A Cohort Study Evaluating the Efficacy of PO Magnesium in the Treatment of Acute Traumatic Brain Injury in Adolescents

Introduction Mild traumatic brain injuries are a growing problem in sports, and are now
becoming publicly relevant. Mild traumatic brain injuries account for 700,000 ED visits,
hospitalizations, and deaths annually. Today, 1 out of 5 adolescents will be affected by mild
traumatic brain injuries. Magnesium is a critical neuromodulator that plays an important role
in controlling neural signaling in the brain, and studies have shown a transiently low level
of magnesium in CNS neurons following traumatic brain injury. If these electrolyte imbalances
could be corrected with magnesium supplementation during the acute injury, this could
potentially decrease the symptomatic period in those with mild TBI. The investigators aim to
show a correlation between administration of PO magnesium and increased resolution of
symptoms thereby improving the subjective recovery course of adolescents with concussion.

Study objective This randomized, cohort study will compare the clinical efficacy of PO
magnesium and Zofran, to that of PO Tylenol and Zofran in the treatment of adolescents
presenting within 48 hours of a mild traumatic brain injury.

Purpose With current studies and the sports media revolving around the long-term effects of
repetitive mild TBI, it is important to continue to improve treatment of these injuries.
Current therapy revolves around symptomatic care, rest, and return to school/sport after
symptoms have resolved and the patient has been cleared by a physician. After a concussion,
there is a period of 7-10 days where the patient has a transient decrease in the participants
mental functioning. The investigators hope to decrease the length of the acute symptomatic
period by supplementing oral magnesium along with the current symptomatic care. Studies have
shown that IV magnesium in high doses can improve the function of patients with severe TBI.
There have not been many studies looking at the efficacy of PO magnesium in this setting.
While there is no evidence that concussions have long term effects on neurocognitive
function, this study could add to the existing algorithm for concussion management.

Hypothesis The investigators believe that administration of magnesium in patients who present
with mild traumatic brain injuries will decrease post concussive symptoms, thereby speeding
recovery.

Methods Study design and setting Randomized, prospective, parallel cohort study comparing two
non-invasive treatments for Mild traumatic brain injury in patients ages 12-18 that present
to the Lakeland Health Emergency departments in either St. Joseph, MI or Niles, MI. The data
collection period will take approximately 2 years with a minimum goal of 76 patients enrolled
in the study.

Patient selection Patients ages 12-18 presenting to the emergency department with a mild
traumatic brain injury and GCS >13 meeting inclusion criterial will be provided a study
participation form to receive informed consent. ED staff will assess the patient's symptom
severity with the Concussion Symptom Severity Score listed below. After this ED staff will
assess the patient for inclusion criteria, followed by a healthcare provider Exclusion
criteria will be evaluated by the healthcare provider at this time, and medical therapy can
be initiated.

Inclusion criteria

- Age 12 to 18 years

- Presenting chief complaint of headache, head injury, or concussion following injury to
the patient above the clavicles, within the first 48 hours of injury.

- GCS > 13 on arrival.

Exclusion criteria

- Age < 12 years or > 18 years

- Inability to provide informed consent

- Vomiting > 2 episodes following injury

- Physical or mental disability hindering adequate response to assessment of symptoms

- Hemodynamic instability/medical condition requiring further acute life-saving medical
intervention

- Known brain mass, intracranial hemorrhage, skull fracture

- Known contraindications to magnesium use

- Known contraindication to Zofran use

Interventions Informed consent will be obtained after initial assessment of the patient by
the healthcare provider, and inclusion/exclusion criteria are met.

After informed consent is obtained, and the patient meets the criteria for further acceptance
into the study, then the patient's current symptoms will be screened by the healthcare
providers. This will be the symptom score at time "0". After this the participants will
receive 1 of 2 therapies that will be randomized by date of service whether it is an odd or
even date. The treatment arm of the study (Even Days) will include 800mg of oral magnesium
oxide along with a 4mg Zofran ODT as an initial dose in the emergency department. These
participants will then continue to take 2 tablets of prescribed Magnesium oxide 400mg daily
until their follow up with a physician at a local sports medicine clinic. The placebo arm
(Odd days) of the study will receive 650 mg Acetaminophen, and a 4mg Zofran ODT in the
emergency department. These participants continue to take scheduled acetaminophen 500 mg q8hr
until follow up with a physician in the sports medicine clinic. The participants will have
their symptom score re-evaluated after 1 hour of observation. If stable they will be
discharged. A 24 hour follow up phone conversation will be placed by the primary
investigators for a repeat of their symptom severity score. Finally, the participant will
follow up in the outpatient sports medicine concussion clinic at 120 hours where a 4th
symptom severity score will be obtained. These data will be collected and analyzed to compare
the overall change in symptom severity score between the two treatment arms. The Aim of this
study is to have a total n > 76. This will likely require 2 years of data collection. Our
primary endpoint will be to evaluate if magnesium has an impact on participant's
post-concussion severity index and a change in symptom severity score over time.

Symptom assessment Symptom assessment primarily described above, the investigators will use
the standardized Post Concussion Severity. If the participant continues to have pain and a
further intervention is required outside of the treatment and placebo arm the investigators
will provide Ibuprofen weight adjusted for the participant's weight.

ED staff will re-assess the participant and record level of pain at time of study drug
administration and at 60 minutes after study drug administration.

Data collection Primary data collection through the Concussion symptom severity index.
Outcome measures Primary outcome is a comparison between the treatment and placebo groups in
their changes in symptom severity scores over a 5-day period. Secondary endpoints include
development of adverse effects related to medication administration, need for further
intervention in the emergency department, and whether the participant's have returned to
their baseline function by 120 hours.

Data analysis To be coordinated with Dr. William Corser, and an associated statistician team
through Michigan State University. The study design will be a randomized cohort,
repeat-measures efficacy study. The analysis of study results will look at data
categorically, involving case or control group, and will also evaluate symptom scores at set
intervals. An independent sample t test comparing the mean symptom severity scores among the
cases and control groups at initial time of entry into the study, followed by repeat
measurements after 1 hour, 24 hours and 120 hours will then be conducted. Point biserial
correlation testing will also be employed to measure the strength of the relationship between
being a member of either the case or control group with symptom severity scores. The primary
outcome of this study will be the comparison of symptom severity scores between the treatment
and placebo groups over a 5-day period. Anticipated secondary outcomes include but are not
limited to adverse effects relating to medications administered, need for further
intervention in the emergency department and return to baseline function within 120 hours.

Ethical Considerations Risks The risks of this study are minimal and related to the
administration of medications. Acetaminophen, Zofran, and magnesium have low risk for
development of adverse effects.

If an adverse reaction to these medications is to occur, while unlikely, the participant will
be treated for these reactions symptomatically. Further medication administration will be
based on the ED provider's discretion at the current standard of care and the participant's
reactions will be documented/included in the secondary outcomes of the study.

Benefits Participant benefits include potential decreased duration of symptoms in the acute
phase of injury following concussion. Magnesium is a relatively benign medication that is
used frequently, and if this can contribute positively to acute concussion management, the
investigators hope to change how mild traumatic brain injuries are managed.

Risk/benefit ratio Benefits of subject participation outweighs risk. Current standard of care
is symptomatic care with rest, and follow up if symptoms persist 5-7 days following initial
intervention. Adding magnesium, which has a low adverse effect profile and is an inexpensive
option that could have a large impact on concussion management.

Participation Duration Participation in the proposed study will last the duration of their
emergency department visit. Participation will involve a minimum of 30-60 minutes. The
continued participation through the next 5 days is critical to the study to allow proper
follow up, along with medication dosing.

Rationale for the use of selected subject population Concussions are a growing problem with
socialization and media attention nationally. While there are no long term effects of
concussions, there is an acute phase of injury that if decreased would benefit those with
mild traumatic brain injury. With adolescents, there is a drive to return to normal health,
and often an immediacy for treatment allowing appropriate initial intervention and follow up
in the outpatient office prior to returning to daily activities. The interventions proposed
in this study contain the current standard of care, thereby the addition of magnesium
supplementation is medically benign but could have physiologic potential.

Inclusion Criteria:

- • Age 12 to 18 years

- • Presenting chief complaint of headache, head injury, or concussion within the first
48 hours of injury.

- • GCS > 13 on arrival.

Exclusion Criteria:

- • Age < 12 years or > 18 years

- • Inability to provide informed consent

- • Vomiting > 2 episodes following injury

- • Physical or mental disability hindering adequate response to assessment of symptoms

- • Hemodynamic instability/medical condition requiring further acute life-saving
medical intervention

- • Known brain mass, intracranial hemorrhage, skull fracture

- • Known contraindications to magnesium use

- • Known contraindication to Zofran use