Clinical Characteristics and Pathophysiology of Post-Traumatic Headache

NCT03791515 | Completed DMC

• 1 other identifier: H-18011477
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

To better understand the clinical characteristics and complex pathophysiological events that constitute persistent post-traumatic headache (PPTH) and to identify possible calcitonin gene-related peptide (CGRP) hypersensitivity in PPTH patients.

Conditions

Post-Traumatic Headache; Concussion, Mild

Outcome Measures

Primary Outcomes (20)

• Headache Characteristics

  Headache characteristics will be assessed using a semi-structured interview.

  50 minutes

• Headache Characteristics

  Headache characteristics will be assessed using Headache Under-Response to Treatment Index (HURT-Index) questionnaire. The total score ranges from 0 to 24 with a higher score indicating a lower effectiveness of intervention against headache.

  10 minutes

• Cognitive Function

  Cognitive function will be assessed using Montreal Cognitive Assessment (MoCA) questionnaire. The total score ranges from 0 to 30 points. The MoCA is divided into 7 subscores: visuospatial/executive (5 points); naming (3 points); memory (5 points for delayed recall); attention (6 points); language (3 points); abstraction (2 points); and orientation (6 points). One point is added if the subject has ≤12 years of education. A total of 30 points may be given. A score ≤25 indicates some degree of cognitive impairment.

  10 minutes

• Depression

  Depression will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The total score ranges from 0-21. A score of 0-7 points is regarded as being in the normal range. A score of 8-10 points is suggestive of a depressive state (borderline abnormal). A score of 11-21 points indicates a probable presence of a depressive state (abnormal).

  10 minutes

• Anxiety

  Anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The total score ranges from 0-21. A score of 0-7 points is regarded as being in the normal range. A score of 8-10 points is suggestive of a state of anxiety (borderline abnormal). A score of 11-21 points indicates a probable presence of an anxiety disorder (abnormal).

  10 minutes

• Allodynia

  Allodynia will be assessed using Allodynia Symptom Checklist (ASC-12) questionnaire. The total score ranges from 0-24 points. A score of 0-2 suggests no allodynia. A score of 3-5 suggests mild allodynia. A score of 6-8 suggests moderate allodynia. A score of 9 or more suggests severe allodynia.

  10 minutes

• Post-Traumatic Stress Disorder

  Post-traumatic stress disorder will be assessed using Harvard Trauma Questionnaire (HTQ). The total score ranges from 16-64. The total score is divided with 16 and a clinical cut-off score of 2.5 is set to be indicative of PTSD.

  10 minutes

• Quality of Sleep: Pittsburgh Sleep Quality Index (PSQ-I)

  Quality of Sleep will be assessed using Pittsburgh Sleep Quality Index (PSQ-I). The measure consists of 19 individual items, creating 7 components that produce one global score. The total PSQ-I score ranges from 0 to 21 with lower scores indicating a healthier sleep quality.

  10 minutes

• Muscle Tenderness

  Muscle tenderness will be assessed using Total Tenderness Score (TTS). The total score ranges from 0-48 with higher scores indicating a higher degree of muscle tenderness.

  10 minutes

• Pressure Pain Threshold

  Pressure Pain Threshold will be assessed using an Algometer.

  10 minutes

• Cortical Density

  Cortical density will be assessed using Voxel-Based Morphometry.

  10 minutes

• Cortical Thickness

  Cortical thickness will be assessed using Surface-Based Morphometry

  10 minutes

• Number and Location of Microhemorrhages

  The number and location of microhemorrhages will be assessed using Susceptibility-Weighted Imaging.

  6 minutes

• White Matter Structural Fiber Integrity

  The white matter structural fiber integrity will be assessed using Diffusion Tensor Imaging

  10 minutes

• Number and Location of White Matter Lesions

  The number and location of white matter lesions will be assessed using T2-weighted Fluid-Attenuated Inversion Recovery.

  6 minutes

• Cerebral Blood Flow

  Cerebral blood flow will be assessed using arterial spin labelling (ASL).

  7 minutes

• Brain Network Functional Connectivity

  Brain network functional connectivity will be assessed using blood oxygen level-dependent functional magnetic resonance imaging.

  11 minutes

• Incidence of Headache Exacerbation with Migraine-Like Features

  Migraine-like features are defined as headache fulfilling at least two of the following four characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) And during headache at least one of the following must be fulfilled: 1. Nausea and/or vomiting 2. Photophobia and phonophobia 3. Headache mimicking the usual exacerbated headache with migraine-like features If the participant fulfills these criteria at baseline, then incidence of exacerbated headache with migraine-like features is defined as: \- An increase in headache intensity combined with an increase in the degree nausea and/or photophobia and phonophobia (based on a mild / moderate / severe scale)

  60 minutes

• Headache Area under the Curve

  Headache area under the curve is defined as headache intensity x duration up to 12 h after CGRP infusion

  12 hours

• Time to Maximum Headache

  Time to maximum headache score on CGRP day compared to placebo day will be assessed using a headache questionnaire

  12 hours

Study Arms (2)

Calcitonin Gene-Related Peptide (CGRP)

ACTIVE COMPARATOR

30 patients with PPTH will be allocated to receive intravenous infusion of 1.5 µg/min calcitonin-gene related peptide over 20 minutes Other Name: CGRP

Drug: Calcitonin Gene-Related Peptide

Placebo

PLACEBO COMPARATOR

30 patients with PPTH wil be allocated to receive 40 mL Placebo (isotonic saline) over 20 minutes. Other Name: Isotonic Saline

Drug: Placebo

Interventions

Calcitonin Gene-Related Peptide DRUG

A randomized clinical trial with a double-blinded, randomized, placebo-controlled crossover design. 30 PPTH patients will be included. All participants will receive continuous intravenous infusion of 1.5 µg/min CGRP over 20 min. The following variables will be recorded before, during and after infusion (every 10 min over 60 min): headache intensity on a verbal rating scale from 0 to 10 and headache characteristics. At 90 min, participants will be discharged and instructed to fill out a headache diary for 24 hours from start of infusion.

Also known as: CGRP

Calcitonin Gene-Related Peptide (CGRP)

Placebo DRUG

A randomized clinical trial with a double-blinded, randomized, placebo-controlled crossover design. 30 PPTH patients will be included. All participants will receive continuous intravenous infusion of 40 mL placebo (isotonic saline) over 20 min. The following variables will be recorded before, during and after infusion (every 10 min over 60 min): headache intensity on a verbal rating scale from 0 to 10 and headache characteristics. At 90 min, participants will be discharged and instructed to fill out a headache diary for 24 hours from start of infusion.

Also known as: Isotonic Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age
• Subject has PPTH in accordance with the diagnostic criteria of the International Headache Society (IHS)
• Concussion (mild traumatic brain injury) occured \> 12 months ago
• Subject, who are fertile women, must be on safe contraceptives

You may not qualify if:

• Pre-trauma existing primary headache disorder (maximum 1 day/per month with tension-type headache) and medication-overuse headache
• \> 1 episode with a sustained concussion
• Whiplash
• Pregnant or lactating women
• Cardiovascular disease of any kind
• Hypertension on the experimental day
• Hypotension on the experimental day
• Pre-trauma existing psychiatric disorder of any kind - unless well-regulated
• Any anamnestic or clinical signs of any kind deemed relevant for the study by the physician examining the subject
• Any MRI contraindication and a wish of not being informed about unexpected MRI changes

Sponsors & Collaborators

• Danish Headache Center: lead

Study Sites (1)

Danish Headache Center

Glostrup Municipality, 2600, Denmark

Location

Related Publications (1)

• Schytz HW, Smilkov E, Carroll I, Dobrocky T, Al-Khazali HM, Tolnai D, Jensen RH, Amin FM. No evidence of intracranial hypotension in persistent post-traumatic headache: A magnetic resonance imaging study. Cephalalgia. 2025 Apr;45(4):3331024251325556. doi: 10.1177/03331024251325556. Epub 2025 Apr 21.

  PMID: 40255022 DERIVED

MeSH Terms

Conditions

Post-Traumatic Headache; Brain Concussion

Interventions

Calcitonin Gene-Related Peptide; Sodium Chloride

Condition Hierarchy (Ancestors)

Headache Disorders, Secondary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Injuries, Traumatic; Brain Injuries; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds and Injuries; Wounds, Nonpenetrating

Intervention Hierarchy (Ancestors)

Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Henrik Schytz, MD

  Associate Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurology

Model Details: 100 patients with PPTH and 100 healthy controls will undergo a deep phenotyping of clinical characteristics and associated comorbidities. This is followed by a single MRI-session for all subjects. Lastly, the 30 patients with PPTH will participate in a randomized, double-blind, placebo-controlled, 2-way crossover study. These patients will be allocated to receive intravenous infusion of CGRP or placebo (isotonic saline) over 20 minutes on 2 study days.

Study Record Dates

• First Submitted: July 27, 2018
• First Posted: January 2, 2019
• Study Start: July 26, 2018
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: January 29, 2020

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)