Double Dose 4-AP on Functional Recovery After Spinal Cord Injury

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

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 twice-daily in combination of Spike-timing-dependent plasticity (STDP) stimulation and STDP stimulation with limb training.

Study Overview

• Status: Recruiting
• Conditions: SCI - Spinal Cord Injury
• Intervention / Treatment: Other: STDP stimulation; Behavioral: Exercise training; Drug: Dalfampridine; Drug: Placebo

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. A pharmacokinetic study showed that twice-daily administration of sustained release 4-AP maintains a steadier plasma concentration. 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 to enhance the beneficial effects of motor training by promoting plasticity in the corticospinal pathway. Training effects on physiological pathways will be explored and correlated with lower limb motor function. We hypothesize that introducing 4-AP into the STDP stimulation and STDP stimulation with training will further improve motor function rehabilitation in patients with chronic SCI.

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Monica Perez, PT, PhD; Phone Number: 312-238-2886; Email: mperez04@sralab.org
• Study Contact Backup: Name: Bing Chen, PhD; Phone Number: 312-238-7895; Email: bchen03@sralab.org

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Shirley Ryan Abilitylab
      • Contact: Monica Perez, PT, PhD; Phone Number: 312-238-2886; Email: mperez04@sralab.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and females between ages 18-85 years
• SCI 6 months post injury
• Spinal Cord injury at or above L2
• ASIA A, B, C, or D, complete or incomplete
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4-AP(AM) + STDP stimulation + training + 4-AP(PM); The effects of the functional recovery of the lower-limb muscles will be determined after 40 sessions of twice-daily-dosing 4-AP, STDP stimulation and training.	Other: STDP stimulation; 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.; Other Names: spike timing dependent plasticity; Hebbian stimulation; Behavioral: Exercise training; Lower-limb exercises will involve over-ground walking, treadmill, walking and stair climbing training.; Drug: Dalfampridine; The study drug (4-AP) will be administered as a 10 mg dose twice a day.
Placebo Comparator: Placebo(AM) + STDP stimulation + training + Placebo(PM); The effects of the functional recovery of the lower-limb muscles will be determined after 40 sessions of twice-daily-dosing Placebo, STDP stimulation and training.	Other: STDP stimulation; 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.; Other Names: spike timing dependent plasticity; Hebbian stimulation; Behavioral: Exercise training; Lower-limb exercises will involve over-ground walking, treadmill, walking and stair climbing training.; Drug: Placebo; The placebo provided by the SRAL pharmacy that looks identical to the 4-AP, will be administered twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	TMEPs measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
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. Ankle flexion torque will be measured by measured by force sensors.	MVC measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	10-m walk measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
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.	6-min walk measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
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.	Scores measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
Change in EPT	We use electrical perceptual threshold (EPT) to measures the minimum amount of electrical current that the participant can perceive when applied to the lower limb dermatomes (L2-S2).	EPT will be measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
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.	SCI-QOL measured at at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).
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.	MRI measured at baseline, and at 12 weeks (post 40 sessions).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in spinal excitability	We will measure spinal excitability by measuring F-wave and H-reflex in soleus and TA muscles. Post-Activation Depression (PAD) of the H-reflex will also be quantified in soleus muscle	Changes in spinal excitability will be measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).

Collaborators and Investigators

• Sponsor: Shirley Ryan AbilityLab
• Investigators: Principal Investigator: Monica Perez, PT, PhD, Shirley Ryan Ability Lab

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Actual): March 1, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: February 14, 2025
• First Submitted That Met QC Criteria: February 24, 2025
• First Posted (Actual): February 28, 2025

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: rehabilitation; spinal cord injury; neurostimulation; 4-AP
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Amines; Aminopyridines; 4-Aminopyridine; Exercise
• Other Study ID Numbers: STU00221545

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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