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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. Male or female ≥18 to maximum of 80 years of age, inclusive.
3. 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.
4. Ambulatory (with or without the use of a walking assistive device).
5. Modified Ashworth Scale (MAS) score ≥2 in the ankle plantar flexors of the affected lower limb at screening and at baseline.
6. 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.
7. 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:

1. Quadriplegia/tetraplegia, lower limb diplegia or triplegia.
2. Uncontrolled epilepsy or any type of seizure disorder with a seizure(s) within the previous year.
3. Neuromuscular disorders including, but not limited to, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), multiple sclerosis (MS), myasthenia gravis, or muscular dystrophy.
4. 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.
5. Unresolved fracture(s) in the affected lower limb.
6. Severe atrophy in the affected lower limb.
7. Known hypersensitivity to botulinum toxins type A or B or to any MYOBLOC solution components.
8. 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.
9. Treatment with a neurolytic agent (e.g., phenol, alcohol blocks) to the affected lower limb within 1 year before randomization.
10. Presence of a spinal stimulator or intrathecal baclofen pump that has not been turned off within 30 days before screening.
11. Changes to treatment regimen or any new treatment with oral antispasmodics and/or muscle relaxants within 30 days before randomization.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. Prior surgery to treat spasticity in the affected lower limb (i.e., tendon lengthening or tendon transfer).
18. 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.
19. Major surgery within 3 months before screening.
20. Pregnancy or breastfeeding.
21. 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).
22. History of drug or alcohol abuse within 6 months before screening.
23. Obstructive pulmonary disease with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \<70%.
24. Slow vital capacity (SVC) \<60% of predicted.
25. Chronic or current use of inhaled corticosteroids.
26. 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.
27. Infection at the planned sites of injection.
28. Treatment with an investigational drug, device, or biological agent within 30 days before screening or while participating in this study.
29. Malignancy diagnosed 3 months before screening.
30. 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.
31. 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.
32. 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.