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

Phase 1

Recruiting

• Conditions: SCI - Spinal Cord Injury
• Interventions: Drug: Dalfampridine; Drug: Placebo; Other: STDP stimulation; Behavioral: Exercise training

• Registration Number: NCT06853015
• Lead Sponsor: Shirley Ryan AbilityLab

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 twice-daily 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. 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 Timeline

• Study Start: 2025-02-01
• Study First Submitted: 2025-02-14
• Study First Submitted QC: 2025-02-24
• Study First Posted: 2025-03-25
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-01
• Last Update Posted: 2025-04-03
• Primary Completion: 2026-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 27

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
4-AP(AM) + STDP stimulation + training + 4-AP(PM)	Dalfampridine	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.
4-AP(AM) + STDP stimulation + training + 4-AP(PM)	STDP stimulation	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.
Placebo(AM) + STDP stimulation + training + Placebo(PM)	Placebo	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.
Placebo(AM) + STDP stimulation + training + Placebo(PM)	STDP stimulation	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.
4-AP(AM) + STDP stimulation + training + 4-AP(PM)	Exercise training	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.
Placebo(AM) + STDP stimulation + training + Placebo(PM)	Exercise training	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.

Primary Outcome Measures

Name	Time	Method
Change in TMEPs	TMEPs measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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	MVC measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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.

Secondary Outcome Measures

Name	Time	Method
Change in 10-meter walk test	10-m walk measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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	6-min walk measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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	Scores measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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 EPT	EPT will be measured at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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).
Change in surveys on ambulation, basic mobility, bowel and bladder management difficulties	SCI-QOL measured at at baseline, at 6 weeks (post 20 sessions), and at 12 weeks (post 40 sessions).	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	MRI measured at baseline, and at 12 weeks (post 40 sessions).	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.

Trial Locations

Locations (1)

Shirley Ryan Abilitylab; 🇺🇸 Chicago, Illinois, United States