Efficacy and Safety Study of Botulinum Neurotoxin A With Rehabilitation Versus Botulinum Neurotoxin A Alone in Treatment of Post-stroke Spasticity

The purpose of this study is to determine if a combination of botulinum neurotoxin A and rehabilitation therapy is better than botulinum neurotoxin A alone for improvement in function based on the Fugl-Meyer and other validated measures.

Hypothesis: The combination of botulinum neurotoxin A and rehabilitation therapy will produce better functional improvement than botulinum neurotoxin A alone in post-stroke upper limb spasticity measured by the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke.

This trial is a multi-center, parallel design comparing open label BoNT-A paired with rehabilitation therapy (OT) versus BoNT-A alone in patients diagnosed with post-stroke focal upper limb spasticity. Cohort 1 will receive BoNT-A plus rehabilitation therapy for the duration of the study (for up to 2 injections of BoNT-A) while Cohort 2 will receive BoNT-A alone. The injection protocol will closely follow the design of the Allergan 191622-056 study with the inclusion of rehabilitation therapy intervention. Those randomized to BoNT-A alone will not be able to start any new therapy or exercise therapy while in the study. Two types of patients will be recruited for the study, those naïve to BoNT-A and those who have received BoNT-A for treatment of their spasticity. Given that BoNT-A has temporary effects, the second group of patients is not expected to react differently that patients naïve to the intervention. The sites will contact patients previously enrolled in the 191622-008, 025 and 056 protocols to determine if they are eligible for involvement in the BoNT-A / rehabilitation study. In addition, the sites will recruit from the local community patients who have and have not received BoNT-A treatment for their spasticity by placing a notice in the stroke club newsletters, contacting local physician and rehabilitation offices, and posting fliers in area hospitals. Patients will be screened for eligibility during an interview with a study team member. Eligible patients will complete the informed consent process, sign a consent form, HIPPA. A blinded study physician will perform a physical examination and focal exam of the affected limb obtaining Modified Ashworth Scale scores for the elbow, wrist, finger, and thumb. Following the baseline visit, appointments will be scheduled for the next visit (Study Visit 1 {Week 0}, injection of BoNT-A. Prior to injection,, patients will be evaluated by a Therapist, blinded to treatment who will do the Functional Independence Measure (FIM) and the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke (Upper Extremity subsection). Participants will receive IM injections of BoNT-A between 200 and 400 Units with the total dose not to exceed 6 U / kg. The primary targets for BoNT-A injection are the wrist and finger flexor muscles (flexor carpi radialis, flexor carpi ulnaris, flexor digitorum profundus, flexor digitorum superficialis). Additional target muscles include biceps, brachioradialis, brachialis, pronator quadratus, pronator teres, flexor pollicis brevis / opponens, adductor pollicis, flexor pollicis longus, and lumbricales / interossei. The goal of the injections is to reduce spasticity causing such events as flexed elbow, pronated forearm, flexed wrist, thumb in palm, clenched fist, and hand deformity. It is not necessary to administer the same dose or inject the same muscles at each injection visit. The treatment should be guided by the spasticity measured and the clinical judgment of the Investigator. All injections will be performed with the assistance of EMG guidance for muscle localization. Randomization to either BoNT-A + rehab or BoNT-A alone will occur after the first injection. Randomization schedule will be determined by sequential lettered sealed envelopes sent to each site, generated by the independent analyst.

Participants assigned to Cohort 1 (determined by a randomization scheme) will also be scheduled for weekly therapy appointments to begin within 2 weeks of injection. An attempt will be made to have all study patients seen by the same therapists at each site and efforts will be made to standardize therapy as much as possible. The evaluating therapist who is blinded to treatment assignment will complete the Fugl-Meyer upper extremity subsection every 6 weeks and the FIM at week 1 and at the final visit. Participants will be seen every 6 weeks by the coordinator and physician for Study Visits 2, 3/3A, 4, and 5 at which time they will have the following assessments: Modified Ashworth Scale (MAS), , Patients' Disability and Carer Burden Rating Scale, Visual Analog Scale and the Disability Assessment Scale. The participants in Cohort 2 will follow the same injection and assessment schedule (including Fugl-Meyer upper extremity subsection every 6 weeks and FIM at week 1 and at the final visit), but will not participate in therapy. If, by visit 3, the participants' upper limb spasticity has reached a MAS score of 2 or greater in the wrist and/or fingers, they will be eligible for a second injection of BoNT-A. Any subjects who do not meet re-injection criteria by Visit 3 (week 12) will be re-evaluated in another 3 weeks, Visit 3A. If participants do not meet re-injection criteria by Study Visit 3A (week 15) they will not receive another injection, but will be followed until Visit 5 (final visit). If subjects are injected at visit 3A, visit 4 will occur at 21 weeks (6 weeks after 2nd injection). Visit 5 will occur at week 27 (12 weeks after 2nd injection). Participants receiving both injections will complete the study no sooner than Study Visit 5. The expected time to recruit patients and complete the study is 18 months.

All participants will be queried at each visit regarding the occurrence of adverse events (AE) or serious adverse events (SAE). All unexpected AE and all SAEs will be reviewed by the Site Principal Investigator and reported to the local IRB and reported to Dr. Glenn Graham who will then report to the VA Research \& Development Committee and the University of New Mexico Health Science Center Human Research Review Committee. (See Appendix I for AE and SAE definitions). Study sites will be in regular contact with study participants whether or not they receive weekly therapy.

Eligibility Criteria:
Inclusion Criteria:

* Adults 18 years of age or older
* Stroke (ischemic or hemorrhagic) diagnosed by a neurologist at least 6 months prior to enrollment
* Focal spasticity in upper limb measured at the elbow, wrist, fingers and thumb with a Modified Ashworth Scale (MAS) of 3 or greater in the wrist and/or fingers
* Functional impairment secondary to spasticity such as difficulty with hygiene, dressing, posture or pain
* Minimum weight of 44 kg (88 lbs) in order to tolerate the minimum required dosage of 200 U
* Written informed consent has been obtained
* Written authorization for Use and Release of Health and Research Study Information has been obtained
* Laboratory findings required (if applicable)
* Ability to follow study instructions and likely to complete all required visits
* Negative urine pregnancy test on the day of treatment prior to the administration of study medication (for females of childbearing potential). (If applicable.)

Exclusion Criteria:

* Uncontrolled clinically significant medical condition other than the condition under evaluation
* Known allergy or sensitivity to any of the components in the study medication
* Females who are pregnant, breast-feeding, or planning a pregnancy during the study or who think that they may be pregnant at the start of the study, or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study
* Concurrent participation in another investigational drug or device study or participation in the 30 days immediately prior to study enrollment
* Fixed contracture or profound atrophy in the spastic limb
* Prior or current treatment with neurolytic agents such as phenol or surgery; any version of botulinum toxin (other than BoNT-A more than 6 months prior to enrollment)
* Current rehabilitation therapy that cannot be altered to the treatment plan in the study
* Unable or unwilling to participate in a weekly rehab program
* Any medical condition that may put the subject at increased risk with exposure to BOTOX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disorder that might interfere with neuromuscular function
* Current treatment with agents affecting neuromuscular transmission
* Evidence of recent alcohol or drug abuse
* Infection or skin disorder at an anticipated injection site (if applicable)
* Any condition or situation that, in the investigator's opinion, may put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study