Application of an ankle-foot orthosis (AFO) <30 days before randomization. Subjects regularly using an AFO ≥30 days before randomization must be willing to maintain use of the AFO through Week 4 of the Double-Blind Period. Prior botulinum toxin type A (BoNT/A) or B (BoNT/B) treatment in the affected lower limb within 24 weeks before screening. Prior BoNT/A or BoNT/B treatment in areas other than the affected lower limb is not exclusionary but must have occurred at least 12 weeks before screening. Prior toxin exposure must have been well tolerated and without any significant long-term side effects in the case of repeated prior exposure. Subjects should not receive nor have any plans to receive any botulinum toxin treatment, other than the study drug (MYOBLOC), from the point informed consent is obtained until participation in the study is complete. Severe dysphagia (i.e., inability to swallow liquids, solids or both without choking or medical intervention), or dysphagia with a history of aspiration pneumonia, within 6 months before screening. Prior surgery to treat spasticity in the affected lower limb (i.e., tendon lengthening or tendon transfer). Any anticipated or scheduled surgery during the study period, with the exception of dermatological procedures performed under local anesthesia for the purposes of removing precancerous and cancerous lesions. Major surgery within 3 months before screening. Pregnancy or breastfeeding. Females of childbearing potential must agree to practice a medically acceptable method of contraception (e.g., intrauterine device, hormonal contraception started at least one full cycle before study enrollment or barrier method in conjunction with spermicide) for the duration of the study (including 2 months after study completion). For the purposes of this study, all females are considered to be of childbearing potential unless they are confirmed by the Investigator to be post-menopausal (at least 1 year since last menses and laboratory test confirmation), biologically sterile, or surgically sterile (e.g., hysterectomy with bilateral oophorectomy, tubal ligation). History of drug or alcohol abuse within 6 months before screening. Obstructive pulmonary disease with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <70%. Slow vital capacity (SVC) <60% of predicted. Chronic or current use of inhaled corticosteroids. Ventilator dependence (i.e., 24-hour ventilator dependence when intubated, or due to a failure to wean the subject from the ventilator while hospitalized in the intensive care unit or respiratory care center). Subjects who use oxygen on an as-needed basis or during sleeping hours only via a nasal cannula are eligible for the study. Infection at the planned sites of injection. Treatment with an investigational drug, device, or biological agent within 30 days before screening or while participating in this study. Malignancy diagnosed 3 months before screening. Has one or more screening clinical laboratory test values outside the reference range that, in the opinion of the Investigator, are clinically significant, or any of the following : Serum creatinine >1.5 times the upper limit of normal (ULN); Serum total bilirubin > 1.5 times ULN; Serum alanine aminotransferase or aspartate aminotransferase >2 times ULN. Has any of the following cardiology findings at screening: Abnormal ECG that is, in the Investigator's opinion/evaluation, clinically significant; PR interval >220 ms; QRS interval >130 ms; QTcF interval >450 ms (for men), or >470 ms (for women) (QT corrected using Fridericia's method); Second-or third-degree atrioventricular block; Any rhythm, other than sinus rhythm, that is interpreted or assessed by the Investigator to be clinically significant. Any other medical illness, condition, or clinical finding that, in the opinion of the Investigator and/or the Sponsor, would put the subject at undue risk.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2; Low Dose MYOBLOC<br>Low Dose MYOBLOC is a single treatment and will be compared to volume-matched placebo | Drug: Phase 2; Low Dose MYOBLOC<br>* Intramuscular injections on Day 1<br>* Other names: botulinum toxin type B;|
| Experimental: Phase 2; High Dose MYOBLOC<br>High Dose MYOBLOC is a single treatment and will be compared to volume-matched placebo | Drug: Phase 2; High Dose MYOBLOC<br>* Intramuscular injections on Day 1<br>* Other names: botulinum toxin type B;|
| Placebo Comparator: Phase 2; Placebo<br>Volume-matched placebo is a single treatment | Drug: Phase 2; Placebo<br>* Intramuscular injections on Day 1<br>* Other names: PBO;|
| Experimental: Phase 3; MYOBLOC<br>MYOBLOC is a single treatment and will be compared to volume-matched placebo | Drug: Phase 3; MYOBLOC<br>* Intramuscular injections on Day 1<br>* Other names: botulinum toxin type B;|
| Placebo Comparator: Phase 3; Placebo<br>Volume-matched placebo is a single treatment | Drug: Phase 3; Placebo<br>* Intramuscular injections on Day 1<br>* Other names: PBO;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of MYOBLOC on the Modified Ashworth Scale (MAS) for Tone of the Ankle Plantar Flexors [Phase 2 and Phase 3] | The first co-primary endpoint is the change from baseline in the Modified Ashworth Scale (MAS) score in the tone of the ankle plantar flexors at Week 4 post-injection. The MAS is an internationally accepted and validated instrument used to measure resistance during passive soft-tissue stretching. Resistance will be measured and recorded using a 6-point scale ranging from 0 (no increase in muscle tone) to 4 (affected part[s] rigid in flexion or extension). A lower change from baseline MAS score (<0) represents a better outcome. | Baseline and Week 4 | 
| The Effect of MYOBLOC on Clinical Global Impression of Change (CGI-C) in functional ability [Phase 2 and Phase 3] | The second co-primary endpoint is the Clinical Global Impression of Change (CGI-C) score in functional ability at Week 4 post-injection. The CGI-C scale is a single item clinician assessment of how much the patient's functional ability has improved, worsened or has not changed relative to the patient's baseline state prior to treatment (injection). The CGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of MYOBLOC on the Patient Global Impression of Change (PGI-C) [Phase 2 and Phase 3] | An additional secondary endpoint is the Patient Global Impression of Change (PGI-C) score at Week 4 post-injection. The PGI-C scale is a single item patient reported (self) assessment of how much his/her ability to function has improved, worsened or has not changed relative to his/her baseline state prior to treatment (injection). The PGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Baseline and Week 4 | 
| Effect of MYOBLOC on the Caregiver Global Impression of Change (GGI-C) [Phase 2 and Phase 3] | An additional secondary endpoint is the Caregiver Global Impression of Change (GGI-C) score at Week 4 post-injection. The GGI-C scale is a single item caregiver assessment on how much the patient's ability to function has improved, worsened or has not changed relative to the patient's baseline state prior to treatment (injection). The GGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Week 4 | 
| Effect of MYOBLOC on the Numeric Rating Scale of Pain (Pain-NRS) [Phase 2 and Phase 3] | An additional secondary endpoint is the change from baseline in the Pain Numeric Rating Scale (Pain-NRS) score at Week 4 post-injection. The Pain-NRS is a unidimensional measure of pain intensity in adults. It is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The common format is a horizontal bar or line. Similar to the VAS, the Pain-NRS is anchored by terms describing pain severity extreme on 11-point scale ranging from 0 (no pain) to 10 (worse pain imaginable). A lower change from baseline Pain-NRS score (<0) represents a better outcome | Baseline and Week 4 | 
| Effect of MYOBLOC on the Walking Impairment Questionnaire (WIQ) [Phase 2 and Phase 3] | An additional secondary endpoint is the change from baseline (CFB) Walking Impairment Questionnaire (WIQ) percent scores at Week 4 post-injection. The WIQ is a 14-item survey of a patient's self-perceived walking distance (20, 50, 150, 300, 600, 900, 1500 feet), walking speed (1.5, 2, 3, 5 mph), and stair-climbing ability (12, 24, 36 stairs). Each item is rated on a 5-point Likert scale by degree of physical difficulty; where 0=unable, 1=much, 2=some, 3=slight, 4= none. A percent maximal score (0-100%) for walking distance, walking speed, and stair-climbing is derived by dividing the sum of each rating multiplied by its respective distance, speed or number of stairs by the maximal score (14080, 46 or 288, respectively) multiplied by 100. A higher percent score represents less impairment. A higher change from baseline percent score (>0%) represents a better outcome. | Baseline and Week 4 | 
| Effect of MYOBLOC on Walking and Resting Comfort Scale (WRCS) [Phase 2 and Phase 3] | An additional secondary endpoint is change from baseline Walking and Resting Comfort Scale (WRCS) score at Week 4 post-injection. WRCS is a 5-item self-report assessment of patients degree of comfort he/she experiences when walking (with and without ankle-foot orthosis and with waking device) or at rest (with and without ankle-foot orthosis). Each item is rated on a 5-point scale ranging from 1=very comfortable to 5=very uncomfortable. A higher change from baseline WRCS score (>0) represents a better outcome. | Baseline and Week 4 | 
| Effect of MYOBLOC on Modified Ashworth Scale (MAS) Responder Rate Tone of the Ankle Plantar Flexors [Phase 2 and Phase 3] | An additional secondary endpoint is the Modified Ashworth Scale (MAS) Responder Rate for MAS score in the ankle plantar flexors at Week 4 post-injection. The MAS is an internationally accepted and validated instrument used to measure resistance during passive soft-tissue stretching. Resistance will be measured and recorded using a 6 point scale ranging from 0 (no increase in muscle tone) to 4 (affected part[s] rigid in flexion or extension). The MAS responder rate is defined as the percent of subjects with ≥1 grade reduction in their change from baseline MAS score at Week 4. Values range from 0 to 100%. A higher percentage represents a greater number of responders. | Baseline and Week 4 | 
| The Effect of MYOBLOC on the Modified Ashworth Scale (MAS) for Tone of the Ankle Plantar Flexors [Phase 2 and Phase 3] | An additional secondary endpoint is the change from baseline in the Modified Ashworth Scale (MAS) score in the tone of the ankle plantar flexors at Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. The MAS is an internationally accepted and validated instrument used to measure resistance during passive soft-tissue stretching. Resistance will be measured and recorded using a 6-point scale ranging from 0 (no increase in muscle tone) to 4 (affected part[s] rigid in flexion or extension). A lower change from baseline MAS score (<0) represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| The Effect of MYOBLOC on Clinical Global Impression of Change (CGI-C) in functional ability [Phase 2 and Phase 3] | An additional secondary endpoint is the Clinical Global Impression of Change (CGI-C) score in functional ability at Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. The CGI-C scale is a single item clinician assessment of how much the patient's functional ability has improved, worsened or has not changed relative to the patient's baseline state prior to treatment (injection). The CGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Weeks 2, 8, and13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Clinical Global Impression of Severity (CGI-S) [Phase 2 and Phase 3] | An additional secondary efficacy endpoint is the change From baseline in the Clinical Global Impression of Severity (CGI-S) score at Weeks 2, 4, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. The CGI-S is a single item clinician assessment of the severity of impairment the patient's spasticity has on his or her ability to function based on the clinician's total clinical experience with patients with upper limb spasticity. The CGI-S is rated on a 7-point Likert scale from 1 to 7, where 1=normal; 2=borderline impaired; 3=mildly impaired; 4=moderately impaired; 5=markedly impaired; 6=severely impaired; 7=among the most extremely impaired. A change from baseline CGI-S score <0 represents a better outcome. | Baseline and Weeks 2, 4, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Patient Global Impression of Change (PGI-C) [Phase 2 and Phase 3] | An additional secondary endpoint is the Patient Global Impression of Change (PGI-C) score at Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. The PGI-C scale is a single item patient reported (self) assessment of how much his/her ability to function has improved, worsened or has not changed relative to his/her baseline state prior to treatment (injection). The PGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Weeks 2, 8, 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Patient Global Impression of Severity (PGI-S) [Phase 2 and Phase 3] | An additional secondary efficacy endpoint is the change from baseline in the Patient Global Impression of Severity (PGI-S) score at Weeks 2, 8, 13 (and, if applicable, at re-evaluation visit) post-injection. The PGI-S is a single item patient reported (self) assessment of his/her severity of impairment their spasticity has on his or her ability to function. The PGI-S is rated on a 7-point Likert scale from 1 to 7, where 1=normal; 2=borderline impaired; 3=mildly impaired; 4=moderately impaired; 5=markedly impaired; 6=severely impaired; 7=among the most extremely impaired. A change from baseline PGI-S score <0 represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Caregiver Global Impression of Change (GGI-C) [Phase 2 and Phase 3] | An additional secondary endpoint is the Caregiver Global Impression of Change (GGI-C) score at Weeks 2, 8 and 13 (and, if applicable, at re-evaluation visit) post-injection. The GGI-C scale is a single item caregiver assessment on how much the patient's ability to function has improved, worsened or has not changed relative to the patient's baseline state prior to treatment (injection). The GGI-C is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (<4) in subsequent testing. | Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Caregiver Global Impression of Severity (GGI-S) [Phase 2 and Phase 3] | An additional secondary efficacy endpoint is the change from baseline in the Caregiver Global Impression of Severity (GGI-S) score at Weeks 2, 8 and 13 (and, if applicable, at re-evaluation visit) post-injection. The GGI-S is a single item caregiver assessment of the severity of impairment the patient's spasticity has on his or her ability to function. The GGI-S is rated on a 7-point Likert scale from 1 to 7, where 1=normal; 2=borderline impaired; 3=mildly impaired; 4=moderately impaired; 5=markedly impaired; 6=severely impaired; 7=among the most extremely impaired. A change from baseline GGI-S score <0 represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Pain Numeric Rating Scale (Pain-NRS) [Phase 2 and Phase 3] | An additional secondary endpoint is change from baseline in the Pain Numeric Rating Scale (Pain-NRS) score at Weeks 2, 8 and 13 (and, if applicable, at re-evaluation visit) post-injection. The Pain-NRS is a unidimensional measure of pain intensity in adults. It is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The common format is a horizontal bar or line. Similar to the VAS, the Pain-NRS is anchored by terms describing pain severity extreme on 11-point scale ranging from 0 (no pain) to 10 (worse pain imaginable). A lower change from baseline Pain-NRS score (<0) represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on the Walking Impairment Questionnaire (WIQ) [Phase 2 and Phase 3] | The fifteenth secondary endpoint is the change from baseline (CFB) Walking Impairment Questionnaire (WIQ) percent scores at Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. The WIQ is a 14-item survey of a patient's self-perceived walking distance (20, 50, 150, 300, 600, 900, 1500 feet), walking speed (1.5, 2, 3, 5 mph), and stair-climbing ability (12, 24, 36 stairs). Each item is rated on a 5-point Likert scale by degree of physical difficulty; where 0=unable, 1=much, 2=some, 3=slight, 4= none. A percent maximal score (0-100%) for walking distance, walking speed, and stair-climbing is derived by dividing the sum of each rating multiplied by its respective distance, speed or number of stairs by the maximal score (14080, 46 or 288, respectively) multiplied by 100. A higher percent score represents less impairment. A higher change from baseline percent score (>0%) represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 
| Effect of MYOBLOC on Walking and Resting Comfort Scale (WRCS) [Phase 2 and Phase 3] | The sixteenth secondary endpoint is change from baseline Walking and Resting Comfort Scale (WRCS) score at Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) post-injection. WRCS is a 5-item self-report assessment of patients degree of comfort he/she experiences when walking (with and without ankle-foot orthosis and with waking device) or at rest (with and without ankle-foot orthosis). Each item is rated on a 5-point scale ranging from 1=very comfortable to 5=very uncomfortable. A higher change from baseline WRCS score (>0) represents a better outcome. | Baseline and Weeks 2, 8, and 13 (and, if applicable, at re-evaluation visit) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Traumatic Brain Injury (TBI), Monoplegia, Hemiplegia, Lower limb