Clinical trial NCT02903823
Conditions: Muscle Spasticity
Keywords: spinal cord injury cerebral palsy stroke
Sponsor: Vanderbilt University
Start date: 2016-04-22; Completion date: 2019-02-01
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this pilot study to determine whether there is a significant therapeutic advantage to place the ITB catheter within the cervical, thoracic or lumbar region of the spine. It is also a goal of this pilot study to determine whether the origin of spasticity influences the effect of Lioresal Intrathecal (baclofen injection) on ITB catheters located in the cervical, thoracic or lumbar regions of the spine. The investigators propose to study the impact of catheter location on the reduction in spasticity within a group of patients who are scheduled for ITB trial.

Detailed description:
While ITB therapy is commonly recommended for treatment of severe spasticity due to a variety of diseases, the location of optimal drug (baclofen) delivery has not been defined in a controlled study. Furthermore, the cost of pharmacological management in these patients is significant, and optimal location for drug delivery through an implantable drug pump may have significant impact on the cost burden of maintenance refills. It is the goal of this pilot study to determine whether there is a significant therapeutic advantage to place the ITB catheter within the cervical, thoracic or lumbar region of the spine. It is also a goal of this pilot study to determine whether the origin of spasticity influences the effect of Lioresal Intrathecal (baclofen injection) on ITB catheters located in the cervical, thoracic or lumbar regions of the spine. The investigators propose to study the impact of catheter location on the reduction in spasticity within a group of patients who are scheduled for ITB trial. In studying the impact of catheter location among patients with spinal versus cerebral origin of spasticity, the disease origin may also have a significant impact on baclofen dosing relative to the placement of the catheter.

In addition, the pharmacokinetic half-life and the variability of intrathecal baclofen is poorly understood as data is limited. In order to provide initial data regarding CSF baclofen washout, samples of spinal fluid obtained just prior to- and following IT baclofen administration will be obtained for delayed analysis. The results of these pharmacological analysis may refine the understanding of how quickly baclofen is distributed from a given catheter location, and whether it is affected by catheter location or disease origin. Since multiple catheter locations will be studied within a given patient, it also affords the opportunity to sample small amounts of CSF at key anatomical sites along the spinal axis as a secondary objective.

Arms: arm 1: Days 2,3,4,5 a baclofen injection bolus will be given in the catheter, located at C4, T4, T10 and L2 respectively. Effect of baclofen injection (50 microgram bolus) upon rigidity will be assessed manually using the Modified Ashworth rating score for selected upper and lower extremities.
Interventions: intervention 1: Baclofen bolus injection
Intervention descriptions: intervention 1: A baclofen bolus injection (50 micrograms) will be administered daily after the patient returns from radiology to position catheter injection location. The injection may be given at C4, T4, T10 or L2 spinal locations depending on the catheter tip location.

Protocol documents:
Prot_SAP_000.pdf: 
ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
IT Baclofen Drug Distribution Pilot Study: Proposal to Medtronic 
Goal:  
While ITB therapy is commonly recommended for treatment of severe spasticity due to a variety of 
diseases, the location of optimal drug (baclofen) delivery has not been defined in a controlled study. 
Furthermore, the cost of pharmacological management in these patients is significant, and optimal 
location for drug delivery through an implantable drug pump may have significant impact on the cost 
burden of maintenance refills. It is the goal of this pilot study to determine whether there is a significant 
therapeutic advantage to place the ITB catheter within the cervical, thoracic or lumbar region of the spine. 
It is also a goal of this pilot study to determine whether the origin of spasticity influences the effect of 
Lioresal Intrathecal (baclofen injection) on ITB catheters located in the cervical, thoracic or lumbar 
regions of the spine. We propose to study the impact of catheter location on the reduction in spasticity 
within a group of patients who are scheduled for ITB trial. Furthermore, we intend to enroll patients 
whose spasticity originates from two different mechanisms (SCI causing spastic paraplegia vs. cerebral 
palsy causing spastic spasticity of spinal and cerebral origin. In studying the impact of catheter location 
among patients with spinal versus cerebral origin of spasticity, the disease origin may also have a 
significant impact on baclofen dosing relative to the placement of the catheter. 
In addition, the pharmacokinetic half-life and the variability of intrathecal baclofen is poorly understood 
as data is limited. In order to provide initial data regarding CSF baclofen washout, samples of spinal fluid 
obtained just prior to- and following IT baclofen administration will be obtained for delayed analysis. The 
results of these pharmacological analysis may refine the understanding of how quickly baclofen is 
distributed from a given catheter location, and whether it is affected by catheter location or disease origin. 
Since multiple catheter locations will be studied within a given patient, it also affords the opportunity to 
sample small amounts of CSF at key anatomical sites along the spinal axis as an independent secondary 
study protocol. 
Hypotheses: 
 
Ho1: There is no significant (p> 0.05) difference in clinical spasticity (as measured by using the 
Modified Ashworth Spasm Rating Score) when the same amount of baclofen is delivered (50µg) 
to the cervical, thoracic, or lumbar area on separate days. 
 
Ho2: There is no significant (p>0.05) difference in the response to Lioresal Intrathecal (baclofen 
injection) between patients with spinal versus cerebral origin of spasticity relative to catheter tip 
placement. 
Specific Aims:  
1. Measure the degree of spasticity based on the Modified Ashworth Scale for Grading Spasticity in 
patients undergoing daily, single ITB bolus injections through an intrathecal catheter located in 
the mid-cervical (C4), mid-thoracic (T3), thoraco-lumbar (T10) and upper lumbar (L2) regions. 
2. Measure the Spasm Rating of patients undergoing daily, single ITB bolus injections through an 
intrathecal catheter located in the mid-cervical (C4), mid-thoracic (T3), thoraco-lumbar (T10) and 
upper lumbar (L2) regions. 


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
3. Sample CSF at each of the catheter tip locations just prior to ITB injection. Sample CSF at 1, 5, 
10, 20, 60 min following ITB administration.  
4. Each subject will receive prophylactic antibiotics for the duration of the IT catheter placement. 
Methods: 
Subjects who have spasticity and have consented for a trial of ITB therapy as part of a normal therapeutic 
evaluation, will be asked to enroll in this study. As a pilot study, we are interested in observing significant 
changes (p< 0.05) in either Ashworth Rigidity or Spasm scores related to catheter tip location along the 
spinal axis. Each subject will serve as their own control and will be assessed by the same rater throughout 
the study. The subjects will initially undergo temporary implantation of an intrathecal catheter placed 
under sedation or light anesthesia with fluoroscopic guidance. This will be done by the neurosurgeon with 
the intent of positioning the catheter initially in the mid-cervical region (C4) of the spine. The following 
day, after sedation / anesthetic effects are worn off, the subject will undergo a spasticity evaluation in the 
morning prior to ITB injection (See Tables 2 and 3 regarding Modified Ashworth and Spasm rating 
scores). Then a 50 microgram (µg) dose of IT baclofen will be injected into the CSF through the catheter. 
Samples of CSF (3cc) will be withdrawn from the IT catheter just prior to injection and at 10, 30, 60, 120, 
and 360 min following the ITB injection. The rater (Nurse Practitioner) will perform an Ashworth and 
Spasm rating exam on the subject at 2, 4, and 6 hours following the ITB injection. Each subject will be 
allowed to recover and observed overnight in the Clinical Research Center (CRC) at Vanderbilt 
University.  
The following morning, each subject will be brought to the radiology department fluoroscopy room and 
the IT catheter withdrawn to the next lower level being studied – viz. T3, T10, or L2. Catheter position 
prior to- and after repositioning will be documented on digital radiograph. The subjects will then be 
returned to the CRC area and dosed with IT baclofen (50 micrograms IT baclofen). The same protocol for 
assessing spasticity (Ashworth score) and spasms (Spasm rating) will be performed that day associated 
with the new catheter position. In other words, a spasticity assessment will be performed just prior to 
injection, and at 2 hour intervals following injection up to 6 hours after injection. Likewise, a CSF sample 
will be withdrawn just prior to injection, and at logarithmic intervals up to 6 hours following injection. 
Each CSF sample will be no more than 3 cc and must represent a clean sample of CSF from the subject. 
At the end of the fifth day of study, the IT catheter will be withdrawn and a stitch placed over the hole in 
the skin. The subject will be allowed to stay overnight for observation and then released the following 
morning. Implantation of the ITB pump will be determined as usual by the implanting neurosurgeon and 
his staff (note: The decision as to whether the subject or the clinical team decides to implant an ITB pump 
is outside the scope of this project, and would be considered part of their routine medical care following 
the trial of ITB). 
Selection of subjects. We will attempt to enroll ten subjects for each disease category by the end of two 
years. A total of 20 subjects would be enrolled to complete this study. We wish to enroll subjects with 
similar mechanisms of spasticity for each disease category. Our initial disease categories will involve 
subjects who have spasticity from very different mechanisms to determine if ITB dosing is significantly 
different due to origin of spasticity. One group of subjects would have spasticity due to spinal cord injury 
and are paraplegic, thereby recognizing that their spasticity originates from the lower half of the spinal 
cord in general. Another group of subjects would have spasticity due to cerebral palsy and are 


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
quadriparetic, thereby recognizing that their spasticity originates from loss of upper motor neurons as a 
result of cerebral disease (typically associated with a perinatal infarct). Other disease categories, such as 
cervical spine SCI, stroke, hereditary spastic paraparesis, multiple sclerosis, can be considered in the 
future if a significant difference (p < 0.05 on ANOVA analysis) exists between the two broad categories 
represented in this pilot study. 
There may be reasons why subjects may not be able to complete the study. Some foreseeable reasons 
include:  
 
Intradural blockage that prevents advancing the IT catheter to the level of C4, verified by a total 
MRI of the spine (Cervical, Thoracic, and Lumbar levels), without contrast injectyion, sagittal 
views only. 
 
Significant left over effect of the previous day’s administration of IT baclofen thereby prevent a 
detectable change in spasticity in subsequent injections 
 
Allergic reaction to IT baclofen 
 
Withdrawal of the subject from the study 
 
IT catheter malfunction 
 
Significant headache from CSF withdrawal 
 
CSF leak that is intolerable (headache or otherwise) from the IT catheter entry site 
Results Anticipated: 
The data will be collected according to the following schedule per patient. 
Table 1. Study variables and the timing of data collection. Each table is for a specific catheter location within a given 
patient. This table, for example, would be filled out 4 times corresponding to the four different catheter locations studied 
each day. 
Time 
Catheter 
Location 
Modified 
Ashworth Score 
Spasm Score 
CSF Sample 
Baseline 
C4, T3, T10, L2 
0-4 
0-4 
3cc 
Injection (50µg) 
- 
- 
- 
- 
1 min 
- 
- 
- 
3cc 
2 min 
- 
- 
- 
3cc 
10 min 
- 
- 
- 
3cc 
20 min 
- 
- 
- 
3cc 
60 min 
- 
- 
- 
3cc 
2 hours (120min) 
- 
0-4 
0-4 
- 
4 hours (240 min) - 
0-4 
0-4 
- 
6 hours (360 min) - 
0-4 
0-4 
- 
Total 
 
 
 
18 cc / day 
 
Table 2. Modified Ashworth Scale for Grading Spasticity 
Grade 
Clinical Rating of Tone 
0 
No increase in tone 
1 
Slight increase in muscle tone, manifested by a catch and release, or  
by minimal resistance at the end of the range of motion when the affected  


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
part(s) is moved in flexion or extension 
1+ 
Slight increase in muscle tone, manifested by a catch, followed by minimal 
resistance throughout the remainder (less than half) of the ROM 
2 
More marked increase in muscle tone through most of the ROM, but affected 
part(s) easily moved 
3 
Considerable increase in muscle tone, passive movement difficult 
4 
Affected part(s) rigid in flexion or extension 
 
Table 3. Penn Spasm Frequency Scale 
Spasm Score 
Spasm Frequency  
0 
No spasms 
1 
Mild spasms induced by stimulation 
2 
Infrequent full spasms occurring less than once per hour 
3 
Spasms occurring more than once per hour 
4 
Spasms occurring more than 10 times per hour 
 
Spasm Severity 
Severity Rating  
1 
Mild 
2 
Moderate 
3 
Severe 
 
For a given subject, the data will be 
analyzed for the following effects: 
1. What was the effect of 
identical baclofen doses 
(50µg) administered at 
different spinal levels within 
each subject on rigidity? 
(expect reduction in score 
over 4-6 hours with possible 
return towards baseline at 6-
10 hours) 
2. What was the effect of 
identical baclofen doses (50µg) administered at different spinal levels within each subject on 
spasms? (expect reduction in score over 4-6 with possible return towards baseline at 6-10 hours) 
3. Is there a significant difference in location of the catheter on the maximum reduction in either 
spasticity or spasm scores? (expect this to show as the largest “dip” in scores on 3D graph) 
4. Is there a “washout” effect from day to day? (if so, expect the baseline scores to be lower each 
day) If present, this would suggest that the daily dosing is too high. 
For each group (SCI vs CP), the data will be analyzed as follows: 
1. What catheter location caused the greatest change in spasticity scores? (the location of the 
catheter – C4, T3, T10 or L2 – would be noted and averaged among the ten subjects). Expect that 
C4
T3
T10
L2
1
2
3
4
5Baseline246
R
i
g
i
d
t
y
S
c
o
r
e
Modified Ashworth Score (example)
C4
T3
T10
L2


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
SCI group would favor greater change when catheter is located at T10 or L2. Expect that CP 
group might not show a significant difference in catheter location. 
2. What catheter location caused the greatest change in spasm scores? (the location of the catheter – 
C4, T3, T10 or L2 – would be noted and averaged among the ten subjects) Expect that SCI group 
would favor greater change when the catheter is located at T10 or L2. Expect that the CP group 
would not have much spasm change based on catheter location.
 
 
 
Parameter 
SCI Paraplegic  (n=10) 
CP Quadriparetic (n=10) 
Greatest change in Ashworth 
Score vs Location 
? ANOVA 
? ANOVA 
Greatest change in Spasm 
Rating vs Location 
? ANOVA 
? ANOVA 
Difference in Ashworth Score 
between days (assess washout 
effect) 
 
 
 
Subject Recruitment and Length of Study:  
We expected to be able to recruit 20 patients for this study within two years. The subjects would be solely 
recruited and managed through the Adult Neurosurgery practice at Vanderbilt. Patients would be 
approached for enrollment after first choosing to undergo an ITB trial for the treatment of their spasticity.  
 
 
0
1
2
3
4
5
C4
T3
T10
L2
Max Change in Ridigity Score
Effect of catheter position on rigidity change (SCI Paraplegic group 
example)
P1
P2
P3
P4
P5
P6
P7
P8
P9


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
Procedure/Activity 
Frequency 
Patient consent 
Clinic visit 1                            1 
MRI Total Spine 
without contrast 
             Outpatient Radiology              1 
 
 
Implantation of 
intrathecal catheter 
under light sedation 
and fluoroscopy 
guidance to C4 
             Inpatient MCE Day 1       1  
             Transfer to CRC after wake-up from MCE procedure (CRC Day 1) 
Baclofen Injection 
(50µg) 
 
             Inpatient CRC Day 2 
Modified Ashworth 
Rigidity testing and 
Spasm rating 
             Inpatient CRC Day 2 at 2, 4, and 6 hours following injection 
CSF Specimen  
3cc 
             Inpatient CRC Day 2 
             10 min, 30 min, 60 min, 120 min, 360 min 
Repositioning of 
intrathecal catheter 
to next lower level 
or T3 under 
fluoroscopy 
Inpatient Radiology Day 3                 1 (for this day) 
 
 
Baclofen Injection 
(50µg) 
 
 
Inpatient, CRC, Day 3 
Modified Ashworth 
Rigidity testing and 
Spasm rating 
Inpatient, CRC Day 3 at 2, 4, and 6 hours following injection 
CSF Specimen  
3cc 
 
              Inpatient CRC Day 3 
 10 min, 30 min, 60 min, 120 min, 360 min 
Repositioning of 
intrathecal catheter 
to next lower level 
or T10 under 
fluoroscopy 
 Inpatient Radiology Day 4                1 (for this day) 
Baclofen Injection 
(50µg) 
 
 
 Inpatient CRC Day 4 
Modified Ashworth 
Rigidity testing and 
Spasm rating 
 
Inpatient CRC Day 4 at 2, 4, and 6 hours following injection,  
CSF Specimen  
3cc 
 
              Inpatient CRC Day 4 
 10 min, 30 min, 60 min, 120 min, 360 min 


ITB Drug Dist Study 
Konrad, P- PI 
4/5/16 
 
Repositioning of 
intrathecal catheter 
to next lower level 
or L2 under 
fluoroscopy 
              Inpatient Radiology Day 5                    1 (for this day) 
Baclofen Injection 
(50µg) 
 
             Inpatient CRC Day 5 
Modified Ashworth 
Rigidity testing and 
Spasm rating 
             Inpatient CRC Day 5 at 2, 4, and 6 hours following injection  
            CSF Specimen  
3cc 
 
             Inpatient CRC Day 5 
            10 min, 30 min, 60 min, 120 min, 360 min  
Catheter 
withdrawal 
 
 
              Inpatient CRC, Day 5 
Discharge 
 
              Inpatient, CRC, Day 6