The Role of Trans-spinal Direct Current Stimulation (tsDCS) in Treating Patients With Hand Spasticity After Stroke

• Sponsor: Northwell Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT03080454
• Collaborator: PathMaker Neurosystems Inc. (Industry), Dr. Zaghloul Ahmed (Other)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 17.9
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate if 5 consecutive sessions of PathMaker anodal DoubleStim treatment, which combines non-invasive stimulation of the spinal cord (tsDCS- trans-spinal direct current stimulation) and of the median nerve at the peripheral wrist (pDCS-- peripheral direct current stimulation), can significantly reduce spasticity of the wrist and hand after stroke.

Condition or Disease	Intervention/Treatment	Phase
Stroke; Cerebrovascular Accident (CVA); Hemiparesis; Spasticity as Sequela of Stroke; Muscle Spasticity; Upper Extremity Paralysis	Device: sham Doublestim; Device: anodal Doublestim	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: All participants received both stimulation conditions (sham Doublestim and anodal Doublestim), separated by a 1-week washout period.All participants received both stimulation conditions (sham Doublestim and anodal Doublestim), separated by a 1-week washout period.
• Masking: Single (Participant)
• Masking Description: The sham stimulation condition preceded the anodal stimulation condition for all participants, and subjects were told they would receive both conditions, but were blinded to order of assignment.
• Primary Purpose: Treatment
• Official Title: The Effect of Treatment With the PathMaker Myoregulator Neuromodulation System Incorporating Trans-spinal Direct Current Stimulation (tsDCS) in Patients With Severe Hand Spasticity After Stroke
• Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: Mar 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Sham Doublestim Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.	Device: sham Doublestim; PathMaker MyoRegulator device; Other Names: sham trans-spinal direct current stimulation + peripheral direct current stimulation (tsDCS + pDCS)
Active Comparator: Anodal Doublestim Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.	Device: anodal Doublestim; PathMaker MyoRegulator device; Other Names: anodal trans-spinal direct current stimulation + peripheral direct current stimulation (tsDCS + pDCS)

Outcome Measures

Primary Outcome Measures

1. Mean Percent Change From Baseline in Area Under the Curve for Objectively Measured Spastic Catch Response of the Wrist Flexors at Fast Speed [baseline, final session at day 5, 1 week FU]

   Subjects' wrists were passively extended at fast speed by a stepper motor to induce a spastic catch response, and its resistance torque was calculated in Newton meters (Nm). Mean percent change from baseline in the area under the curve for the resistance torque were compared across two timepoints (final session at day 5 and 1 week follow-up) in two conditions (sham vs. anodal Doublestim)

Secondary Outcome Measures

1. Mean Modified Tardieu Scale (MTS) Score [baseline, final session at day 5, 1 week FU]

   The Modified Tardieu Scale (MTS) quantifies muscle spasticity for each joint at slow and fast velocities on a 0-5 point scale. MTS scores at fast velocity were summed across 11 joints of the upper extremity (for a total of 0-55 points), with lower scores indicating improved spasticity. Mean summed MTS scores (out of 55 total points) were compared across two timepoints (final session at day 5 and 1 week FU) in two conditions (sham vs. anodal Doublestim).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. First single focal unilateral hemisphere lesion with diagnosis verified by brain imaging (MRI or CT scans) that occurred at least 6 months prior

2. Cognitive function sufficient to understand the experiments and follow instructions

3. A Modified Ashworth Scale score between 1-3 points for wrist flexor and extensor muscles

4. A minimum of 15 degrees wrist passive range of motion (ROM) for wrist flexion and extension from wrist neutral position

Exclusion Criteria:

1. Focal brainstem or thalamic infarcts

2. Prior surgical treatments for spasticity of the upper limb

3. Ongoing use of central nervous system (CNS)-active medications

4. Ongoing use of psychoactive medications, such as stimulants, antidepressants, and anti-psychotic medications

5. Botox or phenol alcohol treatment within 12 weeks of enrollment

6. Pregnancy in women, as determined by self-report

7. History of spinal cord injury or weakness

8. Chronic pain

9. Peripheral neuropathy including insulin dependent diabetes as determined by case history

10. Presence of additional potential tsDCS risk factors:

• Damaged skin at the site of stimulation (i.e., skin with ingrown hairs, acne, razor nicks, wounds that have not healed recent scar tissue, broken skin, etc.)

• Presence of an electrically, magnetically or mechanically activated implant (including cardiac pacemaker), an intracerebral vascular clip, or any other electrically sensitive support system

• Highly conductive metal in any part of the body, including metal injury to the eye (jewelry must be removed during stimulation)

• Past history of seizures or unexplained spells of loss of consciousness during the previous 36 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Feinstein Institute for Medical Research	Manhasset	New York	United States	11030

Sponsors and Collaborators

• Northwell Health
• PathMaker Neurosystems Inc.
• Dr. Zaghloul Ahmed

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 18, 2017
• Informed Consent Form - Aug 18, 2017

More Information

Publications

• Ahmed Z. Trans-spinal direct current stimulation alters muscle tone in mice with and without spinal cord injury with spasticity. J Neurosci. 2014 Jan 29;34(5):1701-9. doi: 10.1523/JNEUROSCI.4445-13.2014.
• Ahmed Z. Trans-spinal direct current stimulation modifies spinal cord excitability through synaptic and axonal mechanisms. Physiol Rep. 2014 Sep 28;2(9). pii: e12157. doi: 10.14814/phy2.12157. Print 2014 Sep 1.
• Bocci T, Vannini B, Torzini A, Mazzatenta A, Vergari M, Cogiamanian F, Priori A, Sartucci F. Cathodal transcutaneous spinal direct current stimulation (tsDCS) improves motor unit recruitment in healthy subjects. Neurosci Lett. 2014 Aug 22;578:75-9. doi: 10.1016/j.neulet.2014.06.037. Epub 2014 Jun 23.
• Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A. Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol. 2008 Nov;119(11):2636-40. doi: 10.1016/j.clinph.2008.07.249. Epub 2008 Sep 10.
• Samaddar S, Vazquez K, Ponkia D, Toruno P, Sahbani K, Begum S, Abouelela A, Mekhael W, Ahmed Z. Transspinal direct current stimulation modulates migration and proliferation of adult newly born spinal cells in mice. J Appl Physiol (1985). 2017 Feb 1;122(2):339-353. doi: 10.1152/japplphysiol.00834.2016. Epub 2016 Dec 8.
• Truini A, Vergari M, Biasiotta A, La Cesa S, Gabriele M, Di Stefano G, Cambieri C, Cruccu G, Inghilleri M, Priori A. Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans. Eur J Pain. 2011 Nov;15(10):1023-7. doi: 10.1016/j.ejpain.2011.04.009. Epub 2011 May 14.
• Winkler T, Hering P, Straube A. Spinal DC stimulation in humans modulates post-activation depression of the H-reflex depending on current polarity. Clin Neurophysiol. 2010 Jun;121(6):957-61. doi: 10.1016/j.clinph.2010.01.014. Epub 2010 Feb 11.

• Responsible Party: Bruce Volpe, Principal Investigator, Northwell Health
• ClinicalTrials.gov Identifier: NCT03080454
• Other Study ID Numbers: 15-110
• First Posted: Mar 15, 2017
• Last Update Posted: Apr 5, 2021
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bruce Volpe, Principal Investigator, Northwell Health: stroke; CVA; Spasticity; hemiparesis; rehabilitation; trans-spinal direct current stimulation (tsDCS); non-invasive stimulation
• Additional relevant MeSH terms: Muscle Spasticity; Stroke; Paralysis; Paresis

Study Results

Participant Flow

Pre-assignment Detail	All participants received both the anodal and sham trans-spinal direct current stimulation + peripheral direct current stimulation (tsDCS + pDCS) conditions, and sequence of stimulation conditions was the same across participants, with sham stimulation preceding active stimulation.

Arm/Group Title	Sham Doublestim, Then Anodal Doublestim
Arm/Group Description	Participants underwent 2-3 baseline evaluations, then received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, sham FU measures were collected. Participants then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation), and again underwent follow-up measures 1 week after the anodal intervention. For all participants, the sham condition preceded the anodal Doublestim condition.
Period Title: Baseline
STARTED	26
COMPLETED	24
NOT COMPLETED	2
Period Title: Baseline
STARTED	24
COMPLETED	24
NOT COMPLETED	0
Period Title: Baseline
STARTED	24
COMPLETED	24
NOT COMPLETED	0
Period Title: Baseline
STARTED	24
COMPLETED	23
NOT COMPLETED	1
Period Title: Baseline
STARTED	23
COMPLETED	19
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Sham Doublestim, Then Anodal Doublestim
Arm/Group Description	Crossover design study: Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation).
Overall Participants	26
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 46.2%
>=65 years	14 53.8%
Sex: Female, Male (Count of Participants)
Female	10 38.5%
Male	16 61.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 7.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 7.7%
White	20 76.9%
More than one race	2 7.7%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%

Outcome Measures

1. Primary Outcome

Title	Mean Percent Change From Baseline in Area Under the Curve for Objectively Measured Spastic Catch Response of the Wrist Flexors at Fast Speed
Description	Subjects' wrists were passively extended at fast speed by a stepper motor to induce a spastic catch response, and its resistance torque was calculated in Newton meters (Nm). Mean percent change from baseline in the area under the curve for the resistance torque were compared across two timepoints (final session at day 5 and 1 week follow-up) in two conditions (sham vs. anodal Doublestim)
Time Frame	baseline, final session at day 5, 1 week FU

Outcome Measure Data

Analysis Population Description

Three subjects (out of 19) were found to be significant outliers for normality testing, and were consequently removed from analysis.

Arm/Group Title	Sham Doublestim	Anodal Doublestim
Arm/Group Description	Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.	Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.
Measure Participants	16	16
Mean percent change at final session (day 5)	13.678 (5.537)	-8.783 (4.911)
Mean percent change at 1 week follow-up (FU)	15.927 (5.537)	-16.333 (6.180)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Doublestim, Anodal Doublestim
	Comments
	Type of Statistical Test	Equivalence
	Comments	Statistical analysis for mean percent change from baseline in area under the curve for the resistance torque measure across 2 conditions (anodal vs. sham Doublestim) and at 2 timepoints (final session at day 5 and 1 week FU). Null hypothesis is that there was no difference in mean percent change in area under the curve between anodal and sham Doublestim conditions. A significance level of 0.05 was used (two-sided).
Statistical Test of Hypothesis	p-Value	0.004
	Comments	A 2x2 repeated measures ANOVA was performed with condition (mean percent change in anodal vs. sham condition) and time (final session at day 5 and 1 week FU in each condition) as factors. A significance level of 0.05 was used (two-sided).
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Mean Modified Tardieu Scale (MTS) Score
Description	The Modified Tardieu Scale (MTS) quantifies muscle spasticity for each joint at slow and fast velocities on a 0-5 point scale. MTS scores at fast velocity were summed across 11 joints of the upper extremity (for a total of 0-55 points), with lower scores indicating improved spasticity. Mean summed MTS scores (out of 55 total points) were compared across two timepoints (final session at day 5 and 1 week FU) in two conditions (sham vs. anodal Doublestim).
Time Frame	baseline, final session at day 5, 1 week FU

Outcome Measure Data

Analysis Population Description

Three subjects (out of 19) were found to be significant outliers for normality testing, and were consequently removed from analysis.

Arm/Group Title	Sham Doublestim	Anodal Doublestim
Arm/Group Description	Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.	Participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). For all participants, the sham condition preceded the anodal Doublestim condition.
Measure Participants	16	16
mean score at final session (day 5)	23.375 (0.275)	21.625 (0.275)
mean score at 1 week FU	23.125 (0.275)	21.975 (0.309)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Doublestim, Anodal Doublestim
	Comments
	Type of Statistical Test	Equivalence
	Comments	Statistical analysis for mean Tardieu Scale Score summed across 11 joints of the upper extremity in 2 conditions (anodal vs. sham Doublestim) and at 2 timepoints (final session at day 5 and 1 week FU). Null hypothesis is that there was no difference in mean change between anodal and sham Doubleestim conditions. A significance level of 0.05 was used (two-sided).
Statistical Test of Hypothesis	p-Value	0.003
	Comments	A 2x2 repeated measures ANOVA was performed with condition (mean score in anodal vs. sham condition) and time (final session at day 5 and 1 week FU in each condition) as factors. A significance level of 0.05 was used (two-sided).
	Method	ANOVA
	Comments

Adverse Events

Time Frame	eight weeks for each subject
Adverse Event Reporting Description	Safety population included all participants who enrolled in study.
Arm/Group Title	Baseline		Sham Doublestim (5 Days) + Sham FU (7days)		Anodal Doublestim (5 Days) + Anodal FU (7days)
Arm/Group Description	Prior to any treatment interventions, participants performed 2-3 clinical and objective measure baseline evaluations.		Following baseline evaluations, participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they received a sham follow-up (FU) measure 7 days post-sham stimulation. Participants then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation), followed by an anodal FU measure 7 days post-anodal Doublestim.		Following baseline evaluations, participants first received 5 daily, consecutive 20 min sessions of sham Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation). After a washout period of 1 week, they received a sham follow-up (FU) measure 7 days post-sham stimulation. Participants then received 5 daily, consecutive 20 min sessions of anodal Doublestim (trans-spinal direct current stimulation + peripheral direct current stimulation), followed by an anodal FU measure 7 days post-anodal Doublestim.
All Cause Mortality
	Baseline		Sham Doublestim (5 Days) + Sham FU (7days)		Anodal Doublestim (5 Days) + Anodal FU (7days)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/24 (0%)		0/24 (0%)
Serious Adverse Events
	Baseline		Sham Doublestim (5 Days) + Sham FU (7days)		Anodal Doublestim (5 Days) + Anodal FU (7days)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/26 (7.7%)		0/24 (0%)		2/24 (8.3%)
Injury, poisoning and procedural complications
Hip fracture	1/26 (3.8%)	1	0/24 (0%)	0	0/24 (0%)	0
Nervous system disorders
seizure	0/26 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2
Vascular disorders
hypotensive vasovagal event	1/26 (3.8%)	1	0/24 (0%)	0	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Baseline		Sham Doublestim (5 Days) + Sham FU (7days)		Anodal Doublestim (5 Days) + Anodal FU (7days)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/24 (0%)		1/24 (4.2%)
Injury, poisoning and procedural complications
persistent skin redness	0/26 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.