Improving Holding Function of the Hemiplegic Hand With Chemodenervation
Conditions: Stroke
Sponsor: Nathaniel Mayer

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Improving Holding Function of the Hemiplegic Hand with Chemodenervation 
 
 
NCT02459951 
 
Date: 4-29-2016 
   

Improving Holding Function of the Hemiplegic Hand with Chemodenervation 
 
 
Specific Aims 
 
 
Inserting and holding an object in the hand is what we mean by ‘hand as a holder’ function. After a 
stroke, the hand typically lacks voluntary finger extension that opens the hand. Simultaneously, the hand 
is also subjected to involuntary contraction of finger flexor muscles that close the hand, resulting in 
clenched fist and thumb-in-palm deformities. Despite these typical hemiplegic configurations, persons 
with stroke may be able to insert an object into the hand by wiggling and pushing it into the hemiplegic 
hand with their uninvolved hand, though struggle is often present and failure is frequent. A main goal of 
this project is to demonstrate that ‘hand as a holder’ function can be improved by blocking overactive 
muscles with medication. The main measure of hand function improvement will be ‘transit time’ i.e. the 
time it takes for the uninvolved hand to insert an object into the hemiplegic clenched fist and hold it 
independently. 
 
This pilot study of 9 patients aims to demonstrate reliability and validity of a digital video method that 
will be used to measure ‘transit time’. It also aims to establish initial statistical support for improved 
object transit time into the hemiplegic clenched fist after Botox A injections. [Botox A, injected directly 
into offending muscles, is a neuromuscular blocking agent that was approved by the FDA in 2010 to treat 
spasticity, a form of involuntary muscle contraction, in finger and wrist flexor muscles of persons 
sustaining a hemiplegic stroke.] 
 
 
 
Experimental Design 
 
 
Study hypothesis: Given hemiplegic patients, of stroke etiology, with a neurally driven clenched fist, 
who may also have a thumb-in-palm and/or a flexed wrist and who have severely impaired voluntary 
finger and thumb extension, we hypothesize that ‘hand as a holder’ function will improve after 
chemodenervation of relevant finger, thumb and wrist muscles selected by clinical examination. 

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The study objective is a pilot demonstration of the clinical hunch that objects will be inserted for holding 
by the hemiplegic hand more quickly and easily after chemodenervation, and, in some cases, insertion of 
larger diameter objects will be achieved as well. 
 
Inclusion Criteria 
 
 
1. Participant (or legal guardian) has been informed of the study procedures, participant is willing to 
comply with the study protocol and written informed consent has been given. 
 
2. Age greater than 35 and less than 80 years. 
 
3. Participant has experienced a documented, anemic or hemorrhagic, unilateral (right or left) 
hemiplegic stroke 1 year or more prior to enrollment. 
 
4. While aphasia and hemianopsia are not absolute criteria for exclusion, a participant must be able 
to understand verbal and visual instructions and demonstration regarding task protocol. 
 
5. A ‘resting’ wrist angle 0 is an inclusion criterion. It will be measured as follows: The forearm of 
a participant will be placed on a foam wedge, allowing the wrist and hand to hang down over 
the front wall of the wedge. Wrist angle will be measured with a clinical goniometer. 
 
6. Spasticity is present in finger flexors and thumb coupled with marked voluntary paresis of finger 
extension (no finger has more than half range of active extension at any joint). By squeezing the 
examiner’s finger, participants will have demonstrated, at least, some detectable voluntary 
contraction of finger flexors. Participants may have a flexed wrist (typical). 
 
7. Impaired sensation is acceptable but participants must be aware that they are holding something, 
as tested clinically. 
 
8. Participants present with at least two finger flexors with an Ashworth score ≥ 3 
 
9. Participant will have moderate motor severity as defined by an upper limb Fugl-Meyer (14) motor 
scores between 21-50. 
 
10. Participant does not have joint capsule contractures as determined by clinical exam. 
 

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11. Participant may have tightness/shortening of extrinsic finger flexors but composite extension of 
wrist and fingers comes to at least neutral (i.e. fingers and wrist can be brought to neutral 
position simultaneously). 
 
Exclusion Criteria 
 
 
1. Profound sensory loss/absent touch sensation. 
 
2. Known hypersensitivity/allergy to Botox A. 
 
3. Acute illness or unresolved medical/psychiatric conditions at time of assessment. 
 
4. Participant is pregnant or breast-feeding. 
 
5. Participant had Botox injections   4 months previously. 
 
6. Clenched fist associated with tenodesis of an extended wrist i.e. resting position of wrist is > 0 
 
 
Project Design 
 
 
9 participants with spastic hemiparesis greater than 12 month’s duration will be studied using a repeated 
measures design. Two baseline sessions separated by at least 3 days will be conducted along with one 
 
post Botox treatment session, approximately 3 to 5 weeks later. [The peak response of Botox for 
spasticity has been reported as 4 weeks (1). Our clinical experience also confirms that four weeks is a 
reasonable time to expect a treatment effect. However, practical considerations such as participant 
 
schedules and transportation encourage us to target 4 weeks 7 days.] Each participant will use their uninvolved 
hand to insert cylinders with 5 graduated diameters into the receiving hemiplegic hand. The same scripted 
instructions will be used for all participants, including visual demonstration of cylinder insertion through the 
web space entrance of the hand. Cylinder diameters will range between 0.5 and 2.5 inches and will be 
approximately similar in weight and height. Each session will consist of 15 trials (5 cylinder diameter sizes 
times 3 insertions for each diameter → 15 trials, the order of diameter size being randomized). A 30 second 
trial duration will be allotted. Three synchronized Sony AS100VR recording cameras will provide side, front 
and top views, strategically placed to observe the “onset” time i.e. time of 

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initial object contact with the hemiplegic hand and the “offset” time i.e. the time the uninvolved hand lets 
go of the cylinder and the hemiplegic hand holds the cylinder independently. [The hemiplegic hand must 
visibly be holding the object independently for 5 seconds without being dropped or otherwise supported 
by contact with other parts of the body or the environment.] Using Final Cut Pro video software, 
playback of the synchronous views of the three cameras will be used by two independent coders to 
measure onset and offset times in order to calculate object transit time. Given that all insertions will be 
video recorded, it may be useful for coders to score qualitative aspects of performance when a participant 
doesn’t meet the 5-sec criterion of unsupported grasp. In addition, we are unaware of another measure of 
holding function that could be administered to test convergent validity, emphasizing one aspect of the 
novelty of this project’s work. 
 
One reason why this pilot is exploratory and small in number is to learn more about variability in the 
primary measure. In addition, we will note stability of task performance as well the presence of short-term 
practice effects that may materialize across baseline sessions. In order to be informative, treatment effect 
would have to be greater than short-term practice effects. Since persons with hemiparesis would not have 
prior experience with insertion of the specific objects used in this project, we plan to give participants two 
practice trials prior to the experimental ones in each of the three sessions. 
 
TREATMENT PLAN: Injection of Botox A will be done using customized dosing because participants 
typically present variable configurations reflecting the variability of underlying muscle involvement. 
Clinical assessment and judgment will be used to determine which muscles contribute to the hand 
deformities of a given participant. Therefore, we expect that any of the following muscles may be injected 
using the following typical ranges: 20-60 U into the flexor digitorum sublimis (up to 3 sites), 20-60 U into 
the flexor digitorum profundus (up to 3 sites), 10-40 U into the interossei (up to 4 sites), 20-40 U into 
flexor pollicis longus, 10-20 U into adductor pollicis, 10 U into flexor pollicis brevis, 40-70 U into flexor 
carpi radialis, 30-60 U into palmaris longus and 20-40 U into flexor carpi ulnaris. Maximum dose (if all 

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muscle were injected maximally) totals 400 U. Current clinical practice uses an upper limit of 600 U in 
adults. 
 
Data Analysis Plan 
 
 
Statistical Methods 
 
 
Utilizing Final Cut Pro software, two coders independently used three synchronized camera views to 
identify onset and offset times of cylinder insertion in order to calculate cylinder Transit Time (Offset 
Time minus Onset Time). During a practice period, coding rules were established and coder training 
practice was done with hemiparetic volunteers. A concordance correlation coefficient (CCC) [Lin LI. A 
concordance correlation coefficient to evaluate reproducibility. Biometrics 1989; 45:255-68] was 
computed as a measure of agreement between the two coders. Results indicated that the CCC for Onset 
Time was 0.961 (95% CI: 0.938, 0.996); the CCC for Offset Time was 0.998 (95% CI: 0.993, 0.999) and 
the CCC for Transit Times was 0.977 (95% CI: 0.945, 0.991). 
 
Statistical Methods 
 
 
Protocol 1: Analysis of Transit Time [time to insert a cylinder into the affected hand] 
 
 
The log-transformed Transit Times were analyzed using a linear mixed effects (LME) model with the 
fixed effects of cylinder diameter (0.5, 1, 1.5, 2, 2.5 inches), evaluation session (Pre 1, Pre 2 and Post 
Treatment) and their interaction. The random effects of subject and evaluation session were included to 
allow for correlation among repeated measures for the same participant. Though two statistical models 
were considered, the model reported here included Pre2 and Post-treatment Transit Times as repeated 
measures of response variable, and Pre1 Transit Times as a covariate in the model, using the average of 
the three cylinder insertion trials for each cylinder diameter and evaluation session. The residuals of the 
LME model were evaluated for consistency with the assumption of the normal distribution. 

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The data included 69 (17%) of trials with missing transit times meaning that a subject was not able to do 
the insertion. A linear mixed effects methodology is appropriate for modeling data with missing 
observations if the ‘misses’ (i.e. participant was unable to insert a cylinder into the affected hand within 
30 seconds) are ignorable or missing at random. For non-ignorable ‘misses’, it is required to specify the 
response mechanism (a probability model for missing indicator or non-response). A repeated measures 
logistic regression model was used to model the missing data indicator and investigate whether the 
‘misses’ depended on cylinder diameter, evaluation session or Transit Times observed at the first baseline 
session (Pre1). 
 
The data analysis was performed in SAS (SAS Institute Inc., Cary, NC, USA) and R (R Core Team 
(2016). R: A language and environment for statistical computing. R Foundation for Statistical 
Computing, Vienna, Austria. URL http://www.R-project.org/.) 
 
Protocol 2: The counts of successful holds (i.e. participants had to hold a given cylinder 
independently with the affected hand for 5 seconds) in 3 trials for each cylinder diameter were 
modeled using a repeated measures negative binomial model with the 3 trials as an exposure. 
 
The predictors of expected number of successful holds included the cylinder diameter and evaluation 
session (Pre-1 baseline session, Pre-2 baseline session, and Post-treatment). The interaction between 
cylinder diameter and evaluation session was also considered, but was not a significant predictor of mean 
successful holds. The model allowed for correlation among counts for multiple cylinder diameters and 
evaluation sessions for the same participant using an exchangeable correlation structure. Correlation 
among counts was estimated using the GEE approach (as implemented in SAS PROC GENMOD, SAS 
Institute Inc., Cary, NC, USA). 

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Primary Outcome Measure(s): 
 
 
1. Geometric Ratios of Log-transformed Transit Time [Time Frame: transit times were measured 
at Pre-injection session 2 and Post-injection session] 
 
Secondary Outcome Measure(s): 
 
 
2. Incidence Rate of Successful Holds [Time Frame: evaluation sessions Pre1, Pre2, and Post] 
 
 
3. Incidence Ratio of Successful Holds [Time Frame: evaluation sessions pre1, pre2, and post] 
 
 
4. Modified Ashworth Scores (MAS) for injected muscles [Time Frame: evaluation sessions Pre1, 
Pre2, and Post]; [MAS are obtained to verify that a biological effect of neurotoxin is, indeed, present] . 
 
Subject Recruitment Plan: The MCAL treats over 400 patients a year and clenched fist problems occur 
in 20%. We anticipate no difficulty in obtaining 9 participants for this pilot study.