Clinical trial NCT03974048: Identification of the Epigenetic Response to Trauma
Official title: Identification of the Epigenetic Response to Trauma - a Prospective, Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Trauma
Injuries
Keywords: Epigenetics
DNA methylation
Trauma
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2019-06-04
Enrollment: 365
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population consists of all trauma patients admitted to RH's trauma center generating a trauma team activation.

The control group will consist of patients admitted to RH's orthopedic department for elective surgery.

Brief summary: The objective of this study is to investigate potential early alterations in the DNA methylation profile after severe trauma and to investigate if the early marks persist.

Detailed description: Background: Severe trauma is an extreme physical exposure, which may have significant consequences for the patient. In addition to anatomical injury and hemodynamic compromise, severe trauma causes an immense and rapid systemic immune reaction. At the genomic level, trauma has been found to significantly increase gene expression in circulating leukocytes, and preliminary data is also emerging that trauma may even cause epigenetic (DNA methylation) alterations.

Epigenetics, including DNA methylation, have been suggested as a mediator of genetic risk and to play a significant role in subsequent non-traumatic disease. Within the field of trauma DNA methylation has only been sparsely studied, but a few studies of traumatized animals have suggested that DNA methylation alterations may occur in relation to trauma. Even though DNA methylation is highly dynamic, some marks have been found to be stable over time, and thus may have long-term consequences.

An increasing understanding of the role of epigenetics in disease development and response may pave the way for new treatment targets and modalities for multiple diseases including trauma.

Research question: Does trauma induce immediate (\<4 hours) and persistent (30 days post-trauma) changes in the epigenome of peripheral blood cells, and do epigenetic changes correlate with patient recovery?

Objectives: To identify potential early alterations in the DNA methylation profile after severe trauma AND to investigate if the early marks persist.

Study design: A prospective, observational, cohort study of trauma patients admitted to RH's trauma center. The trauma cohort will be compared to a cohort of patients admitted for elective orthopedic surgery in terms of DNA methylation profile in blood cells pre-trauma/surgery, immediately post-trauma/surgery, and 30-45 days post-trauma/surgery.

DNA methylation profiles will be assessed by array technique using Illumina's MethylationEPIC Bead-Chip.

Primary outcome: Immediate (\<4 hours) post-trauma DNA methylation profile in blood cells.

Secondary outcomes: Pre-trauma/surgery DNA methylation profile, change in DNA methylation from pre-trauma/surgery to immediately and 30 days post-trauma/surgery, occurrence of organ dysfunction, sepsis, septic shock, 30-day mortality, ICU admission \> 24 hours, ICU length of stay (LOS), hospital LOS.

Eligibility criteria: Inclusion Criteria:

* Age 18-65 years.
* Trauma patients: Admitted to Rigshospitalet's trauma center generating a trauma team activation.
* Surgical controls: Admitted for elective surgery (non-traumatic cause) at the orthopedics department AND

  * Only one surgical procedure planned from study day 0 to study day 45.
  * Expected procedure length of at least 60 minutes.

Exclusion Criteria:

* Not able to obtain informed consent and not possible to obtain consent from a next-of-kin.
* Trauma patients:

  * Secondary transfers.
  * Pre-hospital blood transfusion OR blood transfusion in the trauma center before the first blood sample is obtained.
  * First blood sample taken later than 4 hours after the trauma.
  * Patients in cardiac arrest before/after hospital admission.
  * Additional traumatic exposure requiring hospital admission between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample).
  * Surgery not related to the trauma between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample).
* Surgical controls:

  * Surgical procedures due to cancer or fractures.
  * Traumatic exposure requiring hospital admission between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample).
  * Additional, unplanned surgery between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample).
  * First post-operative blood sample taken later than 4 hours after surgical end time.

Primary outcomes:
measure: Immediate DNA methylation profile
timeFrame: Day of trauma/surgery
Secondary outcomes:
measure: Pre-trauma/-surgery DNA methylation profile
timeFrame: Pre-trauma/surgery
measure: Stability of DNA methylation profile
timeFrame: 30-45 days after trauma/surgery
measure: Change in DNA methylation profile; pre-trauma/-surgery to post-trauma/-surgery
timeFrame: Day of trauma/surgery
measure: Change in DNA methylation profile; immediately post-trauma/-surgery to one month post-trauma/-surgery
timeFrame: 0 to 30-45 days after trauma/surgery
measure: DNA methylation changes in relation to injury severity
timeFrame: Day 0-45 after trauma/surgery
measure: Organ dysfunction
timeFrame: Day 30 after trauma/surgery
measure: Sepsis/septic shock
timeFrame: Day 30 after trauma/surgery
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Jacob Steinmetz, MD, Ph.D.
role: STUDY_DIRECTOR
References: