Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness

• Sponsor: Edward Hines Jr. VA Hospital (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT02025439
• Collaborator: (none)
• Enrollment: 4
• Locations: 2
• Arms: 2
• Duration (Months): 28.9
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with Amantadine relative to rTMS Alone and Amantadine Alone for persons in chronic states of seriously impaired consciousness. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or accelerates functional recovery.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Device: rTMS; Drug: Amantadine	N/A

Detailed Description

The R21 research objective is to examine the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with Amantadine (TMS + Amantadine) relative to rTMS Alone and Amantadine Alone for persons in chronic states of seriously impaired consciousness. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or accelerates functional recovery. This hypothesis is based on (a) preliminary data indicating partially improved neurobehavioral functioning mechanistically related to rTMS-induced neural activity and connectivity as well as improved integrity of white fiber tracts, (b) relationship between dopamine (DA) and common traumatic brain injury (TBI) impairments, (c) role of DA in mediating consciousness, (d) the commonality between and DA and rTMS-targeted pathways, (e) clinical efficacy and safety of Amantadine, (f) mechanisms of action of Amantadine, and (g) the association between rTMS and Amantadine with up-regulating brain derived neurotrophic factor. The rationale is that pairing rTMS with Amantadine will have a complementary and synergistic effect on factors promoting conscious behavior. The specific aims are to: (1) Demonstrate that rTMS+Amantadine is safely tolerated, (2) Determine neurobehavioral effect of rTMS+Amantadine, and (3) Characterize pre-and post-treatment neural changes in neural activation. Aim 1 is based on our preliminary safety data and safety data regarding Amantadine. To address Aims 2 & 3 we use a repeated measures baseline control design with randomized treatment orders yielding three treatment groups; rTMS + Amantadine, rTMS Alone and Amantadine Alone. Analyses for Aims 2 and 3 involve comparing these treatment groups according to neurobehavioral growth trajectories, mean amount of neural activation and connectivity within and between brain regions, and indices of fiber tract directionality.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rTMS Alone followed by rTMS+AMA Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.After first completing rTMS Alone, subjects will receive rTMS plus Amantadine. A total of 30 rTMS sessions are provided, 2 rTMS sessions per day, four days per week, while receiving 200mg of Amantadine daily.	Device: rTMS; Other Names: Repetitive Transcranial Magnetic Stimulation ; Drug: Amantadine; Other Names: Symadine Symmetrel
Experimental: AMA Alone followed by rTMS+AMA Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days. After first completing Amantadine Alone subjects will receive rTMS plus Amantadine. A total of 30 rTMS sessions are provided, 2 rTMS sessions per day, four days per week, while receiving 200mg of Amantadine daily.	Device: rTMS; Other Names: Repetitive Transcranial Magnetic Stimulation ; Drug: Amantadine; Other Names: Symadine Symmetrel

Outcome Measures

Primary Outcome Measures

1. Intensity of Adverse Event [30 days after treatment "alone" and an additional 30 days after treatment "combined" (i.e., 60 days)]

   If an adverse event occurred, the intensity was also indicated. The intensity of an adverse event was determined using a scale from 1-5 with 5 being the worst. The purpose of the study is to examine safety of rTMS combined with AMA relative to rTMS Alone and AMA alone. Results are not reported "per arm" rather, the arms are combined so as to compare the outcome when the interventions are provided separately (i.e., rTMS alone and amantadine alone) vs interventions are combined (rTMS +Amantadine alone).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18-64 years of age

• Suffered a severe brain injury of traumatic origin at least 1-year prior to study enrollment

• Remain in a state of disordered consciousness

• Brain injuries will include injury with resulting coup-contre-coup injuries, excluding persons with trauma due to blunt injuries and/or non-traumatic encephalopathy

Exclusion Criteria:

• Have 1 or more Amantadine contraindications: On monoamino oxidase inhibitor-B, hypersensitivity/idiosyncrasy to sympathomimetic amines, uncontrolled hypertension, glaucoma or Congestive Heart Failure

• Have contraindications to Amantadine Dose of 200 mg Daily as determined by estimated Glomerular Filtration Rate (eGFR) ≤ 60 (ml/min)

• Abnormal results of Liver Function Test at screening

• Receiving anti-epileptic medications to control active seizures or have had a documented seizure within three months of study enrollment

• Incurred large cortically based ischemic infarction/encephalomalacia subsequent to TBI

• Have documented history of previous TBI, psychiatric illness (DSM criteria) and/or organic brain syndrome such as Alzheimer's

• Are using medications which may interfere with Amantadine and cannot be safely titrated or discontinued

• Are pregnant

• Have implanted cardiac pacemaker or defibrillator, cochlear implant, nerve stimulator, intracranial metal clips

• Have MRI and/or TMS contraindications such as: History of claustrophobia, metal in eyes/face, shrapnel/bullet remnants in brain

• Are fully conscious as indicated by a score of 6 on the Motor Function scale and/or a score of 2 on the Communication scale of the CRS-R,

• Are within first year of injury

• Are <18 years of age and > 65 years of age

• Have an injury or condition due to blunt trauma only or non-traumatic encephalopathy

• Have programmable CSF shunt or are ventilator dependent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
2	Edward Hines, Jr. VA Hospital	Hines	Illinois	United States	60141

Sponsors and Collaborators

• Edward Hines Jr. VA Hospital

Investigators

• Principal Investigator: Theresa BenderPape, DrPH, Edward Hines Jr. VA Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Louise-Bender Pape T, Rosenow J, Lewis G, Ahmed G, Walker M, Guernon A, Roth H, Patil V. Repetitive transcranial magnetic stimulation-associated neurobehavioral gains during coma recovery. Brain Stimul. 2009 Jan;2(1):22-35. doi: 10.1016/j.brs.2008.09.004. Epub 2008 Oct 23.
• Pape TL, Rosenow J, Lewis G. Transcranial magnetic stimulation: a possible treatment for TBI. J Head Trauma Rehabil. 2006 Sep-Oct;21(5):437-51. Review.

• Responsible Party: Theresa Pape, Clinical Neuroscientist, Edward Hines Jr. VA Hospital
• ClinicalTrials.gov Identifier: NCT02025439
• Other Study ID Numbers: 1R21HD075192
• First Posted: Jan 1, 2014
• Last Update Posted: Aug 24, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Theresa Pape, Clinical Neuroscientist, Edward Hines Jr. VA Hospital: Traumatic Brain Injury; Transcranial Magnetic Stimulation; Amantadine; Vegetative State; Minimally Conscious State
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Amantadine

Study Results

Participant Flow

Pre-assignment Detail	nothing to report

Arm/Group Title	rTMS Alone Followed by rTMS+AMA	AMA Alone Followed by rTMS+AMA
Arm/Group Description	Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.upon completion of assigned treatment order, the subject will then receive 30 sessions of combination therapy of rTMS + Amantadine rTMS	Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days. upon completion of assigned treatment order, the subject will then receive 30 sessions of combination therapy of rTMS + Amantadine Amantadine
Period Title: Overall Study
STARTED	2	2
COMPLETED	2	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	rTMS First	Amantadine First	Total
Arm/Group Description	Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week. rTMS	Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days. Amantadine	Total of all reporting groups
Overall Participants	2	2	4
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 100%	2 100%	4 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	24	33	28
Sex: Female, Male (Count of Participants)
Female	0 0%	1 50%	1 25%
Male	2 100%	1 50%	3 75%
Region of Enrollment (participants) [Number]
United States	2 100%	2 100%	4 100%

Outcome Measures

1. Primary Outcome

Title	Intensity of Adverse Event
Description	If an adverse event occurred, the intensity was also indicated. The intensity of an adverse event was determined using a scale from 1-5 with 5 being the worst. The purpose of the study is to examine safety of rTMS combined with AMA relative to rTMS Alone and AMA alone. Results are not reported "per arm" rather, the arms are combined so as to compare the outcome when the interventions are provided separately (i.e., rTMS alone and amantadine alone) vs interventions are combined (rTMS +Amantadine alone).
Time Frame	30 days after treatment "alone" and an additional 30 days after treatment "combined" (i.e., 60 days)

Outcome Measure Data

Analysis Population Description

Results are reported both "per arm" at the end of 30 days when a single treatment (either rTMS or AMA) was ended, and additional results are reported with both arms combined to report the outcome after 60 days

Arm/Group Title	rTMS Alone	rTMS+AMA	AMA Alone
Arm/Group Description	Subjects assigned to start with rTMS Alone	All subjects that received rTMS plus Amantadine. A total of 30 rTMS sessions are provided, 2 rTMS sessions per day, four days per week, while receiving 200mg of Amantadine daily.	Subjects assigned to start with amantadine alone
Measure Participants	2	4	2
Mean (Standard Deviation) [score on a scale]	0.5 (0.52)	0.98 (0.38)	0.33 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rTMS Alone, rTMS+AMA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.071
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	3 months and 6 months
Adverse Event Reporting Description	A Clinical Data Monitoring Log was used to record. Most were collected daily. CNS changes were collected once during MRI scan. clinical indices include fatigue, fever, hypertension, hypotension, infection at IV site, weight loss/gain, seizures, skin breakdown at IV site, skin breakdown on scalp, general skin breakdown, sweating and neurochecks hourly between rTMS sessions on the same day.
Arm/Group Title	rTMS Alone		rTMS+AMA		AMA Alone
Arm/Group Description	Subjects assigned to rTMS Alone 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.		Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days.Then, A total of 30 rTMS sessions are provided, 2 rTMS sessions per day, four days per week, while receiving 200mg of Amantadine daily.		Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days.
All Cause Mortality
	rTMS Alone		rTMS+AMA		AMA Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/4 (0%)		0/2 (0%)
Serious Adverse Events
	rTMS Alone		rTMS+AMA		AMA Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/4 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	rTMS Alone		rTMS+AMA		AMA Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		4/4 (100%)		2/2 (100%)
General disorders
Fatigue	2/2 (100%)	2	2/4 (50%)	19	1/2 (50%)	4
Fever	1/2 (50%)	1	0/4 (0%)	0	0/2 (0%)	0
hypertension	1/2 (50%)	1	2/4 (50%)	7	0/2 (0%)	0
Hypotension	0/2 (0%)	0	2/4 (50%)	10	1/2 (50%)	8
Infection at IV site	0/2 (0%)	0	2/4 (50%)	2	0/2 (0%)	0
Weight Loss	0/2 (0%)	0	1/4 (25%)	2	0/2 (0%)	0
Neurocheck	2/2 (100%)	3	3/4 (75%)	8	0/2 (0%)	0
Seizure	0/2 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Skin breakdown at venous site	0/2 (0%)	0	1/4 (25%)	4	0/2 (0%)	0
General Skin Integrity	0/2 (0%)	0	1/4 (25%)	2	0/2 (0%)	0
Skin breakdown at scalp	0/2 (0%)	0	1/4 (25%)	4	0/2 (0%)	0
Sweating	1/2 (50%)	1	1/4 (25%)	2	0/2 (0%)	0

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.