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Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury (SCI)

Primary Purpose

Spinal Cord Injury

Status
Unknown status
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lexapro
Placebo
Sponsored by
Shirley Ryan AbilityLab
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Cord Injury focused on measuring Gait training, Lexapro, Tizanidine

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A) Subjects with motor incomplete SCI (AIS C or D) of 1-9 mo. duration will be selected, with anatomical lesions between C1-T10.

B) Subjects will be between 18 and 75 years of age . Note: grant application states 16-75, however, we will be only including subjects 18-75.

C) All subjects must be previously ambulatory with passive range of motion consistent with normal walking, and must include: ankle dorsiflexion ankle to 10° and plantarflexion to 30°, knee flexion from 0 to 90°, hip flexion/extension to 90° - -10°.

D) Subjects will be medically stable with medical clearance to participate, with absence of concurrent severe medical illness, including unhealed decubiti, existing infection, significant cardiovascular or metabolic disease which limits exercise participation, significant osteoporosis (as indicated by history of fractures following injury), active heterotrophic ossification in the lower extremities, known history of peripheral nerve injury in lower legs, history of known traumatic head injury, and history of pulmonary complications, including significant obstructive and/or restrictive lung diseases.

E) Individuals who are undergoing concurrent physical therapy will not be excluded from the study population, secondary to the use of the cross-over design. Physical therapy records will be obtained to ascertain the amount and types of physical therapy services being provided.

F) Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the pharmacological agents on the developing fetus.

G) Patients with known liver, renal, or other metabolic disease that may interfere with drug action and/or clearance will be excluded from the proposed study. These complications will be partially obviated by requiring all patients to undergo specific medical procedures (liver function tests, urinalysis) prior to admission.

H)Men and women will be recruited for participation in the proposed clinical trial at rates consistent with national and local average of gender disparities of SCI (80% male, 20% women). Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will not be assessed for TIZ experiments and will be excluded from Aim 1.

I) Individuals of different ethnicities will be recruited at rates similar to the national and local ethnicity rates. Current data since 2005 indicate that of the entire population of SCI, 66.1% are Caucasian, 27.1% are African American, 6.6% are of Hispanic origin, and 2.0% are Asian. These populations closely resemble those at RIC and in our previous studies in human SCI.

Exclusion Criteria:

A) Subjects who are ventilator-dependent will be excluded secondary to severely impaired respiratory capacity.

B) Subjects with substantial orthopedic bracing to stabilize the cervical or thoracic vertebral column and are unable to fit in the safety harness without increased risk of injury are not eligible.

C) Patients will also be excluded if they are unable to tolerate 10 minutes of standing without orthostasis (decrease in blood pressure by 20 mmHg systolic and 10 mmHg diastolic); previous experience in the sub-acute population suggests that 10 minutes of standing is more than sufficient for tolerating 45 minutes of walking secondary to increased activity/muscle pump minimizing risk for orthostasis.

D) Women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the pharmacological agents on the developing fetus.

E) Subjects with height and weight limitations which restrict participation in Lokomat Training(LT) will be excluded. For height, subjects who are > 78 inches or < 60 inches tall may present with thigh/shank lengths that may limit use of the Lokomat. If subjects are not able to step independently on the treadmill and require use of robotic-assistance during treadmill stepping, attempts to fit all subjects in the robotic orthosis prior to enrollment and randomization. For weight, the maximum weight limit for use of the safety harness/counterweight system is 300 lbs.

F) Individuals with concurrent severe medical illness, including unhealed decubiti, existing infection, significant cardiovascular or metabolic disease which limits exercise participation, significant osteoporosis (as indicated by history of fractures following injury), active heterotrophic ossification in the lower extremities, known history of peripheral nerve injury in lower legs, history of known traumatic head injury, and history of pulmonary complications, including significant obstructive and/or restrictive lung diseases will be excluded.

G) Patients prescribed other anti-depressant medications, including specific monoaminergic agents, their precursors or their agonists, or other medications with known interactions to the SSRIs or TIZ will be excluded. With consultation and supervision of the patients' physician and the attending physicians for each individual patient, subjects will be required to wean of their medications on an appropriate and safe dosing schedule to minimize side effects of drug cessation or withdrawal. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 14-day washout period for SSRIs and a 72 hour washout for TIZ will be utilized.

H) All subjects prescribed anti-spastic medications will be excluded. Specific agents to be excluded include baclofen (Lioresal®) and benzodiazepines (Diazepam®). Selected agents used for pain modulation will be evaluated per subject to ascertain potential interactions with test agent. With consultation and supervision of the patients' physician and the attending physicians for each individual patient, subjects will be required to wean of their medications on an appropriate and safe dosing schedule to minimize side effects of drug cessation or withdrawal. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 72-hour minimum washout period for all such medications will be utilized. (Note: exception to use of TIZ during training - see above).

I) Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will not be assessed for TIZ experiments and will be excluded from Aim 1.

Sites / Locations

  • Rehabilitation Institute of Chicago

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Gait Training with Lexapro

Gait Training with Placebo

Arm Description

Gait training 2 weeks, gait training for 4 weeks (3X week) with Lexapro (10 mg SSRI), wash out period of 1 week, gait training for 4 weeks with placebo (10 mg). Patients will also be provided prescribed TIZ by their physician to help control of spastic motor behaviors.

Gait training 2 weeks, gait training for 4 weeks (3X week) with Placebo (10 mg), wash out period of 1 week, gait training for 4 weeks with Lexapro(10 mg). Patients will also be provided prescribed TIZ by their physician to help control of spastic motor behaviors.

Outcomes

Primary Outcome Measures

Walking Index for Spinal Cord Injury (WISCI II)
Evaluation of bracing, assistive device, and assistance required for ambulation
Peak treadmill velocity
During graded treadmill test

Secondary Outcome Measures

Volitional Strength
Ankle, knee, hip flexors/extensors strength (Nm) tested bilaterally (Biodex®)
Gait kinematics
Kinematic excursions of hip/knee/ankle (Motion Analysis®)
Fastest possible walking velocity over ground (FV; m/s)
Subject walks a distance of 10m with the middle 6m being timed. Instructions to walk normal comfortable pace.
Six minute walking distance (m)
Subject asked to walk normal comfortable pace for 6 minutes. Total distance is recorded. Subject can take rest breaks as needed but are encouraged to continue walking throughout the 6 minutes.
Lower Extremity Motor Scores (LEMS)
Measure of lower extremity muscle strength on 0-5 point scale.
Modified Ashworth of knee extensors/flexors (modAsh)
Measure of spasticity of knee flexors and extensors during passive range of motion
Spinal Cord Assessment Tool for Spasticity (SCATS)
Measure of spasticity tested in supine

Full Information

First Posted
December 6, 2012
Last Updated
April 18, 2019
Sponsor
Shirley Ryan AbilityLab
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1. Study Identification

Unique Protocol Identification Number
NCT01753882
Brief Title
Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury (SCI)
Official Title
Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Unknown status
Study Start Date
February 2012 (undefined)
Primary Completion Date
July 2020 (Anticipated)
Study Completion Date
July 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Shirley Ryan AbilityLab

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary goal of the proposed clinical trial is to investigate the combined effects of walking training and monoaminergic agents (SSRIs and TIZ) on motor function of individuals in sub-acute (2-7 mo) human motor incomplete Spinal Cord Injury (SCI), with a primary emphasis on improvement in locomotor capability. We hypothesize that the use of these drugs applied early following SCI may facilitate independent stepping ability, and its combination with intensive stepping training will result in improved locomotor recovery following incomplete SCI. Loss of descending control via norepinephrine inputs following spinal cord injury can impair normal sensorimotor function through depressing motor excitability and impairing walking capacity. Replacing these inputs with drugs can alter the excitability and assist with reorganization of locomotor circuits. Assessment of single-dose administration of these agents has been tested in patients with motor incomplete spinal cord injury; only limited changes in walking performance have been noted. The resultant onset of weakness and increase in involuntary reflexes following motor incomplete SCI may partly be a result of damage to descending pathways to the spinal cord that control the release of serotonin. In models of SCI, for example, application of agents that simulate serotonin has been shown to change voluntary motor behaviors, including improvement of walking recovery. In humans following neurological injury, the effects of 5HT agents are unclear. Few previous reports indicate improved motor function following administration of agents which enhance the available serotonin in the brain, although some data suggests that increased serotonin may be beneficial. In this application, we propose to study the effects of clinically used agents that increase or decrease intrinsic serotonin activity in the brain on strength and walking ability following human motor incomplete SCI. Using detailed electrophysiological recordings, and biomechanical and behavioral measures, we will determine the effects of single or chronic doses of these drugs on voluntary and involuntary motor behaviors during clinical measures and walking measures. The novelty of this proposed research is the expectation that agents that increase serotonin activity may increase abnormal reflexes in SCI, but simultaneously help to facilitate motor and walking recovery. Despite potential improvements in voluntary function, the use of pharmacological agents that may enhance spastic motor behaviors following SCI is in marked contrast to the way in which drugs are typically used in the clinical setting.
Detailed Description
This is a phase I double blinded randomized control clinical trial. The procedures for participation in both Aims of the study are described below in chronological order. Aim 1 and 2: Explanation of the consent form and study procedures/protocol will be performed in the Neurolocomotion laboratory (room 1382), with subjects and their families provided ample time for questions. Subjects are provided substantial time to choose to participate, and are provided the laboratory phone numbers/emails to contact the PI and research personnel with any potential questions. In situations where the subject is unable to be transported to the laboratory, the PI will explain the consent form at a time and location convenient for the subject and/or their family. Subjects will then undergo a screening procedure to determine if they are eligible to participate in the study based on inclusion/exclusion criteria. Aim 1: Modified Ashworth scale (mod Ash, no units) will be used to detect velocity-dependent resistance to passive muscle stretch/joint rotation. The modAsh will grossly assess spasticity at bilateral knee extensors and knee flexors, with scores from 0-5 (1+ scores will be converted to 2 and higher scores increased accordingly). Spinal Cord Assessment Tools for Spasticity (SCATS, no units) will be employed to assess flexor and extensor spasms and clonic activity of the plantarflexors (Benz et al. , 2005). Independence in walking ability will be assessed at each assessment period using the Walking Index for SCI II (WISCI II, which is a 21 point (0-20) ordinal scale which assigns a score based on amount of physical assistance, bracing, and assistive device used to ambulate. Notably, subjects will not be allowed to ambulate with braces extending above the knee. Six minute walk test (m) will be assess walking around a continuous hall-way at subjects' self-selected velocity, with distance determined each minute and summed over the entire six minute duration (van Hedel et al. , 2005). Subjects will be asked to "walk at your (their) normal, comfortable pace" with minimal physical assistance and bracing/devices as needed This measure is significantly association with measures of community walking in subjects with incomplete SCI (Saraf et al. , 2009). BERG balance test will be administered. Gait Mat testing will be performed to guage spatiotemporal aspects of walking. 6 minute walk test will be performed. Lower Extremity Motor Score, Peak treadmill speed (m/s) Aim 2: Same as above including strength evaluations : Ankle, knee, hip flexors/extensors tested bilaterally (Biodex®). Subjects in Aim 2 will be tested at initial evaluation, after four weeks of initial training, and will be repeated after each four weeks of training on either the placebo or study medication. Subjects in Aim 2 will additionally be requested to return for follow up testing after one year. Subjects will be offered to participate in audio, videotaping and/or photography. Women who are of childbearing age and are contemplating becoming pregnant will be required to submit a pregnancy test and must notify the principal investigator immediately.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Cord Injury
Keywords
Gait training, Lexapro, Tizanidine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
88 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Gait Training with Lexapro
Arm Type
Experimental
Arm Description
Gait training 2 weeks, gait training for 4 weeks (3X week) with Lexapro (10 mg SSRI), wash out period of 1 week, gait training for 4 weeks with placebo (10 mg). Patients will also be provided prescribed TIZ by their physician to help control of spastic motor behaviors.
Arm Title
Gait Training with Placebo
Arm Type
Active Comparator
Arm Description
Gait training 2 weeks, gait training for 4 weeks (3X week) with Placebo (10 mg), wash out period of 1 week, gait training for 4 weeks with Lexapro(10 mg). Patients will also be provided prescribed TIZ by their physician to help control of spastic motor behaviors.
Intervention Type
Drug
Intervention Name(s)
Lexapro
Other Intervention Name(s)
escitalopram
Intervention Description
Agent + training vs Placebo + training
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
microcrystalline dextrose
Intervention Description
Agent + training vs Placebo + training
Primary Outcome Measure Information:
Title
Walking Index for Spinal Cord Injury (WISCI II)
Description
Evaluation of bracing, assistive device, and assistance required for ambulation
Time Frame
Compare changes in WISCI II pre to post training with placebo to pre to post training with Lexapro during a 10-12 week time period.
Title
Peak treadmill velocity
Description
During graded treadmill test
Time Frame
Compare changes in peak treadmill velocity pre to post training with placebo to pre to post training with Lexapro during a 10-12 week time period.
Secondary Outcome Measure Information:
Title
Volitional Strength
Description
Ankle, knee, hip flexors/extensors strength (Nm) tested bilaterally (Biodex®)
Time Frame
Pre Training (Day 1), Pre Drug B (approx end of week 5), Post-Final (approx end of week 10)
Title
Gait kinematics
Description
Kinematic excursions of hip/knee/ankle (Motion Analysis®)
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)
Title
Fastest possible walking velocity over ground (FV; m/s)
Description
Subject walks a distance of 10m with the middle 6m being timed. Instructions to walk normal comfortable pace.
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)
Title
Six minute walking distance (m)
Description
Subject asked to walk normal comfortable pace for 6 minutes. Total distance is recorded. Subject can take rest breaks as needed but are encouraged to continue walking throughout the 6 minutes.
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)
Title
Lower Extremity Motor Scores (LEMS)
Description
Measure of lower extremity muscle strength on 0-5 point scale.
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)
Title
Modified Ashworth of knee extensors/flexors (modAsh)
Description
Measure of spasticity of knee flexors and extensors during passive range of motion
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)
Title
Spinal Cord Assessment Tool for Spasticity (SCATS)
Description
Measure of spasticity tested in supine
Time Frame
Pre Training (Day 1), Pre Drug A (approx end of week 2), Post Drug A (approx end of week 4), Pre Drug B (approx end of week 5), Post Drug B (approx end of week 9), Post-Final (approx end of week 10)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A) Subjects with motor incomplete SCI (AIS C or D) of 1-9 mo. duration will be selected, with anatomical lesions between C1-T10. B) Subjects will be between 18 and 75 years of age . Note: grant application states 16-75, however, we will be only including subjects 18-75. C) All subjects must be previously ambulatory with passive range of motion consistent with normal walking, and must include: ankle dorsiflexion ankle to 10° and plantarflexion to 30°, knee flexion from 0 to 90°, hip flexion/extension to 90° - -10°. D) Subjects will be medically stable with medical clearance to participate, with absence of concurrent severe medical illness, including unhealed decubiti, existing infection, significant cardiovascular or metabolic disease which limits exercise participation, significant osteoporosis (as indicated by history of fractures following injury), active heterotrophic ossification in the lower extremities, known history of peripheral nerve injury in lower legs, history of known traumatic head injury, and history of pulmonary complications, including significant obstructive and/or restrictive lung diseases. E) Individuals who are undergoing concurrent physical therapy will not be excluded from the study population, secondary to the use of the cross-over design. Physical therapy records will be obtained to ascertain the amount and types of physical therapy services being provided. F) Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the pharmacological agents on the developing fetus. G) Patients with known liver, renal, or other metabolic disease that may interfere with drug action and/or clearance will be excluded from the proposed study. These complications will be partially obviated by requiring all patients to undergo specific medical procedures (liver function tests, urinalysis) prior to admission. H)Men and women will be recruited for participation in the proposed clinical trial at rates consistent with national and local average of gender disparities of SCI (80% male, 20% women). Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will not be assessed for TIZ experiments and will be excluded from Aim 1. I) Individuals of different ethnicities will be recruited at rates similar to the national and local ethnicity rates. Current data since 2005 indicate that of the entire population of SCI, 66.1% are Caucasian, 27.1% are African American, 6.6% are of Hispanic origin, and 2.0% are Asian. These populations closely resemble those at RIC and in our previous studies in human SCI. Exclusion Criteria: A) Subjects who are ventilator-dependent will be excluded secondary to severely impaired respiratory capacity. B) Subjects with substantial orthopedic bracing to stabilize the cervical or thoracic vertebral column and are unable to fit in the safety harness without increased risk of injury are not eligible. C) Patients will also be excluded if they are unable to tolerate 10 minutes of standing without orthostasis (decrease in blood pressure by 20 mmHg systolic and 10 mmHg diastolic); previous experience in the sub-acute population suggests that 10 minutes of standing is more than sufficient for tolerating 45 minutes of walking secondary to increased activity/muscle pump minimizing risk for orthostasis. D) Women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the pharmacological agents on the developing fetus. E) Subjects with height and weight limitations which restrict participation in Lokomat Training(LT) will be excluded. For height, subjects who are > 78 inches or < 60 inches tall may present with thigh/shank lengths that may limit use of the Lokomat. If subjects are not able to step independently on the treadmill and require use of robotic-assistance during treadmill stepping, attempts to fit all subjects in the robotic orthosis prior to enrollment and randomization. For weight, the maximum weight limit for use of the safety harness/counterweight system is 300 lbs. F) Individuals with concurrent severe medical illness, including unhealed decubiti, existing infection, significant cardiovascular or metabolic disease which limits exercise participation, significant osteoporosis (as indicated by history of fractures following injury), active heterotrophic ossification in the lower extremities, known history of peripheral nerve injury in lower legs, history of known traumatic head injury, and history of pulmonary complications, including significant obstructive and/or restrictive lung diseases will be excluded. G) Patients prescribed other anti-depressant medications, including specific monoaminergic agents, their precursors or their agonists, or other medications with known interactions to the SSRIs or TIZ will be excluded. With consultation and supervision of the patients' physician and the attending physicians for each individual patient, subjects will be required to wean of their medications on an appropriate and safe dosing schedule to minimize side effects of drug cessation or withdrawal. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 14-day washout period for SSRIs and a 72 hour washout for TIZ will be utilized. H) All subjects prescribed anti-spastic medications will be excluded. Specific agents to be excluded include baclofen (Lioresal®) and benzodiazepines (Diazepam®). Selected agents used for pain modulation will be evaluated per subject to ascertain potential interactions with test agent. With consultation and supervision of the patients' physician and the attending physicians for each individual patient, subjects will be required to wean of their medications on an appropriate and safe dosing schedule to minimize side effects of drug cessation or withdrawal. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 72-hour minimum washout period for all such medications will be utilized. (Note: exception to use of TIZ during training - see above). I) Women of childbearing potential will not be excluded, although women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will not be assessed for TIZ experiments and will be excluded from Aim 1.
Facility Information:
Facility Name
Rehabilitation Institute of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States

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Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury (SCI)

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