Trial Outcomes & Findings for Amitriptyline to Prevent Headache After Traumatic Brain Injury (NCT NCT01856270)

NCT ID: NCT01856270

Last Updated: 2024-09-19

Results Overview

Number of subjects reporting an average of at least one headache per week

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 50 participants
• Primary outcome timeframe: 90 days
• Results posted on: 2024-09-19

Participant Flow

Participant milestones

Measure	Amitriptyline Immediate The Immediate group will begin study drug immediately after enrollment. Immediate Drug participants will be started on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3. Amitriptyline: Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups. Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when receiving initial ramp-up dosage containers), Day 30 and 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance/distribute study drug) and Day 90 (final outcome).	Amitriptyline Delayed The Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3. Amitriptyline: Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups. Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers), Day 30 and Day 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).
Overall Study STARTED	24	26
Overall Study COMPLETED	13	14
Overall Study NOT COMPLETED	11	12

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Amitriptyline to Prevent Headache After Traumatic Brain Injury

Baseline characteristics by cohort

Measure	Amitriptyline Immediate n=24 Participants The Immediate group will begin study drug immediately after enrollment. Immediate Drug participants will be started on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3. Amitriptyline: Participants with headache will be enrolled within the first 12 weeks post injury and will be randomly assigned to 2 groups. Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers), Day 30 and 60 (to monitor compliance/distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until Day 30 visit. Those in group 2 who report headache at Day 30 will receive initial dosage container and reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).	Amitriptyline Delayed n=26 Participants The Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3. Amitriptyline: Participants with headache will be enrolled within the first 12 weeks post injury and will be randomly assigned to 2 groups. Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers), Day 30 and 60 (to monitor compliance/distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive initial dosage container and then reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).	Total n=50 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	24 Participants n=5 Participants	26 Participants n=7 Participants	50 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	36.8 years STANDARD_DEVIATION 11.7 • n=5 Participants	34.6 years STANDARD_DEVIATION 12.7 • n=7 Participants	35.7 years STANDARD_DEVIATION 12.2 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	17 Participants n=7 Participants	28 Participants n=5 Participants
Region of Enrollment United States	24 participants n=5 Participants	26 participants n=7 Participants	50 participants n=5 Participants

PRIMARY outcome

Timeframe: 90 days

Population: The two arms are combined for this analysis to answer the question of frequency of headache at the 3 month outcome data point and only difference between arms was related to onset time of medication which was not expected to result in significant change in headache frequency, but only potentially in cognitive status.

Number of subjects reporting an average of at least one headache per week

Outcome measures

Measure	Amitriptyline Sample n=43 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Frequency of Headaches	10 Participants	—

PRIMARY outcome

Timeframe: 90 days

Population: The two arms are combined for this analysis to answer the question of severity of headache at the 3 month outcome data point and only difference between arms was related to onset time of medication which was not expected to result in significant change in headache frequency, but only potentially in cognitive status.

Number of subjects with headache reporting an average pain of at least 6 on a 0-10 scale with 0=no pain and 10=worst pain.

Outcome measures

Measure	Amitriptyline Sample n=38 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Severity of Headache	7 Participants	—

SECONDARY outcome

Timeframe: Day 1 through Day 90

The number and types of treatment related adverse events will be monitored on a weekly basis and will be divided by severity if differing.

Outcome measures

Measure	Amitriptyline Sample n=24 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=26 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Number of Participants With Adverse Events Possibly Related to Study Medication Number wth any events	5 Participants	3 Participants
Number of Participants With Adverse Events Possibly Related to Study Medication # with Possible, probable or definite rel to tx	4 Participants	1 Participants
Number of Participants With Adverse Events Possibly Related to Study Medication # with tx related moderate/severe events	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 30 days

The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from a list of 15 across 5 trials (max score of 75) with higher score indicating better learning.

Outcome measures

Measure	Amitriptyline Sample n=12 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=11 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Rey Auditory Verbal Learning Test (Total)	26.3 words recalled Standard Deviation 4.7	27.1 words recalled Standard Deviation 5.0

SECONDARY outcome

Timeframe: 30 days

The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from the original list of 15 after a new list of 15 is given (used as distraction). Higher scores indicate better short-term memory.

Outcome measures

Measure	Amitriptyline Sample n=12 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=11 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Rey Auditory Verbal Learning Test (Short)	10.3 words recalled Standard Deviation 1.8	9.4 words recalled Standard Deviation 2.5

SECONDARY outcome

Timeframe: 30 days

The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from the original list of 15 after a 30 minute time delay. Higher scores indicate better long-term memory.

Outcome measures

Measure	Amitriptyline Sample n=10 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=11 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Rey Auditory Verbal Learning Test (Long)	13.6 words recalled Standard Deviation 1.3	13.3 words recalled Standard Deviation 1.4

SECONDARY outcome

Timeframe: 30 days

Trail Making Test will be given at 30 days to detect any impact of study drug on cognition. This is a test of visual attention and is scored by the number of seconds it takes to complete the task of making a trail through letters.

Outcome measures

Measure	Amitriptyline Sample n=12 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=11 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Trail Making Test (A)	28.7 seconds Standard Deviation 9.0	26.3 seconds Standard Deviation 5.3

SECONDARY outcome

Timeframe: 30 days

Trail Making Test will be given at 30 days to detect any impact of study drug on cognition. This is a test of visual attention and task switching and is scored by number of seconds it takes to complete the task (switching from letters to numbers in order).

Outcome measures

Measure	Amitriptyline Sample n=11 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=11 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Trail Making Test (B)	87.5 seconds Standard Deviation 34.9	60.3 seconds Standard Deviation 21.3

SECONDARY outcome

Timeframe: 30 days

The WAIS IV Digit Symbol test will be given to detect any effect of study drug on cognition. This test assesses processing speed and new learning and requires an individual to substitute the relevant digit for a symbol and are given a time limit. The total number of correct digits are summed and converted to a scaled score (range 1-20 with 10 being at the 50th percentile) with higher scores indicating better performance.

Outcome measures

Measure	Amitriptyline Sample n=12 Participants Individuals enrolled into the study and who have completed headache diaries through 3 months post injury.	Amitriptyline Delayed n=12 Participants The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Wechsler Adult Intelligence Scale (WAIS) IV Digit Symbol	7.5 standard score Standard Deviation 2.5	9.3 standard score Standard Deviation 2.3

Adverse Events

Amitriptyline Immediate

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Amitriptyline Delayed

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Amitriptyline Immediate n=24 participants at risk The Immediate group will begin study drug immediately after enrollment. Immediate Drug participants will be started on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.	Amitriptyline Delayed n=26 participants at risk The Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening to assess whether there is any cognitive impact of the medication (comparing to those who started immediately after enrollment. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.
Gastrointestinal disorders Dry Mouth	12.5% 3/24 • Number of events 4 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Nervous system disorders Groggy	0.00% 0/24 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	3.8% 1/26 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Cardiac disorders Increased QTc	4.2% 1/24 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Nervous system disorders headache	4.2% 1/24 • Number of events 2 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	3.8% 1/26 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Renal and urinary disorders decreased libido	4.2% 1/24 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Nervous system disorders possible metabolic encephalopathy	0.00% 0/24 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	3.8% 1/26 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Nervous system disorders sleep difficulties	4.2% 1/24 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Infections and infestations respiratory infection	4.2% 1/24 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.
Skin and subcutaneous tissue disorders rash	4.2% 1/24 • Number of events 1 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.	0.00% 0/26 • Adverse events were collected throughout the duration of medication usage at baseline, then at day 30, day 60, and at day 90 when medication was discontinued.

Additional Information

Dr. Jeanne Hoffman

University of Washington

Phone: 206-221-6511

Email: jeanneh@uw.edu

Results disclosure agreements

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