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Pharmacological Agents for Chronic Spinal Cord Injury (SCI)

Primary Purpose

Spinal Cord Injuries

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CPH + hand training
CD-LD + hand training
ATX + hand training
Placebo + hand training
Sponsored by
Bronx VA Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Cord Injuries focused on measuring Transcranial magnetic stimulation, Pharmacological agents, Transcutaneous spinal cord stimulation, Hand exercise

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Male or female between 18 and 65 years of age; clinically stable chronic (> 12 months) SCI at or above C8 spinal segment; Motor-incomplete with a score of 2 or more (out of 5) on manual muscle testing (MMT) of finger extension, finger flexion, or finger abduction in left or right hand(s); or able to perform thumb-index finger pinch of the left or right hand; Detectable stimulation-evoked muscle responses of the left or right first dorsal interosseous (FDI) and/or abductor pollicis brevis (APB); Detectable FDI/APB surface electromyography (EMG) muscle activity during thumb-index finger pinch; Must have stable: medication [≥ 30 days prior]; rehabilitation regimen [≥ 15 days prior]; Must be able to: abstain from alcohol, smoking and caffeine consumption on the day prior/of each experiment; abstain from recreational drugs for the entirety of the study; commit to study requirements (i.e., 7 visits); provide informed consent. Exclusion Criteria: History of moderate or severe head trauma (loss of consciousness for greater than one hour or evidence of brain contusion or hemorrhage or depressed skull fracture on prior imaging); History of other serious central or peripheral neurological injury; History of implanted brain/spine/nerve stimulators, aneurysm clips, ferromagnetic metallic implants in the head (except inside mouth); cochlear implants; cardiac pacemaker/defibrillator; intracardiac lines; currently increased intracranial pressure; or other contraindications to brain stimulation or task performance; Ventilator dependence or patent tracheostomy site; Unstable syrinx, or multiple spinal cord lesions; Unclear diagnosis; History of stroke, brain tumor, brain abscess, or multiple sclerosis; Personal history of seizures; extensive family history of seizures; use of medications that lower seizure threshold (e.g., amphetamines, dalfampridine, and bupropion); Use of the study medications; Use of medications known to have significant adverse interactions with the study medication as described in the manufacturers' prescribing information [14 days prior]; previous allergic reaction or hypersensitivity to study drug(s); Presence of a medical condition that represents a risk for study drug(s) administration; evidence of liver disease or clinical jaundice; neutropenia; glaucoma; gastrointestinal ulcer(s); active malignancy; undiagnosed skin lesions; autoimmune disorders; chronic infectious diseases (e.g. HIV, hepatitis B or C); pregnancy or nursing mothers (a pregnancy urine test may be warranted); neurologic disorders (including a history of serious head trauma or seizures), and uncontrolled cardiovascular, metabolic, pulmonary or renal disease; premorbid, ongoing major depression or psychosis, altered cognitive status; bipolar disorder; suicidal ideation or past suicide attempts; History of severe hearing problems, loss or tinnitus; Presence of urinary infection, fever, pressure ulcer; or open skin lesions (shoulders or arms); Recent history (< 6 months) of recurrent autonomic dysreflexia, defined as a syndrome of sudden rise in systolic pressure greater than 20 mm Hg or diastolic pressure greater than 10 mm Hg, without rise in HR, accompanied by symptoms such as headache, facial flushing, sweating, nasal congestion, and blurry vision (closely monitored during all testing procedures); Heavy alcohol consumption (greater than equivalent of 5 oz of liquor) within previous 48 hours; Recent history (>1 year) of chemical substance dependency or significant psychosocial disturbance; Study participation of an investigational drug or device [60 days prior]; Unsuitable for study participation as determined by the study physician.

Sites / Locations

  • James J. Peters Veterans Affairs Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

CPH + hand training

CD-LD + hand training

ATX + hand training

Placebo + hand training

Arm Description

A single dose of Cyproheptadine (CPH) (8 mg) will be administered. Supplied as 2 over-encapsulated pills of 4 mg each.

A single dose of IR Carbidopa-levodopa (CD-LD) (50/200 mg) will be administered. Supplied as 2 over-encapsulated pills (25 mg carbidopa / 100 mg levodopa each).

A single dose of Atomoxetine (ATX) (40 mg) will be administered. Supplied as 1 over-encapsulated pill of 40 mg plus 1 placebo capsule.

A single dose of Placebo will be administered. Supplied as 2 gelatin capsules, identical in number, size, shape and color, filled with microcrystalline cellulose.

Outcomes

Primary Outcome Measures

Assessing task performance (dexterity)
Unilateral manual dexterity will be assessed using the 9-Hole Peg Test (Aim 1a).

Secondary Outcome Measures

Assessing task performance (dexterity)
Unilateral manual dexterity will be assessed using the Box and Block Test (Aim 1a).
Assessing volitional grip strength
Maximal grip force will be measured (Aim 1b). The attempt with the highest value will be used for analysis.
Assessing volitional pinch strength
Maximal pinch force will be measured (Aim 1b). The attempt with the highest value will be used for analysis.
Assessing corticospinal plasticity
Corticospinal plasticity will be measured via single-pulse TMS recruitment curves (Aim 2a).
Assessing cortical plasticity
Short intracortical inhibition (SICI) and intracortical facilitation (ICF) will be evoked with paired-pulse TMS at various interstimulus intervals according to the methods previously employed (Murray & Knikou, 2017).
Assessing spinal plasticity
Spinal plasticity will be measured via single-pulse TSCS recruitment curves (Aim 2b).
Tracking cardiovascular responses (heart rate)
Observed measures of heart rate (HR) (Aim 3a) will be monitored throughout.
Tracking cardiovascular responses (blood oxygen saturation)
Observed measures of blood oxygen saturation (SpO2) (Aim 3a) will be monitored throughout.
Tracking cardiovascular responses (blood pressure)
Observed measures of blood pressure (BP) (Aim 3a) will be monitored throughout.
Tracking symptoms
Participant-reported safety questionnaire (Aim 3b) will be monitored for any symptoms felt throughout the study.
Tracking side effects (drug administration)
Adverse event (AE) questionnaire (Aim 3b) related to any participant-reported experience following drug administration.
Tracking side effects (study testing stimulation)
Adverse event (AE) questionnaire (Aim 3b) related to any participant-reported experience following brain and/or spinal stimulation received during the experiment.

Full Information

First Posted
December 27, 2022
Last Updated
April 21, 2023
Sponsor
Bronx VA Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT05708274
Brief Title
Pharmacological Agents for Chronic Spinal Cord Injury (SCI)
Official Title
The Role of Pharmacological Agents in Restoring Neuronal Excitability After Chronic Spinal Cord Injury (SCI)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 20, 2023 (Actual)
Primary Completion Date
July 30, 2024 (Anticipated)
Study Completion Date
July 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Bronx VA Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to investigate the short-term effects of 3 approved FDA drugs (cyproheptadine (CPH), carbidopa-levodopa (CD-LD), and atomoxetine (ATX)) on motor responses when delivered in combination with hand training exercises in people with chronic spinal cord injury. The goal is to learn how to better strengthen connections between the brain and spinal cord after spinal cord injury, and if this connection is improved by one(or more) of the drugs. Multiple aspects of nerve transmission and muscle response will be measured via noninvasive brain and spinal cord stimulation, along with motor performance (dexterity and strength).
Detailed Description
Research will take place at the James J. Peters VA Medical Center (JJPVAMC), Bronx, NY. There are seven visits in total, including an initial evaluation and clinical assessment session. Each visit will last roughly 5 hours or less. We plan to enroll 28 participants with spinal cord injury over a two-year period. The study is designed as a double-blind, placebo-controlled, single-dose, randomized crossover investigation involving four study drug visits (CPH, CD-LD, ATX, or placebo). The same participants will partake in all four interventions in randomized order with at least 1-week washout representative of greater than 5x drug half-life; to avoid accumulative effects. To reduce potential learning effects from motor training and task-related outcome measurements, participants will partake in two motor training practice sessions prior to commencing the experiments for task familiarity. This study will consist of electromyography (surface recordings of muscle activity), peripheral nerve stimulation, transcranial magnetic brain stimulation (TMS), and transcutaneous electrical spinal cord stimulation (TSCS), targeting the hand/arm muscles. Though it is unlikely given the single-dose nature, participants may experience side effects following drug administration. Prior to consenting, all volunteers will undergo a comprehensive pre-screening evaluation including blood tests to ensure there are no contraindications. Please note, there is no expectation of long-term benefit from this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Cord Injuries
Keywords
Transcranial magnetic stimulation, Pharmacological agents, Transcutaneous spinal cord stimulation, Hand exercise

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Double-blind, placebo-controlled, single-dose, randomized crossover investigation to one of four conditions: 1) CPH + hand training; 2) CD-LD + hand training; 3) ATX + hand training; and 4) placebo + hand training, performed at least a week apart. Outcomes measures will be assessed before and 60 minutes after study drug administration.
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
28 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CPH + hand training
Arm Type
Experimental
Arm Description
A single dose of Cyproheptadine (CPH) (8 mg) will be administered. Supplied as 2 over-encapsulated pills of 4 mg each.
Arm Title
CD-LD + hand training
Arm Type
Experimental
Arm Description
A single dose of IR Carbidopa-levodopa (CD-LD) (50/200 mg) will be administered. Supplied as 2 over-encapsulated pills (25 mg carbidopa / 100 mg levodopa each).
Arm Title
ATX + hand training
Arm Type
Experimental
Arm Description
A single dose of Atomoxetine (ATX) (40 mg) will be administered. Supplied as 1 over-encapsulated pill of 40 mg plus 1 placebo capsule.
Arm Title
Placebo + hand training
Arm Type
Placebo Comparator
Arm Description
A single dose of Placebo will be administered. Supplied as 2 gelatin capsules, identical in number, size, shape and color, filled with microcrystalline cellulose.
Intervention Type
Drug
Intervention Name(s)
CPH + hand training
Intervention Description
Following a 10-minute rest after baseline measurements a single dose pharmacological agent or placebo will be administered, in blinded fashion, with up to 180 mL of noncarbonated water, on an empty stomach (minimum 2 hours without food). After capsule ingestion, participants will spend 50 minutes performing hand task-oriented training, resting for 10 minutes before undertaking post-intervention outcome measurements.
Intervention Type
Drug
Intervention Name(s)
CD-LD + hand training
Intervention Description
Following a 10-minute rest after baseline measurements a single dose pharmacological agent or placebo will be administered, in blinded fashion, with up to 180 mL of noncarbonated water, on an empty stomach (minimum 2 hours without food). After capsule ingestion, participants will spend 50 minutes performing hand task-oriented training, resting for 10 minutes before undertaking post-intervention outcome measurements.
Intervention Type
Drug
Intervention Name(s)
ATX + hand training
Intervention Description
Following a 10-minute rest after baseline measurements a single dose pharmacological agent or placebo will be administered, in blinded fashion, with up to 180 mL of noncarbonated water, on an empty stomach (minimum 2 hours without food). After capsule ingestion, participants will spend 50 minutes performing hand task-oriented training, resting for 10 minutes before undertaking post-intervention outcome measurements.
Intervention Type
Drug
Intervention Name(s)
Placebo + hand training
Intervention Description
Following a 10-minute rest after baseline measurements a single dose pharmacological agent or placebo will be administered, in blinded fashion, with up to 180 mL of noncarbonated water, on an empty stomach (minimum 2 hours without food). After capsule ingestion, participants will spend 50 minutes performing hand task-oriented training, resting for 10 minutes before undertaking post-intervention outcome measurements.
Primary Outcome Measure Information:
Title
Assessing task performance (dexterity)
Description
Unilateral manual dexterity will be assessed using the 9-Hole Peg Test (Aim 1a).
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Secondary Outcome Measure Information:
Title
Assessing task performance (dexterity)
Description
Unilateral manual dexterity will be assessed using the Box and Block Test (Aim 1a).
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Assessing volitional grip strength
Description
Maximal grip force will be measured (Aim 1b). The attempt with the highest value will be used for analysis.
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Assessing volitional pinch strength
Description
Maximal pinch force will be measured (Aim 1b). The attempt with the highest value will be used for analysis.
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Assessing corticospinal plasticity
Description
Corticospinal plasticity will be measured via single-pulse TMS recruitment curves (Aim 2a).
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Assessing cortical plasticity
Description
Short intracortical inhibition (SICI) and intracortical facilitation (ICF) will be evoked with paired-pulse TMS at various interstimulus intervals according to the methods previously employed (Murray & Knikou, 2017).
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Assessing spinal plasticity
Description
Spinal plasticity will be measured via single-pulse TSCS recruitment curves (Aim 2b).
Time Frame
Assess change from baseline to 10 minutes after completion of drug+task training.
Title
Tracking cardiovascular responses (heart rate)
Description
Observed measures of heart rate (HR) (Aim 3a) will be monitored throughout.
Time Frame
Measured every 5-10 minutes, for up to 4 hours. Change will be compared to baseline.
Title
Tracking cardiovascular responses (blood oxygen saturation)
Description
Observed measures of blood oxygen saturation (SpO2) (Aim 3a) will be monitored throughout.
Time Frame
Measured every 5-10 minutes, for up to 4 hours. Change will be compared to baseline.
Title
Tracking cardiovascular responses (blood pressure)
Description
Observed measures of blood pressure (BP) (Aim 3a) will be monitored throughout.
Time Frame
Measured every 5-10 minutes, for up to 4 hours. Change will be compared to baseline.
Title
Tracking symptoms
Description
Participant-reported safety questionnaire (Aim 3b) will be monitored for any symptoms felt throughout the study.
Time Frame
Measured every 5-10 minutes, for up to 4 hours. Change will be compared to baseline.
Title
Tracking side effects (drug administration)
Description
Adverse event (AE) questionnaire (Aim 3b) related to any participant-reported experience following drug administration.
Time Frame
Assess change from end of day 1 testing to 24 hours after study completion.
Title
Tracking side effects (study testing stimulation)
Description
Adverse event (AE) questionnaire (Aim 3b) related to any participant-reported experience following brain and/or spinal stimulation received during the experiment.
Time Frame
Assess change from end of day 1 testing to 24 hours after study completion.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female between 18 and 65 years of age; clinically stable chronic (> 12 months) SCI at or above C8 spinal segment; Motor-incomplete with a score of 2 or more (out of 5) on manual muscle testing (MMT) of finger extension, finger flexion, or finger abduction in left or right hand(s); or able to perform thumb-index finger pinch of the left or right hand; Detectable stimulation-evoked muscle responses of the left or right first dorsal interosseous (FDI) and/or abductor pollicis brevis (APB); Detectable FDI/APB surface electromyography (EMG) muscle activity during thumb-index finger pinch; Must have stable: medication [≥ 30 days prior]; rehabilitation regimen [≥ 15 days prior]; Must be able to: abstain from alcohol, smoking and caffeine consumption on the day prior/of each experiment; abstain from recreational drugs for the entirety of the study; commit to study requirements (i.e., 7 visits); provide informed consent. Exclusion Criteria: History of moderate or severe head trauma (loss of consciousness for greater than one hour or evidence of brain contusion or hemorrhage or depressed skull fracture on prior imaging); History of other serious central or peripheral neurological injury; History of implanted brain/spine/nerve stimulators, aneurysm clips, ferromagnetic metallic implants in the head (except inside mouth); cochlear implants; cardiac pacemaker/defibrillator; intracardiac lines; currently increased intracranial pressure; or other contraindications to brain stimulation or task performance; Ventilator dependence or patent tracheostomy site; Unstable syrinx, or multiple spinal cord lesions; Unclear diagnosis; History of stroke, brain tumor, brain abscess, or multiple sclerosis; Personal history of seizures; extensive family history of seizures; use of medications that lower seizure threshold (e.g., amphetamines, dalfampridine, and bupropion); Use of the study medications; Use of medications known to have significant adverse interactions with the study medication as described in the manufacturers' prescribing information [14 days prior]; previous allergic reaction or hypersensitivity to study drug(s); Presence of a medical condition that represents a risk for study drug(s) administration; evidence of liver disease or clinical jaundice; neutropenia; glaucoma; gastrointestinal ulcer(s); active malignancy; undiagnosed skin lesions; autoimmune disorders; chronic infectious diseases (e.g. HIV, hepatitis B or C); pregnancy or nursing mothers (a pregnancy urine test may be warranted); neurologic disorders (including a history of serious head trauma or seizures), and uncontrolled cardiovascular, metabolic, pulmonary or renal disease; premorbid, ongoing major depression or psychosis, altered cognitive status; bipolar disorder; suicidal ideation or past suicide attempts; History of severe hearing problems, loss or tinnitus; Presence of urinary infection, fever, pressure ulcer; or open skin lesions (shoulders or arms); Recent history (< 6 months) of recurrent autonomic dysreflexia, defined as a syndrome of sudden rise in systolic pressure greater than 20 mm Hg or diastolic pressure greater than 10 mm Hg, without rise in HR, accompanied by symptoms such as headache, facial flushing, sweating, nasal congestion, and blurry vision (closely monitored during all testing procedures); Heavy alcohol consumption (greater than equivalent of 5 oz of liquor) within previous 48 hours; Recent history (>1 year) of chemical substance dependency or significant psychosocial disturbance; Study participation of an investigational drug or device [60 days prior]; Unsuitable for study participation as determined by the study physician.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lynda M Murray, PhD
Phone
718-584-9000
Ext
5426
Email
lynda.murray@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Noam Y Harel, MD PhD
Phone
718-584-9000
Ext
1742
Email
noam.harel@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lynda M Murray, PhD
Organizational Affiliation
Bronx VA Medical Center / James J. Peters Veterans Affairs Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
James J. Peters Veterans Affairs Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10468
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lynda M Murray, PhD
Phone
718-584-9000
Ext
5426
Email
lynda.murray@va.gov

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified, individual-level data will be deposited to appropriate public repositories, such as Open Data Commons for Spinal Cord Injury (https://scicrunch.org/odc-sci), Figshare, or others. This will allow more powerful meta-analysis of disparate smaller studies, a need which is even more urgent in neurorehabilitation than in other fields that are more amenable to large drug studies.
IPD Sharing Time Frame
Within 6 months of manuscript preparation.
IPD Sharing Access Criteria
Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions described in the authorization and consent. A Data Use Agreement (DUA) will indicate adherence to any applicable Informed Consent provisions, and prohibits the recipient from identifying or re-identifying any individual whose data are included in the dataset.

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Pharmacological Agents for Chronic Spinal Cord Injury (SCI)

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