Amitriptyline to Prevent Headache After Traumatic Brain Injury - Full Text View

Purpose

The investigators propose to conduct a 2-arm, open-label pilot study to determine if early treatment with amitriptyline will decrease the frequency and severity of headaches after mild traumatic brain injury (TBI). Amitriptyline is a tricyclic antidepressant that is commonly available and inexpensive. It is used as a first-line drug for primary headache prevention in a very low dose range of 10-50 mg.

Specific Aim 1 is to conduct a 2-arm open-label study to examine the effect of preventive treatment with amitriptyline on the frequency and severity of headache after mild TBI.
Specific Aim 2 is to collect data needed for design of a Phase 3 study, including an estimate of effect size, headache variability, and desirable drug treatment start date.
Specific Aim 3 is to examine the feasibility of using headache diaries with individuals with mild TBI.
Specific Aim 4 is to establish the safety and tolerability of amitriptyline for the prevention of headache after mild TBI.

The investigators hypothesize that early preventive treatment with amitriptyline will avert the development of chronic post-traumatic headache (PTH) as compared to rates of headache from a recent natural history study on PTH after mild TBI.

The investigators propose to enroll inpatient subjects from a Level I trauma center as well as from outpatient clinics and from the general community with a diagnosis of mild TBI. Subjects will be screened for current headache. After baseline assessment, 72 subjects with current headache will be randomized to one of 2 groups. Group 1 will immediately begin amitriptyline and or Group 2 will be followed and begin amitriptyline at Day 30. All subjects will be asked to complete a daily headache diary beginning on Day 1 of the study. A detailed medical history and headache survey will be completed. Subjects will have a scheduled stepped increase in the drug dosage every week for 3 weeks to the maximum study dosage of 50 mg. Weekly telephone calls will monitor for adverse events and compliance with the drug and headache diary. Clinic visits will occur at 30, 60 and 90 days. The 30 day clinic visit will include cognitive testing to assess for differences between groups and initiation of drug treatment for Group 2. Both 30 and 60 day visits will include review of headache diary, potential adverse effects, and pill counts. The 90 day visit will be for outcome assessment. In addition, the headache survey will be repeated by telephone at Day 180.

Condition	Intervention	Phase
Brain Injuries Post-Traumatic Headache	Drug: Amitriptyline	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Amitriptyline to Prevent Headache After Traumatic Brain Injury

Resource links provided by NLM:

MedlinePlus related topics: Headache Traumatic Brain Injury

Drug Information available for: Amitriptyline Amitriptyline hydrochloride Triavil

U.S. FDA Resources

Further study details as provided by University of Washington:

Primary Outcome Measures:

Frequency and severity of headaches [ Time Frame: 90 days ] [ Designated as safety issue: No ]
Headache frequency and severity are the most frequently used measures of medication efficacy in headache research. We will measure the number of headaches per week and severity ratings (1-10)using headache diaries and report to research staff.

Secondary Outcome Measures:

Headache Impact Test - 6 [ Time Frame: Day 90, Day 180 ] [ Designated as safety issue: No ]
The HIT-6 is a well-developed brief measure of the effect headaches are having on patients, that is, a headache disability scale.72, 73 This 6 item test has excellent reliability and validity, including construct validity.
Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [ Time Frame: 90 days ] [ Designated as safety issue: No ]
The RPQ is a widely used measure that details the occurrence and severity of 16 common physical and cognitive symptoms after TBI.
Short Form-12® Health Survey (SF-12) [ Time Frame: 90 days ] [ Designated as safety issue: No ]
The SF-12 was originally developed in 1994 as a shorter alternative to the SF-36. The SF-36 is a well validated, widely used general health related quality of life measure.
Number of participants with adverse events [ Time Frame: Day 1 through Day 90 ] [ Designated as safety issue: Yes ]
The number and types of adverse events will be monitored on a weekly basis and will be divided into likelihood of association with the drug and into severity classes.
Headache characteristic survey [ Time Frame: Day 1, Day 30, Day 60, Day 90, Day 180 ] [ Designated as safety issue: No ]
This survey will gather information on several factors that will be used to comprehensively describe PTH and its treatment including International Classification of Headache Disorders, 2nd edition (ICHD) criteria (type of headache by characteristics such as location, duration, severity, associated symptoms.
Insomnia Severity Index [ Time Frame: 90 days ] [ Designated as safety issue: No ]
This is a brief self-report of the person's subjective evaluation of insomnia. It targets the subject symptoms of insomnia as well as the concern or impact of the symptoms. This includes sleep onset and maintenance, satisfaction with current sleep pattern, interference with daily functioning, impairment and distress or concern.
Patient Health Questionnaire-9 (PHQ-9 [ Time Frame: 90 days ] [ Designated as safety issue: No ]
The PHQ-9 will be used to assess depression. We are including this to measure any antidepressant effect of amitriptyline which was first used for this purpose. The nine items on the measure correspond with Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for depression, with each item scored from "not at all" to "nearly every day".
Rey Auditory Verbal Learning Test [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug.
Trail Making Test [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
Trail Making Test will be given at 30 days to detect any impact of study drug on cognition.
Wechsler Adult Intelligence Scale (WAIS) IV Digit Symbol [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
The WAIS IV Digit Symbol test will be given to detect any effect of study drug on cognition.


Enrollment:	50
Study Start Date:	April 2013
Study Completion Date:	February 2016
Primary Completion Date:	February 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Amitriptyline Immediate The Amitriptyline 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.	Drug: Amitriptyline Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), 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). Other Name: Elavil
Experimental: 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.	Drug: Amitriptyline Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), 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). Other Name: Elavil

Arms

Assigned Interventions

Experimental: Amitriptyline Immediate

The Amitriptyline 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.

Drug: Amitriptyline

Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), 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).

Other Name: Elavil

Experimental: 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.

Drug: Amitriptyline

Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), 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).

Other Name: Elavil

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years to 60 Years (Adult)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Acute mild TBI (Glasgow Coma Scale of 13-15 on emergency department evaluation, any period of loss of consciousness (LOC) < than 30 minutes, alteration of consciousness or post-traumatic amnesia (not to exceed 24 hours)
Ability to give consent
Ages 18-60
Access to a telephone
Current headache (new headache or headache worse than prior to injury)

Exclusion Criteria:

Does not speak English
Diagnosed seizure disorder
Myocardial infarction in prior 6 months
Cardiac arrhythmia requiring medication treatment
Prolonged Q-T interval on electrocardiogram
Psychosis
Intoxication on hospital admission sufficient enough to cloud the diagnosis of mild TBI
Incarceration or homelessness
Allergy to amitriptyline
Current treatment with amitriptyline or other tricyclic antidepressant
Currently taking any medication not recommended for use with amitriptyline due to the potential for Q-T interval prolongation. Examples of this include: Class I, I-A or II antiarrhythmics, TCA's, MAOI's, selected fluoroquinolones (gatifloxacin, moxifloxacin), selected antipsychotic medications (haloperidol, risperidone, quetiapine), selected antiretroviral medications, cisapride, chloroquine, chlorpromazine, prochlorperazine, promethazine, citalopram, fluoxetine, erythromycin, methadone
History of glaucoma
History of prostate disease or current urinary retention

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01856270

Locations


United States, Washington
Harborview Medical Center
Seattle, Washington, United States, 98109

Sponsors and Collaborators

University of Washington

Investigators


Principal Investigator:	Jeanne M Hoffman, PhD	University of Washington

More Information

Additional Information:

University of Washington TBI Model Systems website This link exits the ClinicalTrials.gov site


Responsible Party:	Jeanne Hoffman, Professor, University of Washington
ClinicalTrials.gov Identifier:	NCT01856270 History of Changes
Other Study ID Numbers:	44274-B
Study First Received:	May 10, 2013
Last Updated:	May 20, 2016
Health Authority:	United States: Institutional Review Board
Individual Participant Data
Plan to Share IPD:	No

Keywords provided by University of Washington:


Traumatic brain injury Post-traumatic headache Drug therapy

Additional relevant MeSH terms:


Wounds and Injuries Brain Injuries Headache Post-Traumatic Headache Brain Diseases Central Nervous System Diseases Nervous System Diseases Craniocerebral Trauma Trauma, Nervous System Pain Neurologic Manifestations Signs and Symptoms Headache Disorders, Secondary Headache Disorders Amitriptyline	Amitriptyline, perphenazine drug combination Antidepressive Agents, Tricyclic Antidepressive Agents Psychotropic Drugs Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Adrenergic Uptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Adrenergic Agents Neurotransmitter Agents

Wounds and Injuries
Brain Injuries
Headache
Post-Traumatic Headache
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Pain
Neurologic Manifestations
Signs and Symptoms
Headache Disorders, Secondary
Headache Disorders
Amitriptyline

Amitriptyline, perphenazine drug combination
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on September 30, 2016