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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Rehabilitation Institute of Chicago
Sponsor:
Information provided by (Responsible Party):
T. George Hornby, Rehabilitation Institute of Chicago
ClinicalTrials.gov Identifier:
NCT01753882
First received: December 6, 2012
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Spinal Cord Injury
Drug: Lexapro
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury

Resource links provided by NLM:


Further study details as provided by Rehabilitation Institute of Chicago:

Primary Outcome Measures:
  • Walking Index for Spinal Cord Injury (WISCI II) [ 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. ] [ Designated as safety issue: No ]
    Evaluation of bracing, assistive device, and assistance required for ambulation

  • Peak treadmill velocity [ 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. ] [ Designated as safety issue: No ]
    During graded treadmill test


Secondary Outcome Measures:
  • Volitional Strength [ Time Frame: Pre Training (Day 1), Pre Drug B (approx end of week 5), Post-Final (approx end of week 10) ] [ Designated as safety issue: No ]
    Ankle, knee, hip flexors/extensors strength (Nm) tested bilaterally (Biodex®)

  • Gait kinematics [ 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) ] [ Designated as safety issue: No ]
    Kinematic excursions of hip/knee/ankle (Motion Analysis®)

  • Fastest possible walking velocity over ground (FV; m/s) [ 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) ] [ Designated as safety issue: No ]
    Subject walks a distance of 10m with the middle 6m being timed. Instructions to walk normal comfortable pace.

  • Six minute walking distance (m) [ 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) ] [ Designated as safety issue: No ]
    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) [ 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) ] [ Designated as safety issue: No ]
    Measure of lower extremity muscle strength on 0-5 point scale.

  • Modified Ashworth of knee extensors/flexors (modAsh) [ 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) ] [ Designated as safety issue: No ]
    Measure of spasticity of knee flexors and extensors during passive range of motion

  • Spinal Cord Assessment Tool for Spasticity (SCATS) [ 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) ] [ Designated as safety issue: No ]
    Measure of spasticity tested in supine


Estimated Enrollment: 88
Study Start Date: February 2012
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gait Training with Lexapro
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.
Drug: Lexapro
Agent + training vs Placebo + training
Other Name: escitalopram
Active Comparator: Gait Training with Placebo
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.
Drug: Placebo
Other Name: microcrystalline dextrose

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01753882

Contacts
Contact: Thomas G Hornby, PhD, PT 312-238-1397 g-hornby@northwestern.edu
Contact: Carey L Holleran, PT, NCS 312-238-1396 cholleran@ric.org

Locations
United States, Illinois
Rehabilitation Institute of Chicago Recruiting
Chicago, Illinois, United States, 60611
Principal Investigator: Thomas G Hornby, PhD, PT         
Rehabilitation Institute of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Thomas G Hornby    312-238-1397    g-hornby@northwestern.edu   
Sponsors and Collaborators
Rehabilitation Institute of Chicago
  More Information

No publications provided

Responsible Party: T. George Hornby, Principal Investigator, Rehabilitation Institute of Chicago
ClinicalTrials.gov Identifier: NCT01753882     History of Changes
Other Study ID Numbers: STU00056589
Study First Received: December 6, 2012
Last Updated: April 23, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Rehabilitation Institute of Chicago:
Gait training
Lexapro
Tizanidine

Additional relevant MeSH terms:
Spinal Cord Injuries
Central Nervous System Diseases
Nervous System Diseases
Spinal Cord Diseases
Trauma, Nervous System
Wounds and Injuries
Citalopram
Dexetimide
Anti-Dyskinesia Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Autonomic Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Parasympatholytics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Uptake Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014