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

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.