Amantadine for the Treatment of Traumatic Brain Injury Ir... | NCT00779324

ID	Type	Description	Link
H133A080035	Other Grant/Funding Number	NIDRR

Status Module

Name	Class
Indiana University	OTHER
University of Washington	OTHER
The Institute for Rehabilitaion and Research Foundation	OTHER
Spaulding Rehabilitation Hospital

Description Module

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.

Label	Type	Description	Intervention Names
Amantadine	Experimental	Amantadine 100 mg every morning and Noon	Drug: Amantadine Hydrochloride
Placebo	Placebo Comparator	Placebo tablets	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Amantadine Hydrochloride	Drug	100 mg every morning and noon	Amantadine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer 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).	Day 28

Secondary Outcomes

Measure	Description	Time Frame
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer 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).

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Flora M Hammond, MD	Carolinas Rehabilitation	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Indiana University and the Rehabilitation Hospital of Indiana		Indianapolis	Indiana	46254	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
38145314	Derived	Hammond FM, Zafonte RD, Sherer M, Bell KR, Bogner J, Malec JF, Tang Q, Jang JH. Assessing the benefits and risks of amantadine for irritability and aggression after traumatic brain injury. PM R. 2024 Jul;16(7):661-668. doi: 10.1002/pmrj.13122. Epub 2024 Feb 20.
29742960	Derived	Hammond FM, Sherer M, Malec JF, Zafonte RD, Dikmen S, Bogner J, Bell KR, Barber J, Temkin N. Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial. J Neurotrauma. 2018 Oct 1;35(19):2298-2305. doi: 10.1089/neu.2018.5767. Epub 2018 Jun 7.

Label	URL
Carolinas Rehabilitation	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
FG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
BG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00082 BG00186 BG002168

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer 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).

Posted

Number

percentage of participants NPI improve>2

Day 28

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants	OG00080 OG00181

Title

Denominators

Categories

Title	Measurements
	OG00066.3 OG00166.7

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Chi-squared		0.9554		Difference in percents	-0.4			2-Sided	95	-14.7	13.9					Other

Secondary

Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer Day 28

Posted

Median

Standard Deviation

score on a scale

Day 28

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants

Secondary

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

Posted

Number

percentage of participants NPI improve>2

Day 28

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts

Secondary

Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 28

Posted

Median

Standard Deviation

score on a scale

Day 28

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants

Secondary

Clinical Global Impressions Day 28

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.

Posted

Median

Standard Deviation

score on a scale

28 Days

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants	OG000

Secondary

Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory Irritability Domain Rated by Observers Day 60

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).

Posted

Number

percentage of participants NPI improve>2

60 days

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Secondary

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

Posted

Number

percentage of participants NPI improve>2

Day 60

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts

Secondary

Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observers Day 60

Posted

Median

Standard Deviation

score on a scale

Day 60

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants

Secondary

Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 60

Posted

Median

Standard Deviation

score on a scale

Day 60

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants

Secondary

Clinical Global Impressions Day 60

Posted

Median

Standard Deviation

score on a scale

60 days

ID	Title	Description
OG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon
OG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Myocardial infarction	Cardiac disorders	Non-systematic Assessment	EG0000 events0 affected82 at risk EG0011 events1 affected86 at risk
Other infection	Infections and infestations	Non-systematic Assessment	EG0000 events0 affected82 at risk EG0011 events1 affected86 at risk
Urinary tract infection	Infections and infestations	Non-systematic Assessment	EG0001 events1 affected82 at risk EG0010 events0 affected86 at risk
Paranoia	Psychiatric disorders	Non-systematic Assessment	EG0001 events1 affected82 at risk EG0010 events0 affected86 at risk
Other general medical	General disorders	Non-systematic Assessment	EG0001 events1 affected82 at risk EG0010 events0 affected86 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
headache	Nervous system disorders	Non-systematic Assessment	EG0005 events5 affected82 at risk EG0012 events2 affected86 at risk
Insomnia/ sleep disturbance	Nervous system disorders	Non-systematic Assessment	EG0007 events7 affected82 at risk EG00110 events10 affected86 at risk
Connstipation	Gastrointestinal disorders	Non-systematic Assessment	EG0006 events6 affected82 at risk EG0011 events1 affected86 at risk
Diarrhea	Gastrointestinal disorders	Non-systematic Assessment	EG0005 events5 affected82 at risk EG0011 events1 affected86 at risk
Other general medical	General disorders	Non-systematic Assessment	EG00010 events10 affected82 at risk EG00113 events13 affected86 at risk
Other	General disorders	Non-systematic Assessment	EG0003 events3 affected82 at risk EG0016 events6 affected86 at risk

ID	Term
D001930	Brain Injuries
D000374	Aggression
D000070642	Brain Injuries, Traumatic
D001519	Behavior

ID	Term
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D006259	Craniocerebral Trauma
D020196	Trauma, Nervous System
D014947	Wounds and Injuries
D000096762	Aberrant Motor Behavior in Dementia
D001526	Behavioral Symptoms
D012919	Social Behavior

ID	Term
D000218	Adamantane
D001952	Bridged-Ring Compounds
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Amantadine	Amantadine 100 mg every morning and Noon Amantadine Hydrochloride: 100 mg every morning and noon			3	82	36	82
EG001	Placebo	Placebo tablets Placebo: one placebo tablet every morning and 12 Noon			2	86	33	86