e-CBT DTx for Post Traumatic Headaches in Adults With History of TBI (AMMO)

Single-Blind, Randomized, Controlled Pilot Trial of a Cognitive-Behavioral Therapy Digital Therapeutic Delivered Online for Post-Traumatic Headaches in Adults With History of Concussive Traumatic Brain Injury

The AMMO digital therapeutic (DTx) study will provide an online based program for participants with migraines after head injury to follow for 12 weeks. This study aims to see if using cognitive behavioral therapy aimed at military service members in an online self administered platform is effective therapy in the relief of migraines compared. The study will use a single blind online comparative program to test the effect.

Study Overview

• Status: Completed
• Conditions: Post-Traumatic Headache
• Intervention / Treatment: Device: AMMO PTH DTx; Device: AMMO SHAM

Detailed Description

The AMMO digital therapeutic (DTx) will be a novel intervention for PTH following concussive TBI, therefore this project is a pilot trial designed to test this new treatment. This pilot is a single-blind, randomized, controlled, interventional trial of current and former military personnel along with civilians with a history of concussive TBI and current PTH. The pilot trial will be conducted via online portal accessible by smartphone, tablet, or computer with remote interaction between participants and study staff. The pilot trial will include up to 100 participants randomized to either the active intervention or a comparison condition at a 1:1 ratio, and will provide preliminary data to determine the sample size of a future full clinical trial. Participants will complete a 12 week intervention period followed by a follow-up assessment 4 weeks after intervention is complete. Participants randomized to the comparison group will be provided access to the open label after end of 16 week follow-up.

In addition, updates to the DTx to improve usability and acceptability will be made if necessary based on feedback from the pilot trial, then applied to the final DTx used in a future, larger, clinical trial.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • 100% Remote Recruitment: Center for Neurscience and Regenerative Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Be aged ≥ 18 to ≤ 70 years
• Have a history of concussive TBI ≥ 3 months prior to enrollment:
• A concussive TBI is defined by having at least one of the following after a head trauma (ACRM, 1993) oAny period of loss of consciousness; oAny loss of memory for events immediately before or after the accident; oAny alteration in mental state at the time of the accident (e.g., feeling dazed, disoriented, or confused); and oFocal neurological deficit(s) that may or may not be transient oThe injury must not exceed any of the following (ACRM, 1993):
• Loss of consciousness of approximately 30 minutes or less;
• After 30 minutes an initial GCS score of 13-15; and

• PTA not greater than 24 hours

  • Head trauma resulting in concussive TBI can be due to blast or non-blast mechanisms
  • Head trauma resulting in concussive TBI can have occurred any time in the participant's life: prior to military service, during deployment, in garrison, or after leaving military service

• Have a history of chronic PTH defined as:

  o Headache is reported to have developed (or worsened) after one of the following*:

• The injury to the head;
• Regaining of consciousness following the injury to the head; or
• Discontinuation of medication(s) impairing ability to sense or report headache following the injury to the head

• Not better accounted for by another ICHD-3 diagnosis**

  o The headache persists for >3 months after its onset (ICHD, 2013)

• Have a HIT-6™ score of ≥ 56 to 78 indicative of substantial impact (56-59) or severe impact (60-78) on functioning (Yang, Rendas-Baum, Varon, & Kosinski, 2011)
• Be able to provide written, informed consent in English and follow study-related instructions
• Have ownership of or reliable access to a smartphone with a data plan or internet connecting capabilities
• Be aged ≥ 18 to ≤ 70 years
• Have a history of concussive TBI ≥ 3 months prior to enrollment:

• A concussive TBI is defined by having at least one of the following after a head trauma (ACRM, 1993):

  • Any period of loss of consciousness;
  • Any loss of memory for events immediately before or after the accident;
  • Any alteration in mental state at the time of the accident (e.g., feeling dazed, disoriented, or confused); and
  • Focal neurological deficit(s) that may or may not be transient
  • The injury must not exceed any of the following (ACRM, 1993):
• Loss of consciousness of approximately 30 minutes or less;
• After 30 minutes an initial GCS score of 13-15; and

• PTA not greater than 24 hours

  • Head trauma resulting in concussive TBI can be due to blast or non-blast mechanisms
  • Head trauma resulting in concussive TBI can have occurred any time in the participant's life: prior to military service, during deployment, in garrison, or after leaving military service

• Have a history of chronic PTH defined as:

  o Headache is reported to have developed (or worsened) after one of the following*:

• The injury to the head;
• Regaining of consciousness following the injury to the head; or
• Discontinuation of medication(s) impairing ability to sense or report headache following the injury to the head

• Not better accounted for by another ICHD-3 diagnosis**

  o The headache persists for >3 months after its onset (ICHD, 2013)

• Have a HIT-6™ score of ≥ 56 to 78 indicative of substantial impact (56-59) or severe impact (60-78) on functioning (Yang, Rendas-Baum, Varon, & Kosinski, 2011)
• Be able to provide written, informed consent in English and follow study-related instructions
• Have ownership of or reliable access to a smartphone with a data plan or internet connecting capabilities

Exclusion Criteria:

• They experienced a moderate or severe TBI
• Their secondary headache is better accounted for by the ICHD-3 diagnosis of 8.2 medication-overuse headache; must meet diagnostic criteria for at least 1 medication-overuse headache diagnosis (8.2.1-8.2.8)
• They are currently engaged in psychotherapeutic treatment or have engaged in psychotherapeutic treatment within 8 weeks prior to trial enrollment (for more information regarding recent treatment in potential participants, see section '3.2 Study Procedures,' sub-section 'Baseline Evaluation')
• They report change or discontinuation of headache prophylaxis in the past 4 weeks
• They report active psychotic or bipolar symptoms
• In the opinion of the investigator, they have other considerations that may adversely affect patient safety, participation, or scientific validity of the data being collected (including, but not limited to, active plan or intent for suicide, visual impairment, hand dysfunction or amputation, substantial cognitive impairment, life expectancy of less than 6 months)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active; This arm will receive access to an online program that will guide them through cognitive behavioral therapy program.	Device: AMMO PTH DTx; An online cognitive behavioral therapy program accessed through a online program.
Sham Comparator: Sham comparator; Participants will obtain access to an online program with activities not including the cognitive behavioral therapy	Device: AMMO SHAM; Online activities not including CBT in the AMMO online program.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-Item Headache Impact Test™ (HIT-6™)	The HIT-6™ is a brief standardized headache screening tool and questionnaire, derived from the original 54-item Headache Impact Test. It has been found to have good psychometric properties in assessing headache impact among patients in clinical practice and research (Bjorner, Kosinski, & Ware, 2003; Kosinski et al., 2003).	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the appropriate sample size for a future full clinical trial based on preliminary estimates of effect size for outcome measures	Use of Headache Impact Test and number of headache days per month to compare arms. This data will identify any changes to sample size in future studies.	12 weeks
Post Traumatic Stress Disorder Checklist (DSM-5)	The PCL-5 is a self-report questionnaire designed to assess symptoms of PTSD (Blevins, Weathers, Davis, Witte, & Domino, 2015). The PCL-5 takes approximately 5-10 minutes to complete.	16 weeks
Traumatic Brain Injury Quality of Life Scale (TBI-QOL)	The TBI-QOL is a self-report questionnaire composed of 22 item banks (Tulsky et al., 2016). It was developed to measure multiple domains of life for patients living with TBI, including physical, mental, cognitive, and social. The TBI-QOL takes approximately 30 minutes to complete.	16 weeks
Patient Health Questionnaire-9	The PHQ-9 is a self-report assessment for depressive symptoms (Kroenke, Spitzer, & Williams, 2001). Each item is scored on a scale of 0 to 3 providing a summary score that ranges from 0 to 27, with higher scores representing more severe depression. On the PHQ-9 a total score <5 is considered minimal depression, and scores of 5 to 9, 10 to 14, 15 to 19, and 20 to 27 are considered mild, moderate, moderately severe, and severe depression, respectively.	16 weeks
Insomnia Severity Index (ISI)	The ISI is a self-report questionnaire designed to assess the presence and severity of primary insomnia sleep disorder and is empirically-validated in general and military populations (Bastien et al., 2001; Jenkins et al., 2015; Morin, Belleville, Belanger, & Ivers, 2011).	16 weeks
User Version of the Mobile Application Rating Scale	Adapted from the Mobile Application Rating Scale (MARS), the uMARS is a 26-item self-report questionnaire designed to assess the quality, functionality, and aesthetics of a mobile application and its information (Stoyanov, Hides, Kavanagh, & Wilson, 2016). There is an additional open-text question for further comments on the users' opinions of the application. The uMARS takes approximately 15 minutes to complete. This measure will be optional for participants to complete.	12 weeks
Mobile Agnew Relationship Measure	The mARM is an adaptation of a valid and reliable assessment of therapeutic alliance in face-to-face therapy (Berry, Salter, Morris, James, & Bucci, 2018). The 25-item questionnaire has been adjusted for use with digital health interventions, specifically for mental health. The mARM takes approximately 5 minutes to complete.	12 weeks
User Program Feedback Questionnaire	Brief questionnaire utilizing Likert Scales related to gathering user feedback on personal experience with ease and accessibility of app utilization.	12 weeks

Collaborators and Investigators

• Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine
• Collaborators: Uniformed Services University of the Health Sciences

Publications and helpful links

General Publications

• Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x.
• Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001 Jul;2(4):297-307. doi: 10.1016/s1389-9457(00)00065-4.
• Stoyanov SR, Hides L, Kavanagh DJ, Wilson H. Development and Validation of the User Version of the Mobile Application Rating Scale (uMARS). JMIR Mhealth Uhealth. 2016 Jun 10;4(2):e72. doi: 10.2196/mhealth.5849.
• Morin CM, Belleville G, Belanger L, Ivers H. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011 May 1;34(5):601-8. doi: 10.1093/sleep/34.5.601.
• Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J Trauma Stress. 2015 Dec;28(6):489-98. doi: 10.1002/jts.22059. Epub 2015 Nov 25.
• Tulsky DS, Kisala PA, Victorson D, Carlozzi N, Bushnik T, Sherer M, Choi SW, Heinemann AW, Chiaravalloti N, Sander AM, Englander J, Hanks R, Kolakowsky-Hayner S, Roth E, Gershon R, Rosenthal M, Cella D. TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury. J Head Trauma Rehabil. 2016 Jan-Feb;31(1):40-51. doi: 10.1097/HTR.0000000000000131.
• Berry K, Salter A, Morris R, James S, Bucci S. Assessing Therapeutic Alliance in the Context of mHealth Interventions for Mental Health Problems: Development of the Mobile Agnew Relationship Measure (mARM) Questionnaire. J Med Internet Res. 2018 Apr 19;20(4):e90. doi: 10.2196/jmir.8252.
• Jenkins MM, Colvonen PJ, Norman SB, Afari N, Allard CB, Drummond SP. Prevalence and Mental Health Correlates of Insomnia in First-Encounter Veterans with and without Military Sexual Trauma. Sleep. 2015 Oct 1;38(10):1547-54. doi: 10.5665/sleep.5044.
• Kosinski M, Bjorner JB, Ware JE Jr, Batenhorst A, Cady RK. The responsiveness of headache impact scales scored using 'classical' and 'modern' psychometric methods: a re-analysis of three clinical trials. Qual Life Res. 2003 Dec;12(8):903-12. doi: 10.1023/a:1026111029376.
• Bjorner JB, Kosinski M, Ware JE Jr. Using item response theory to calibrate the Headache Impact Test (HIT) to the metric of traditional headache scales. Qual Life Res. 2003 Dec;12(8):981-1002. doi: 10.1023/a:1026123400242.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2024
• Primary Completion (Actual): January 16, 2026
• Study Completion (Actual): April 27, 2026

Study Registration Dates

• First Submitted: June 24, 2024
• First Submitted That Met QC Criteria: October 31, 2024
• First Posted (Actual): November 1, 2024

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders; Headache Disorders, Secondary; Post-Traumatic Headache
• Other Study ID Numbers: AMMO-TBI-2023

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes