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Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)

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ClinicalTrials.gov Identifier: NCT00970944
Recruitment Status : Completed
First Posted : September 3, 2009
Results First Posted : September 24, 2012
Last Update Posted : September 24, 2012
Sponsor:
Collaborator:
U.S. Department of Education
Information provided by (Responsible Party):
Joseph T Giacino, Spaulding Rehabilitation Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Traumatic Brain Injury
Interventions Drug: Amantadine Hydrochloride
Drug: Placebo
Enrollment 184
Recruitment Details February 23,2003 through March 15, 2010. Eleven rehabilitations centers in the USA (8) and Europe (3)
Pre-assignment Details  
Arm/Group Title Amantadine HCL Placebo
Hide Arm/Group Description 100mg BID administered for 2 weeks, then increased to 150mg BID in week 3 if change on primary outcome measure (ie Disability Rating Scale, DRS) was less than 2 points after week 2. If change in DRS score remained less than 2 points after week 3, dose was increased to 200mg BID in week 4. Visually identical compound administered in the same manner (ie enterally) as the actual study drug.
Period Title: Overall Study
Started 87 97
Completed 86 95
Not Completed 1 2
Reason Not Completed
Death             1             0
Physician Decision             0             2
Arm/Group Title Amantadine HCL Placebo Total
Hide Arm/Group Description 100mg BID administered for 2 weeks, then increased to 150mg BID in week 3 if change on primary outcome measure (ie Disability Rating Scale, DRS) was less than 2 points after week 2. If change in DRS score remained less than 2 points after week 3, dose was increased to 200mg BID in week 4. Visually identical compound administered in the same manner (ie enterally) as the actual study drug. Total of all reporting groups
Overall Number of Baseline Participants 87 97 184
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 87 participants 97 participants 184 participants
<=18 years
5
   5.7%
1
   1.0%
6
   3.3%
Between 18 and 65 years
82
  94.3%
96
  99.0%
178
  96.7%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 87 participants 97 participants 184 participants
35.5  (15.3) 37.2  (15.4) 36.4  (15.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 87 participants 97 participants 184 participants
Female
23
  26.4%
28
  28.9%
51
  27.7%
Male
64
  73.6%
69
  71.1%
133
  72.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 87 participants 97 participants 184 participants
United States 61 73 134
Denmark 3 2 5
Germany 23 22 45
1.Primary Outcome
Title Disability Rating Scale: Functional Status
Hide Description Measure of function after traumatic brain injury (TBI) intended to measure function from "coma to community." Minimum score= 0; Maximum score= 29 (High scores are indicative of greater degree of disability).
Time Frame Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6.
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted according to the intention-to-treat principle. 184 subjects were randomized and included for analysis. Since missing data were infrequent and unrelated to the study outcome, imputation methods were not undertaken.
Arm/Group Title Amantadine Placebo
Hide Arm/Group Description:
Amantadine (200-400 mg/day)
Visually identical compound administered in the same manner (ie enterally) as the actual study drug.
Overall Number of Participants Analyzed 87 97
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 4 (Primary endpoint) 17.3  (4.7) 18.7  (4.5)
Week 6 (Drug washout) 17.1  (5.2) 17.8  (5.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amantadine, Placebo
Comments The planned sample size of 184 patients provided 80% power to detect a difference between the AH and placebo in the rate of Disability Rating Scale (DRS) score change of 0.3 points/week (1.22 DRS point mean difference by the end of the 4-week treatment interval). Two blinded interim analyses were conducted at 60 and 120 patients recruited using the O'Brien-Fleming boundary, with alpha levels of 0.0005 and 0.014. The final analysis used an alpha level of 0.045.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments The final analysis used a significance level of 0.045.
Method Mixed Models Analysis
Comments Final analysis adjusted for early v. late enrollment relative to date of injury, baseline CRS-R rating category (MCS vs. VS), and site.
Method of Estimation Estimation Parameter Slope
Estimated Value -0.24
Confidence Interval 95%
-0.41 to -0.07
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.088
Estimation Comments [Not Specified]
2.Secondary Outcome
Title JFK Coma Recovery Scale-Revised: Neurobehavioral Status
Hide Description

Measure of neurobehavioral function and clinical change for individuals with severe alterations of consciousness.

Minimum score= 0; Maximum score= 23 (Higher scores are indicative of a higher-level of neurobehavioral function).

Time Frame Week 4 (primary endpoint); Week 6 (post-washout)
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted according to the ITT principle so that all 184 patients randomized were included for analysis. Imputation techniques were not undertaken since missing data were infrequent and unrelated to study outcome.
Arm/Group Title Amantadine Placebo
Hide Arm/Group Description:
Amantadine (200-400 mg/day)
Visually identical compound administered in the same manner (ie enterally) as the study drug.
Overall Number of Participants Analyzed 87 97
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 4 (Primary endpoint) 15.8  (6.1) 14.2  (6.6)
Week 6 (Post-washout) 15.7  (6.3) 15.1  (6.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amantadine, Placebo
Comments We will have 80% power to detect a one point difference in DRS score between the groups across the four week treatment window. With this sample size, we will be able to detect any unforeseen adverse events that have a prevalence of at least 2.5% in each group with 90% probability. With 92 patients per group we will be able to estimate the rate of adverse events to within ±10%.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.045
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Amantadine HCL Placebo
Hide Arm/Group Description 100mg BID administered for 2 weeks, then increased to 150mg BID in week 3 if change on primary outcome measure (ie Disability Rating Scale, DRS) was less than 2 points after week 2. If change in DRS score remained less than 2 points after week 3, dose was increased to 200mg BID in week 4. Visually identical compound administered in the same manner (ie enterally) as the actual study drug.
All-Cause Mortality
Amantadine HCL Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Amantadine HCL Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   15/87 (17.24%)      19/97 (19.59%)    
Blood and lymphatic system disorders     
Leukocytosis   0/87 (0.00%)  0 1/97 (1.03%)  1
Other Abnormal Laboratory  [1]  0/87 (0.00%)  0 1/97 (1.03%)  1
Cardiac disorders     
Cardiac arrest   1/87 (1.15%)  1 0/97 (0.00%)  0
Gastrointestinal disorders     
Other Gastrointestinal Problems  [2]  2/87 (2.30%)  2 3/97 (3.09%)  3
General disorders     
General Medical Problems   1/87 (1.15%)  1 2/97 (2.06%)  2
Vomiting   0/87 (0.00%)  0 1/97 (1.03%)  1
Infections and infestations     
Infection   3/87 (3.45%)  3 5/97 (5.15%)  5
Nervous system disorders     
Epilepsy   0/87 (0.00%)  0 2/97 (2.06%)  2
Hydrocephalus   3/87 (3.45%)  3 2/97 (2.06%)  2
Intracranial Hemorrage   0/87 (0.00%)  0 1/97 (1.03%)  1
Other Neurologic  [3]  1/87 (1.15%)  1 1/97 (1.03%)  1
Autonomic Storm   0/87 (0.00%)  0 1/97 (1.03%)  1
Psychiatric disorders     
Hypoarousal/Lethargy/Somnolence   0/87 (0.00%)  0 1/97 (1.03%)  1
Renal and urinary disorders     
Urinary tract infection   1/87 (1.15%)  1 0/97 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Pneumonia   6/87 (6.90%)  6 2/97 (2.06%)  2
Indicates events were collected by systematic assessment
[1]
Anemia
[2]
GI bleeding, gastritis, bowel obstruction, colon carcinoma, peritonitis
[3]
Bilateral subdural fluid collection, arm and head tremor
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Amantadine HCL Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   54/87 (62.07%)      51/97 (52.58%)    
General disorders     
Insomnia / Sleep Disturbance   12/87 (13.79%)  14 14/97 (14.43%)  15
General Medical Problems   9/87 (10.34%)  10 11/97 (11.34%)  16
Infections and infestations     
Infections  [1]  10/87 (11.49%)  14 15/97 (15.46%)  16
Musculoskeletal and connective tissue disorders     
Hypertonia / Spasticity   18/87 (20.69%)  21 14/97 (14.43%)  18
Psychiatric disorders     
Agitation / Aggression   12/87 (13.79%)  16 11/97 (11.34%)  14
Renal and urinary disorders     
Urinary tract infection   13/87 (14.94%)  15 12/97 (12.37%)  13
Indicates events were collected by systematic assessment
[1]
Does not include urinary tract infection
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Name/Title: Joseph T Giacino, PhD
Organization: Spaulding Rehabilitation Hospital
Phone: 617-573-2757
Responsible Party: Joseph T Giacino, Spaulding Rehabilitation Hospital
ClinicalTrials.gov Identifier: NCT00970944     History of Changes
Other Study ID Numbers: H133A031713
First Submitted: September 2, 2009
First Posted: September 3, 2009
Results First Submitted: December 12, 2011
Results First Posted: September 24, 2012
Last Update Posted: September 24, 2012