Amantadine for the Treatment of Traumatic Brain Injury Irritability and Aggression: A Multi-site Study

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT00779324
• Collaborator: Indiana University (Other), University of Washington (Other), The Institute for Rehabilitaion and Research Foundation (Other), Spaulding Rehabilitation Hospital (Other), Ohio State University (Other), Icahn School of Medicine at Mount Sinai (Other)
• Enrollment: 168
• Locations: 6
• Arms: 2
• Duration (Months): 45
• Patients Per Site: 28
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to study the effect of amantadine on irritability and aggression caused by traumatic brain injury.

Condition or Disease	Intervention/Treatment	Phase
Brain Injury; Aggression	Drug: Amantadine Hydrochloride; Drug: Placebo	N/A

Detailed Description

PURPOSE OF PROJECT: To study the effect of amantadine 100 mg administered twice daily compared to placebo on irritability from baseline to treatment Day 28.

SUMMARY OF PROJECT: It is anticipated that 168 subjects with 168 corresponding subject informants will be recruited for the study. Carolinas Rehabilitation, the lead center, and 5 collaborating centers will enroll approximately 28 subjects each.

Subjects will be recruited primarily from the clinics. Also, letters will be sent to patients in our data base. If the first encounter with research personnel is by telephone, the research assistant will obtain verbal (telephone) consent from the subject's informant for the Neuropsychiatric Inventory (NPI) for subject irritability. The score on this questionnaire must be ≥ 6 for qualification. This allows pre-screening to take place and avoid an unnecessary clinic visit.

Subjects who consent and qualify will be randomized in a 1:1 ratio, amantadine to placebo. Stratification to randomization group will occur based on the presence of depression defined by a Beck's Depression Inventory-II (BDI-II) score ≥ 13. Randomized subjects will receive amantadine or placebo 100 mg twice daily every morning and 12 Noon. There will be 4 clinic visits. Visits will occur at baseline, for consenting and screening, day 28, day 60 and day 90. At all 4 clinic visits, both the subject and the informant will be given questionnaires regarding the subject's behavior and mood. Follow up phone calls will occur each week that the subject is not seen in the clinic until the end of the study. Follow up phone calls will assess for study medication compliance, adverse events and concomitant medication changes. Day 60 ends the period of the Randomized Clinical Trial phase of the study and the subjects will begin the 1 month continuation phase of the study when all participants receive active amantadine.

The following questionnaires will be used as measures of irritability for the subject and the informant: Neuropsychiatric Inventory (NPI), State Trait Anger Expression Inventory (STAXI-2), and Global Impression of Change.

The following questionnaires will be dispensed to the subject only: Short Form -12, Satisfaction With Life Scale, Patient Health Questionnaire, Beck Depression Inventory, Brief Symptom Inventory, Family Assessment Device, Fatigue Impact Scale, and tests of cognitive function. The Glasgow Outcome Score-Extended will be completed by the research assistant using information obtained primarily from the informant.

The Investigator will complete the Clinical Global Impression of change at Visits 1, 2, 3, and 4.

History and Physical Exam, creatinine level (kidney function) will be obtained for safety and tolerability. Serum pregnancy tests will be drawn at screening for females of childbearing potential.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Parallel-Group, Randomized, Double-Blind, Placebo-Controlled Trial of Amantadine Hydrochloride in the Treatment of Chronic Traumatic Brain Injury Irritability and Aggression: A Replication Study
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amantadine Amantadine 100 mg every morning and Noon	Drug: Amantadine Hydrochloride; 100 mg every morning and noon; Other Names: Symmetrel
Placebo Comparator: Placebo Placebo tablets	Drug: Placebo; one placebo tablet every morning and 12 Noon

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer Day 28 [Day 28]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

Secondary Outcome Measures

1. Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer Day 28 [Day 28]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

2. Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 28 [Day 28]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

3. Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 28 [Day 28]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

4. Clinical Global Impressions Day 28 [28 Days]

   Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.

5. Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory Irritability Domain Rated by Observers Day 60 [60 days]

   As described above for the primary measure, assessed as a secondary measure at Day 60. The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

6. Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 60 [Day 60]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

7. Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observers Day 60 [Day 60]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

8. Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 60 [Day 60]

   The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

9. Clinical Global Impressions Day 60 [60 days]

   Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Closed head injury (defined as impaired brain function resulting from externally inflicted trauma without penetrating injury) at least 6 months prior to enrollment

• Irritability that is either new or worse than the level of irritability before the traumatic brain injury, by report of the Observer or person with TBI

• Age at time of enrollment: 16 to 75 years

• Voluntary informed consent and authorization of participant and informant

• Subject and informant willing to comply with the protocol

• Informant-rated NPI Irritability Domain score 6 or greater (moderate-to-severe irritability)

• Medically and neurologically stable during the month prior to enrollment

• If taking antidepressant, anxiolytic, hypnotic, or stimulant medications, no change anticipated in these medications during the month prior to enrollment or during the 90-day participation

• No change in therapies or medications planned during the 90-day participation

• No surgeries planned during the 90-day participation

• Vision, hearing, speech, motor function, and comprehension sufficient to complete interviews

• Observer (e.g.: family member, close friend, employer) with whom subject interacts sufficiently to observe occurrences of irritability. The observer interacts with the participant for a period long enough and of a nature to be able to judge the participant's irritability. The interactions would need to be adequate to judge observer distress over the irritability, severity of irritability and frequency of irritability on the following scale: < once weekly; once per week; several times per week, but not every day; essentially continuous.

Exclusion Criteria:

• Previous participation in the Carolinas TBI Model System amantadine irritability study

• Ingestion of amantadine hydrochloride during the month prior to enrollment

• Potential subject without a reliable informant

• Penetrating head injury as defined by head injury due to gunshot, projectile or foreign object

• Injury < 6 months prior to enrollment

• Inability to interact sufficiently for communication with caregiver

• Clinical signs of active infection

• Diagnosis of seizure in the month prior to enrollment

• Creatinine clearance <60 mL/min

• Pregnancy (Beta-HCG + females of child-bearing potential) and lactating females

• Concurrent use of first generation neuroleptic agents or phenelzine

• History of schizophrenia or psychosis

• Active concern of schizophrenia or psychosis

• Diagnosis of progressive or additional neurologic disease that affects brain function, except stroke that occurs at th same time as the TBI

• Previous allergy or adverse reaction to amantadine hydrochloride

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University and the Rehabilitation Hospital of Indiana	Indianapolis	Indiana	United States	46254
2	Spaulding Rehabilitation	Boston	Massachusetts	United States	02114
3	Carolinas Rehabilitation	Charlotte	North Carolina	United States	28203
4	The Ohio State University	Columbus	Ohio	United States	43210
5	TIRR Memorial Herman	Houston	Texas	United States	77030
6	University of Washington	Seattle	Washington	United States	98195

Sponsors and Collaborators

• Wake Forest University Health Sciences
• Indiana University
• University of Washington
• The Institute for Rehabilitaion and Research Foundation
• Spaulding Rehabilitation Hospital
• Ohio State University
• Icahn School of Medicine at Mount Sinai

Investigators

• Principal Investigator: Flora M Hammond, MD, Carolinas Rehabilitation

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Carolinas Rehabilitation
• Carolinas HealthCare System

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT00779324
• Other Study ID Numbers: 09-08-11B; H133A080035
• First Posted: Oct 24, 2008
• Last Update Posted: Jul 12, 2022
• Last Verified: Aug 1, 2021

• Keywords provided by Wake Forest University Health Sciences: traumatic brain injury; irritability; aggression; amantadine; behavior
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Aggression; Amantadine

Study Results

Participant Flow

Recruitment Details	Participant recruitment occurred 2009 - 2013 via referrals, letters from physicians, newsletters, and local brain injury support groups.

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Period Title: Overall Study
STARTED	82	86
Completed 28-day Mid-point	80	81
COMPLETED	75	82
NOT COMPLETED	7	4

Baseline Characteristics

Arm/Group Title	Amantadine	Placebo	Total
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon	Total of all reporting groups
Overall Participants	82	86	168
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.18 (12.67)	38.23 (12.36)	39.21 (12.52)
Sex: Female, Male (Count of Participants)
Female	18 22%	20 23.3%	38 22.6%
Male	64 78%	66 76.7%	130 77.4%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer Day 28
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	80	81
Number [percentage of participants NPI improve>2]	66.3 80.9%	66.7 77.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9554
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percents
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -14.7 to 13.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer Day 28
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	80	81
Median (Standard Deviation) [score on a scale]	-4 (3.39)	-4 (3.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 28
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	80	81
Number [percentage of participants NPI improve>2]	51.3 62.6%	40.5 47.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1662
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percents
	Estimated Value	10.8
	Confidence Interval	(2-Sided) 95%; -4.2 to 25.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 28
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	80	81
Median (Standard Deviation) [score on a scale]	-3 (3.58)	-2 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3488
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Clinical Global Impressions Day 28
Description	Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.
Time Frame	28 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	80	81
Median (Standard Deviation) [score on a scale]	3.00 (1.14)	3.00 (0.92)

6. Secondary Outcome

Title	Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory Irritability Domain Rated by Observers Day 60
Description	As described above for the primary measure, assessed as a secondary measure at Day 60. The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	75	82
Number [percentage of participants NPI improve>2]	74.7 91.1%	68.3 79.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percents
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 95%; -7.2 to 20
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 60
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	75	82
Number [percentage of participants NPI improve>2]	60.5 73.8%	48.8 56.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1373
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percents
	Estimated Value	11.7
	Confidence Interval	(2-Sided) 95%; -3.3 to 26.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observers Day 60
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	75	82
Median (Standard Deviation) [score on a scale]	-5 (3.12)	-4 (3.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 60
Description	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Time Frame	Day 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	75	82
Median (Standard Deviation) [score on a scale]	-3 (2.83)	-2 (2.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amantadine, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0353
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Clinical Global Impressions Day 60
Description	Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Measure Participants	82	75
Median (Standard Deviation) [score on a scale]	3.00 (1.05)	3.00 (1.08)

Adverse Events

Arm/Group Title	Amantadine		Placebo
Arm/Group Description	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon		Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
All Cause Mortality
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/82 (3.7%)		2/86 (2.3%)
Cardiac disorders
Myocardial infarction	0/82 (0%)	0	1/86 (1.2%)	1
General disorders
Other general medical	1/82 (1.2%)	1	0/86 (0%)	0
Infections and infestations
Other infection	0/82 (0%)	0	1/86 (1.2%)	1
Urinary tract infection	1/82 (1.2%)	1	0/86 (0%)	0
Psychiatric disorders
Paranoia	1/82 (1.2%)	1	0/86 (0%)	0
Other (Not Including Serious) Adverse Events
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/82 (43.9%)		33/86 (38.4%)
Gastrointestinal disorders
Connstipation	6/82 (7.3%)	6	1/86 (1.2%)	1
Diarrhea	5/82 (6.1%)	5	1/86 (1.2%)	1
General disorders
Other general medical	10/82 (12.2%)	10	13/86 (15.1%)	13
Other	3/82 (3.7%)	3	6/86 (7%)	6
Nervous system disorders
headache	5/82 (6.1%)	5	2/86 (2.3%)	2
Insomnia/ sleep disturbance	7/82 (8.5%)	7	10/86 (11.6%)	10

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.