Clinical Characteristics and Pathophysiology of Post-Traumatic Headache

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.

Study Overview

• Status: Completed
• Conditions: Concussion, Mild; Post-Traumatic Headache
• Intervention / Treatment: Drug: Calcitonin Gene-Related Peptide; Drug: Placebo

Detailed Description

The present project will embark upon identifying novel PTH-specific biomarkers by incorporating a plethora of scientific approaches. First, clinical biomarkers will be assessed by deep phenotyping of clinical characteristics and associated comorbidities using a semi-structured interview and multiple validated questionnaires. Second, biochemical biomarkers will be determined by plasma levels measurements of blood markers for headache hypersensitivity and neuronal/axonal damage. Third, imaging biomarkers will be established by magnetic resonance imaging (MRI) to assess structural and functional changes in the brain. Lastly, molecular biomarkers will be identified by examining whether intravenous infusion of calcitonin gene-related peptide (CGRP) provokes headache attacks mimicking the usual headache phenotype in subjects with PTH. This would determine whether PTH patients exhibit hypersensitivity to CGRP (molecular biomarker) and advance our understanding of the complex pathophysiological events that constitute the headache phenotypes in PTH sufferers.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Glostrup, Denmark, 2600
    • Danish Headache Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria for PPTH patients:

• 18-65 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

Exclusion Criteria for PPTH patients:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Calcitonin Gene-Related Peptide (CGRP); 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; 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.; Other Names: CGRP
Placebo Comparator: Placebo; 30 patients with PPTH wil be allocated to receive 40 mL Placebo (isotonic saline) over 20 minutes. Other Name: Isotonic Saline	Drug: Placebo; 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.; Other Names: Isotonic Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: Unilateral location; Pulsating quality; Moderate or severe pain intensity; 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: Nausea and/or vomiting; Photophobia and phonophobia; 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

Collaborators and Investigators

• Sponsor: Danish Headache Center
• Investigators: Principal Investigator: Henrik Schytz, MD, Associate Professor

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2018
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: July 27, 2018
• First Submitted That Met QC Criteria: December 29, 2018
• First Posted (Actual): January 2, 2019

Study Record Updates

• Last Update Posted (Actual): January 29, 2020
• Last Update Submitted That Met QC Criteria: January 27, 2020
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Headache Disorders; Head Injuries, Closed; Wounds, Nonpenetrating; Brain Injuries; Brain Injuries, Traumatic; Headache Disorders, Secondary; Headache; Brain Concussion; Post-Traumatic Headache; Physiological Effects of Drugs; Vasodilator Agents; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcitonin; Salmon calcitonin; Calcitonin Gene-Related Peptide; Katacalcin
• Other Study ID Numbers: H-18011477

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No