Trial Outcomes & Findings for Amantadine for the Treatment of Traumatic Brain Injury Irritability and Aggression: A Multi-site Study (NCT NCT00779324)

NCT ID: NCT00779324

Last Updated: 2022-07-12

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 168 participants
• Primary outcome timeframe: Day 28
• Results posted on: 2022-07-12

Participant Flow

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

Participant milestones

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

Reasons for withdrawal

Measure	Amantadine Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Overall Study Lost to Follow-up	2	1
Overall Study Withdrawal by Subject	4	2
Overall Study Missed visit	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Amantadine n=82 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=86 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon	Total n=168 Participants Total of all reporting groups
Age, Continuous	40.18 years STANDARD_DEVIATION 12.67 • n=5 Participants	38.23 years STANDARD_DEVIATION 12.36 • n=7 Participants	39.21 years STANDARD_DEVIATION 12.52 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	20 Participants n=7 Participants	38 Participants n=5 Participants
Sex: Female, Male Male	64 Participants n=5 Participants	66 Participants n=7 Participants	130 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=80 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=81 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer Day 28	66.3 percentage of participants NPI improve>2	66.7 percentage of participants NPI improve>2

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=80 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=81 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer Day 28	-4 score on a scale Standard Deviation 3.39	-4 score on a scale Standard Deviation 3.36

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=80 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=81 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 28	51.3 percentage of participants NPI improve>2	40.5 percentage of participants NPI improve>2

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=80 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=81 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 28	-3 score on a scale Standard Deviation 3.58	-2 score on a scale Standard Deviation 3.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Amantadine n=80 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=81 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Clinical Global Impressions Day 28	3.00 score on a scale Standard Deviation 1.14	3.00 score on a scale Standard Deviation 0.92

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=75 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=82 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory Irritability Domain Rated by Observers Day 60	74.7 percentage of participants NPI improve>2	68.3 percentage of participants NPI improve>2

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=75 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=82 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 60	60.5 percentage of participants NPI improve>2	48.8 percentage of participants NPI improve>2

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=75 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=82 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observers Day 60	-5 score on a scale Standard Deviation 3.12	-4 score on a scale Standard Deviation 3.42

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Amantadine n=75 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=82 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 60	-3 score on a scale Standard Deviation 2.83	-2 score on a scale Standard Deviation 2.83

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Amantadine n=82 Participants Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=75 Participants Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Clinical Global Impressions Day 60	3.00 score on a scale Standard Deviation 1.05	3.00 score on a scale Standard Deviation 1.08

Adverse Events

Amantadine

Serious events: 3 serious events

Other events: 36 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Measure	Amantadine n=82 participants at risk Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=86 participants at risk Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Cardiac disorders Myocardial infarction	0.00% 0/82	1.2% 1/86 • Number of events 1
Infections and infestations Other infection	0.00% 0/82	1.2% 1/86 • Number of events 1
Infections and infestations Urinary tract infection	1.2% 1/82 • Number of events 1	0.00% 0/86
Psychiatric disorders Paranoia	1.2% 1/82 • Number of events 1	0.00% 0/86
General disorders Other general medical	1.2% 1/82 • Number of events 1	0.00% 0/86

Other adverse events

Measure	Amantadine n=82 participants at risk Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon	Placebo n=86 participants at risk Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
Nervous system disorders headache	6.1% 5/82 • Number of events 5	2.3% 2/86 • Number of events 2
Nervous system disorders Insomnia/ sleep disturbance	8.5% 7/82 • Number of events 7	11.6% 10/86 • Number of events 10
Gastrointestinal disorders Connstipation	7.3% 6/82 • Number of events 6	1.2% 1/86 • Number of events 1
Gastrointestinal disorders Diarrhea	6.1% 5/82 • Number of events 5	1.2% 1/86 • Number of events 1
General disorders Other general medical	12.2% 10/82 • Number of events 10	15.1% 13/86 • Number of events 13
General disorders Other	3.7% 3/82 • Number of events 3	7.0% 6/86 • Number of events 6

Additional Information

Flora Hammond, MD

Indiana University School of Medicine

Phone: 3173292106

Email: flora.hammond@rhin.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place