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Effects of 4-AP on Functional SCI Recovery

Primary Purpose

Spinal Cord Injury

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Dalfampridine

Placebo drug

STDP stimulation

Exercise training

About this trial

This is an interventional treatment trial for Spinal Cord Injury focused on measuring SCI, Neural control, 4-AP, Walking, Neuroplasticity

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male and females between ages 18-85 years
SCI at least 4 weeks post injury
Spinal Cord injury at or above L2
ASIA A,B,C, or D, complete or incomplete
Possess the following abilities
The ability to perform a small visible contraction with dorsiflexion and hip flexor muscles

Exclusion Criteria:

Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic disease
Any history of renal impairment
Any debilitating disease prior to the SCI that caused exercise intolerance
Premorbid, ongoing major depression or psychosis, altered cognitive status
History of head injury or stroke
Vascular, traumatic, tumoral, infectious, or metabolic lesion of the brain, even without history of seizure, and without anticonvulsant medication
History of seizures or epilepsy
Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold (see appendix 2)
Pregnant females
If a women of child bearing age is unsure of the pregnancy, and does not want to take the pregnancy test Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease such as spinal stenosis, spina bifida, MS, or herniated disk
Metal plate in skull
Individuals with scalp shrapnel, cochlear implants, or aneurysm clips
Individuals taking Bupropion, Dolutegravir, Lacosamide, Trilaciclib, or PR Interval prolonging drugs

Sites / Locations

Shirley Ryan AbilitylabRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Placebo Comparator

Experimental

Arm Label

Dalfampridine (4-AP)+STDP+training

Placebo+STDP+training

Dalfampridine (4-AP)+STDP+training for extended sessions

Arm Description

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of 4-AP, STDP stimulation and training.

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of placebo drug, STDP stimulation and training.

The long-term effects of the functional recovery of the lower-limb muscles will be determined after 40 sessions of 4-AP, STDP stimulation and training.

Outcomes

Primary Outcome Measures

Change in TMEPs

Electrical stimulation will be performed placing the cathode on the upper thoracic between the spinal processes between T3 and T4 vertebrae and the anode at ~10 cm above

Change in MVC

Individuals will perform a maximum voluntary contraction (MVC) of each targeted muscle (quadriceps femoris, tibialis anterior or soleus) through surface electrodes secured to the skin over the belly of each muscle.

Secondary Outcome Measures

Change in MEPs

Transcranial magnetic stimuli (TMS) will be delivered to the optimal scalp position for activation of quadriceps femoris and tibialis anterior muscles. The optimal scalp position will be determined by moving the coil in small steps along the hand/arm/leg representation of the primary motor cortex to find the region where the largest MEP can be evoked with the minimum intensity in the targeted muscles.

Change in 10-meter walk test

We will use the 10-meter walk test to quantify walking speed in meters per second. The same percentage of body-weight support will be used during pre- and post-assessments. Less time to walk 10-meter indicates better outcome.

Change in 6-minute walk test

We will measure the distance walked over 6 minutes. The same percentage of body-weight support will be used as in 10-meter walk test. The longer distance walked during 6 minutes indicates better outcome.

Change in International Standards for Neurological Classification of Spinal Cord Injury exam

Motor part of the exam is completed through the testing of key muscle functions corresponding to 10 myotomes (C5-T1 and L2-S1) for right and left side separately. The strength of each muscle function is graded on a six-point scale ranging from 0 meaning complete paralysis to 5 meaning full strength. The total motor score is sum of all motor scores range from 0-100. Sensory part of the exam is completed through the testing of a key point in each of the 28 dermatomes (from C2 to S4-5) on the right and left sides of the body. At each of these key points, two aspects of sensation are examined: light touch and pin prick. Appreciation of light touch and pin prick sensation at each of the key points is separately scored on a three-point scale; 0-absent, 1-altered, and 2-normal or intact. 56 is the maximum score for both light touch and pin prick and the total sensory score ranges from 0 to 112. Higher scores represent better outcome for motor and sensory scores.

Change in surveys on ambulation, basic mobility, bowel and bladder management difficulties

The name of the questionnaire is Spinal Cord Injury Quality of Life (SCI-QOL) and we used four subdomains: ambulation, self-care, bowel management difficulties, and bladder management difficulties. Scores on all subdomains of SCI-QOL use a standardized T metric, with a mean of 50 and a standard deviation of 10. Ambulation and basic mobility subdomains assess the ability to engage in walking activities in different locations that vary based on speed, time and condition and the ability to manage stairs under different conditions. Bowel management difficulties subdomain measures an ability to carry out a bowel program; concerns about incontinence and bowel accidents; and the impact of bowel management on everyday living. Bladder management difficulties subdomain measures ability to carry out a bladder program; worry about bladder accidents; concerns about implementing one's bladder program; and impact on everyday living. Higher scores on all subdomains represent better outcome.

Change in morphological characterization of corticospinal and reticulospinal pathways in MRI

In order to identify descending motor tract, brainstem and C2 cervical spinal cord images will be acquired on a MAGNETOM Prisma 3T system using a 64-channel birdcage head/neck coil. To quantify the effect of atrophy in oblique directions, we will measure the radius from the cord shape center of mass to its border, R(α), for angles α over the whole circle with an angular resolution of 6°. Mean measures of all 5 axial slices will be used for statistical from nerve roots, noise, and other confounding effects.

Full Information

NCT ID

NCT05447676

First Posted

June 20, 2022

Last Updated

June 19, 2023

Sponsor

Shirley Ryan AbilityLab

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

1. Study Identification

Unique Protocol Identification Number

NCT05447676

Brief Title

Effects of 4-AP on Functional SCI Recovery

Official Title

Effects of 4-AP on Functional Recovery After Spinal Cord Injury

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 30, 2022 (Actual)

Primary Completion Date

June 30, 2024 (Anticipated)

Study Completion Date

June 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Shirley Ryan AbilityLab

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to test a strategy to potentiate functional recovery of lower limb motor function in individuals with spinal cord injury (SCI). The FDA approved drug, Dalfampridine (4-AP). 4-AP will be used in combination of Spike-timing-dependent plasticity (STDP) stimulation and STDP stimulation with limb training.

Detailed Description

Currently, research has shown that 4-AP has a positive effect on sensory and motor function rehabilitation in humans with chronic SCI in addition to decreasing recorded spasticity, increased sensation, and decreased pain. Utilizing limb training to promote recovery of motor function is enhanced by eliciting STDP in the limbs. An important strength of this aim is the combination of training and STDP, which aims at enhancing the beneficial effects of motor training by promoting plasticity in the corticospinal pathway. We hypothesize that introducing 4-AP into the STDP stimulation and STDP stimulation with lower-limb training will further improve motor function rehabilitation in patients with chronic SCI.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Spinal Cord Injury

Keywords

SCI, Neural control, 4-AP, Walking, Neuroplasticity

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Crossover Assignment

Model Description

Arm 1 and 2 will be studied with randomized crossover design; Participants for Arm 3 will be recruited after finishing the sessions for Arms 1 and 2. Participants who were finished the Arms 1 and 2 study procedures can also participate in Arm 3 study procedures.

Masking

ParticipantCare ProviderOutcomes Assessor

Masking Description

Participants will not know if they receive 4-AP or placebo over the course of the study and the investigators are also blinded except for PI (Dr. Monica Perez).

Allocation

Randomized

Enrollment

44 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dalfampridine (4-AP)+STDP+training

Arm Type

Active Comparator

Arm Description

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of 4-AP, STDP stimulation and training.

Arm Title

Placebo+STDP+training

Arm Type

Placebo Comparator

Arm Description

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of placebo drug, STDP stimulation and training.

Arm Title

Dalfampridine (4-AP)+STDP+training for extended sessions

Arm Type

Experimental

Arm Description

The long-term effects of the functional recovery of the lower-limb muscles will be determined after 40 sessions of 4-AP, STDP stimulation and training.

Intervention Type

Drug

Intervention Name(s)

Dalfampridine

Other Intervention Name(s)

4-AP

Intervention Description

The study drug (4-AP) will be administered as a 10 mg dose.

Intervention Type

Other

Intervention Name(s)

Placebo drug

Intervention Description

The pharmacy will also provide a placebo drug that looks identical to 4-AP to verify participants and therapists do not know who is receiving the drug and who is receiving the placebo.

Intervention Type

Other

Intervention Name(s)

STDP stimulation

Other Intervention Name(s)

spike timing dependent plasticity

Intervention Description

Paired stimulation will be given to the spinal cord and to peripheral nerves so that the signals are received at the spinal cord at a specific interval.

Intervention Type

Behavioral

Intervention Name(s)

Exercise training

Intervention Description

Lower-limb exercises will involve over-ground walking, treadmill, walking and stair climbing training.

Primary Outcome Measure Information:

Title

Change in TMEPs

Description

Electrical stimulation will be performed placing the cathode on the upper thoracic between the spinal processes between T3 and T4 vertebrae and the anode at ~10 cm above

Time Frame

TMEPs measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training and Placebo+STDP+training groups. TMEPs measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in MVC

Description

Time Frame

MVC measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training and Placebo+STDP+training groups. MVC measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Secondary Outcome Measure Information:

Title

Change in MEPs

Description

Time Frame

MEPs measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training and Placebo+STDP+training groups. MEPs measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in 10-meter walk test

Description

Time Frame

10-m walk measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training and Placebo+STDP+training groups. 10-m walk measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in 6-minute walk test

Description

Time Frame

6-min walk measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training & Placebo+STDP+training groups. 6-min walk measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in International Standards for Neurological Classification of Spinal Cord Injury exam

Description

Time Frame

Scores measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training and Placebo+STDP+training groups. Scores measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in surveys on ambulation, basic mobility, bowel and bladder management difficulties

Description

Time Frame

SCI-QOL measured at baseline and 3 weeks (10 sessions) for Dalfampridine+STDP+training & Placebo+STDP+training groups. SCI-QOL measured at baseline, 6 weeks (20 sessions), and 12 weeks (40 sessions) for extended sessions group.

Title

Change in morphological characterization of corticospinal and reticulospinal pathways in MRI

Description

Time Frame

MRI measured at baseline and 12 weeks (40 sessions) for Dalfampridine+STDP+training for extended sessions group.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and females between ages 18-85 years SCI at least 4 weeks post injury Spinal Cord injury at or above L2 ASIA A,B,C, or D, complete or incomplete Possess the following abilities The ability to perform a small visible contraction with dorsiflexion and hip flexor muscles Exclusion Criteria: Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic disease Any history of renal impairment Any debilitating disease prior to the SCI that caused exercise intolerance Premorbid, ongoing major depression or psychosis, altered cognitive status History of head injury or stroke Vascular, traumatic, tumoral, infectious, or metabolic lesion of the brain, even without history of seizure, and without anticonvulsant medication History of seizures or epilepsy Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold (see appendix 2) Pregnant females If a women of child bearing age is unsure of the pregnancy, and does not want to take the pregnancy test Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease such as spinal stenosis, spina bifida, MS, or herniated disk Metal plate in skull Individuals with scalp shrapnel, cochlear implants, or aneurysm clips Individuals taking Bupropion, Dolutegravir, Lacosamide, Trilaciclib, or PR Interval prolonging drugs

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Monica A Perez, PT, PhD

Phone

312-238-2886

mperez04@sralab.org

First Name & Middle Initial & Last Name or Official Title & Degree

Sri Ramya Vemulakonda, M.B.B.S

Phone

3122382993

svemulakon@sralab.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Monica A Perez, PT, PhD

Organizational Affiliation

Shirley Ryan Ability Lab

Official's Role

Principal Investigator

Facility Information:

Facility Name

Shirley Ryan Abilitylab

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Monica A Perez, PT, PhD

12. IPD Sharing Statement

Plan to Share IPD

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Effects of 4-AP on Functional SCI Recovery

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