Identifying and Treating Arousal Related Deficits in Neglect and Dysphagia

• Sponsor: University of Arkansas (Other)
• Overall Status: Completed
• CT.gov ID: NCT01085903
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 28
• Locations: 2
• Arms: 2
• Duration (Months): 65
• Patients Per Site: 14
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to examine how stroke can alter arousal, alertness, neglect and dysphagia, and whether a medication, modafinil, can improve arousal.

Condition or Disease	Intervention/Treatment	Phase
Spatial Neglect; Dysphagia	Drug: Modafinil; Drug: Placebo; Behavioral: Baseline; Behavioral: CPS; Behavioral: Post CPS; Behavioral: Follow up	Phase 2

Detailed Description

Neglect and dysphagia are two of the most problematic behavioral disorders encountered in stroke rehabilitation with 300,000 patients affected annually in the US. Both disorders impede progress in therapy and both lead to costly medical complications, like falls which are associated with neglect and aspiration pneumonia and malnutrition which are associated with dysphagia. No widely accepted pharmacological treatment exists for either disorder.

A new direction of this application is to view neglect and dysphagia as different disorders that share a common deficit in magnitude estimation (ME). ME refers to one's ability to perceive the intensity of sensory stimulation. Deficits in ME explain how much of a stimulus is neglected by stroke patients. Sensory deficits are also known to produce dysphagia. Perceptual deficits influence how patients response to stimuli like failing to act on all stimuli present (neglect) and failing to generate swallowing reflexes sufficient for normal bolus flow (dysphagia).

We know from previous work that ME is altered by change in cortical arousal following stroke (decreased or hypoarousal). Hypoarousal is evidenced by objective and subjective post-stroke fatigue and daytime sleepiness which occurs in 50% of stroke patients and can persist chronically. Increasing arousal could potentially reverse the perceptual deficits associated with hypoarousal and improve neglect and dysphagia. This proposal manipulates arousal in two ways. Cold pressor stimulation (CPS), immersing the foot in cold water for 50 seconds, is used to increase arousal and reverse neglect and dysphagia temporarily. A brief, 3-day trial of modafinil (Provigil) versus placebo is then used in stroke patients to learn if a positive response to cold-pressor stimulation can predicts patients who respond positively to modafinil.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Identifying and Treating Arousal Related Deficits in Neglect and Dysphagia
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: normal subjects Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions.	Behavioral: Baseline; Observations made at baseline before any intervention; Other Names: baseline observation ; Behavioral: CPS; Submerging each participant's foot into ice water (36-44 F) for 50 seconds.; Other Names: cold pressor stimulation ; Behavioral: Post CPS; 20 minutes following the CPS condition.; Other Names: post cold pressor stimulation ; Behavioral: Follow up; Follow up testing occurred at 3 months; Other Names: three month follow up
Active Comparator: stroke subjects Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive modafinil, placebo, baseline, CPS, Post CPS and Follow up interventions.	Drug: Modafinil; 200 mg once daily with morning meal for three days administered only to stroke patients; Other Names: Provigil ; Drug: Placebo; Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients; Other Names: inert ; Behavioral: Baseline; Observations made at baseline before any intervention; Other Names: baseline observation ; Behavioral: CPS; Submerging each participant's foot into ice water (36-44 F) for 50 seconds.; Other Names: cold pressor stimulation ; Behavioral: Post CPS; 20 minutes following the CPS condition.; Other Names: post cold pressor stimulation ; Behavioral: Follow up; Follow up testing occurred at 3 months; Other Names: three month follow up

Outcome Measures

Primary Outcome Measures

1. P50 Percent Habituation Score [baseline and after three days of intervention]

   This is an electrophysiological measure of arousal - a percent change in the P50 evoked response potential amplitudes with a 250 ms inter stimulus interval. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).

Secondary Outcome Measures

1. PVT Fastest 10 Percent of Reaction Times [baseline and after three days of intervention]

   This is a behavioral measure of arousal - the fastest 10 percent of all cued reaction time trials. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).

2. Power Function Exponent for Oral Bolus Estimation [baseline and after three days of intervention]

   This is a behavioral measure of sensation in the oral cavity. The power function exponent is equal to the slope of a regression equation relating bolus size to a person's estimate of that size. An exponent below one implies an underestimate of bolus size. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).

3. Time to Swallow Puree Food [baseline and after three days of intervention]

   This is a behavioral measure of swallowing - the time it takes for pureed food to transition across a part of the throat. The difference score is calculated as CPS - placebo and as modafinil - placebo (for stroke subjects only).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent

• Willingness to complete study procedures

• Ability to comprehend and sign informed consent

• Evidence of unilateral, ischemic stroke based on:

• Neuroimaging (clinically obtained imaging studies showing evidence of stroke)

• Acceptable categories of stroke include:

• Unilateral ischemic stroke

• Atherothrombotic stroke

• Cardioembolic stroke

• Lacunar stroke >1.5 cm

• Chronic stable, unilateral hemorrhagic stroke

• Or Behavioral evidence of stroke including:

• Hemiplegia

• Unilateral sensory impairment

• Localized higher cortical dysfunction (e.g. neglect,dysphagia, apraxia)

Exclusion Criteria:

• Cardiac valvular disease

• Left heart hypertrophy

• Poorly controlled hypertension

• Active variant angina

• Pre-menopausal women capable of having children, including those using active contraception (precaution for study medication and not applicable to normal subjects)

• Severe renal or hepatic disease

• History of psychosis or substance abuse

• Patients on other Central Nervous System (CNS) stimulants, dopamine agonists or antagonists (antipsychotics)

• Severe speech comprehension deficit and/or inability to communicate responses

• Allergies that could put the research subject at risk during the course of the study

• Cannot speak English

• Active cerebral neurologic disease other than stroke such as multiple sclerosis or Alzheimer's Disease

• Active psychiatric illness except past history of treated depression or anxiety disorders

• For persons needing an MRI - standard MRI exclusion criteria (cardiac pacemaker or defibrillator, artificial heart valves, metallic aneurysm clips eye or ear implants, implanted insulin or infusion pumps, battery activated stimulators, and history of claustrophobia)

• Concomitant medications excluded: Based on recommendations of manufacturer, the following concomitant medications are excluded: Tricyclic antidepressants and Monoamine oxidase (MAO) inhibitors. Any other CNS stimulation producing medications. Antifungal agents Itraconazole or Ketoconazole as plasma concentrations of modafinil may be increased.

• Stroke patients will be excluded from the modafinil trial if they cannot swallow a capsule.

• Stroke patients are excluded if they are able to become pregnant

• Any other criteria that the PI or study physicians feel would put the volunteer's health at risk during the course of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Conway Regional Rehabilitation Hospital	Conway	Arkansas	United States	72035
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205

Sponsors and Collaborators

• University of Arkansas
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Mark S Mennemeier, PhD, University of Arkansas
• Principal Investigator: Gary McCullough, PhD, University of Central Arkansas

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arkansas
• ClinicalTrials.gov Identifier: NCT01085903
• Other Study ID Numbers: 110644; R21HD055677
• First Posted: Mar 12, 2010
• Last Update Posted: Oct 18, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by University of Arkansas: Spatial Neglect; Dysphagia; Arousal; Modafinil; Stroke
• Additional relevant MeSH terms: Deglutition Disorders; Vasoconstrictor Agents; Modafinil

Study Results

Participant Flow

Arm/Group Title	Normal Subjects Baseline	Stroke Subjects: Placebo Then Modafinil	Stroke Subjects: Modafinil Then Placebo
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, Cold Pressor Stimulation (CPS), Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition.	Denotes sequence Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition.	Denotes sequence Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition.
Period Title: Overall Study
STARTED	21	4	3
COMPLETED	21	4	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Normal Subjects	Stroke Subjects	Total
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline, CPS, and Post CPS and then are randomized to modafinil or placebo. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients	Total of all reporting groups
Overall Participants	21	7	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.286 (21.462)	71.429 (9.914)	58.2 (15.3)
Sex: Female, Male (Count of Participants)
Female	8 38.1%	3 42.9%	11 39.3%
Male	13 61.9%	4 57.1%	17 60.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.8%	1 14.3%	2 7.1%
White	18 85.7%	6 85.7%	24 85.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 9.5%	0 0%	2 7.1%

Outcome Measures

1. Primary Outcome

Title	P50 Percent Habituation Score
Description	This is an electrophysiological measure of arousal - a percent change in the P50 evoked response potential amplitudes with a 250 ms inter stimulus interval. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).
Time Frame	baseline and after three days of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Subjects: Baseline vs CPS	Stroke Subjects: Baseline vs CPS	Stroke Subjects: Modafinil	Stroke Subjects: Placebo	Stroke Subjects Placebo vs Modafinil
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive modafinil, placebo, baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients	Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients	Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients
Measure Participants	21	7	7	7	7
Mean (Standard Deviation) [percentage of change in amplitude]	-44.12 (59.29)	-45.84 (228.09)	113.63 (154.5)	61.41 (102.5)	52.223 (222.94)

2. Secondary Outcome

Title	PVT Fastest 10 Percent of Reaction Times
Description	This is a behavioral measure of arousal - the fastest 10 percent of all cued reaction time trials. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).
Time Frame	baseline and after three days of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Subjects: Baseline vs CPS	Stroke Subjects: Baseline vs CPS	Stroke Subjects: Modafinil	Stroke Subjects: Placebo	Stroke Subjects Placebo vs Modafinil
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive the baseline and CPS conditions and then are randomized to the placebo and modafinil interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive the baseline and CPS conditions and then are randomized to the placebo and modafinil interventions. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive the baseline and CPS conditions and then are randomized to the placebo and modafinil interventions. Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive the baseline and CPS conditions and then are randomized to the placebo and modafinil interventions. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients
Measure Participants	21	7	7	7	7
Mean (Standard Deviation) [milliseconds]	-10.57 (21.66)	20.57 (29.20)	244.71 (186.62)	235.64 (150.62)	9.07 (38.73)

3. Secondary Outcome

Title	Power Function Exponent for Oral Bolus Estimation
Description	This is a behavioral measure of sensation in the oral cavity. The power function exponent is equal to the slope of a regression equation relating bolus size to a person's estimate of that size. An exponent below one implies an underestimate of bolus size. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).
Time Frame	baseline and after three days of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Subjects: Baseline vs CPS	Stroke Subjects: Baseline vs CPS	Stroke Subjects: Modafinil	Stroke Subjects: Placebo	Stroke Subjects Placebo vs Modafinil
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients
Measure Participants	21	7	7	7	7
Mean (Standard Deviation) [exponent]	.014 (.113)	-.004 (.196)	.54 (.17)	.49 (.19)	.04 (.08)

4. Secondary Outcome

Title	Time to Swallow Puree Food
Description	This is a behavioral measure of swallowing - the time it takes for pureed food to transition across a part of the throat. The difference score is calculated as CPS - placebo and as modafinil - placebo (for stroke subjects only).
Time Frame	baseline and after three days of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Subjects: Baseline vs CPS	Stroke Subjects: Baseline vs CPS	Stroke Subjects: Modafinil	Stroke Subjects: Placebo	Stroke Subjects Placebo vs Modafinil
Arm/Group Description	Normal subjects are persons without stroke who receive baseline and CPS conditions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds.	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients	Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive baseline and CPS conditions before being randomized to placebo and modafinil. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patientseal for three days administered only to stroke patients
Measure Participants	21	7	7	7	7
Mean (Standard Deviation) [seconds]	.029 (.121)	-.058 (.512)	.48 (1.05)	.12 (.11)	.36 (1.06)

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Adverse Events were recorded in a cumulative fashion for stroke participants, and not according to the intervention received at the time of the event or according to the assigned intervention sequence.
Arm/Group Title	Normal Subjects		Stroke Subjects
Arm/Group Description	Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions. Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition. Follow up: Follow up testing occurred at 3 months		Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive modafinil, placebo, baseline, CPS, Post CPS and Follow up interventions. Modafinil: 200 mg once daily with morning meal for three days administered only to stroke patients Placebo: Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients Baseline: Observations made at baseline before any intervention CPS: Submerging each participant's foot into ice water (36-44 F) for 50 seconds. Post CPS: 20 minutes following the CPS condition. Follow up: Follow up testing occurred at 3 months
All Cause Mortality
	Normal Subjects		Stroke Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Normal Subjects		Stroke Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		2/7 (28.6%)
Musculoskeletal and connective tissue disorders
broken hip	0/21 (0%)		1/7 (14.3%)
Vascular disorders
stroke	0/21 (0%)		1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Normal Subjects		Stroke Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		6/7 (85.7%)
Nervous system disorders
headache	0/21 (0%)	0	2/7 (28.6%)	2
difficulty sleeping	0/21 (0%)	0	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
rash	0/21 (0%)	0	3/7 (42.9%)	3
Vascular disorders
vasovagal response	1/21 (4.8%)	1	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.