Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02443142 |
| Other study ID # |
NorthwesternU |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2015 |
| Est. completion date |
July 1, 2016 |
Study information
| Verified date |
March 2015 |
| Source |
Northwestern University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Traumatic brain injury (TBI) is an important public health problem with an estimated 1.7
million new cases in the United States each year. Although the vast majority of these victims
sustain mild TBI, many still develop headache, difficulty concentrating, and decreased memory
with potential for serious long-term consequences. In particular, mild TBI is an important
consequence of combat-related injuries sustained by military personnel and sports-related
injuries in young adults. Unfortunately, treatment of mild TBI is usually limited to oral
analgesics for headache pain such as acetaminophen (Tylenol) or ibuprofen (Motrin or Advil).
Since there are no previous randomized trials of these medications for mild TBI, their
comparative effectiveness is not known. Increasing animal based evidence suggests that mild
TBI is related to brain cell injury caused by overexpression of a cellular enzyme (COX-2)
that causes neuroinflammation. Fortunately, inhibition of COX-2 is easily achieved using
ibuprofen. We hypothesize that head injured patients treated with ibuprofen will have a lower
incidence of mild TBI symptoms than patients treated with acetaminophen. We will conduct a
randomized clinical trial to measure the comparative effects of ibuprofen versus
acetaminophen on the incidence of specific symptoms of mild TBI in emergency department
patients with head injury.
Description:
OBJECTIVES
The long-term goal of the proposed project is to develop an effective pharmacological therapy
for patients with mild TBI to improve functional outcomes. The main objective is to compare
the effects of ibuprofen versus acetaminophen for reducing the short-term development
post-concussion symptoms in patients with mild TBI. We will conduct a double-blinded
randomized clinical trial (RCT) with the specific aim of measuring the comparative effects of
equipotent doses of ibuprofen versus acetaminophen on the incidence of concussion symptoms to
be measured 7 to 10 days after mild TBI in emergency department patients with isolated closed
head injury. The main study hypothesis of our research project is that patients with mild TBI
who are treated with ibuprofen will have a lower incidence of post-concussion symptoms
compared to patients treated with acetaminophen. The proposed investigation is novel because
it will be the very first RCT to compare analgesic medications for the specific treatment of
mild TBI.
BACKGROUND
Pathophysiology of Mild TBI. TBI results from external mechanical force applied to the
cranium leading to parenchymal brain damage. This resultant brain injury can range from mild
temporary impairment to severe disability. TBI transpires in two phases: (1) primary brain
injury occurs at the moment of the application of mechanical force on the cranium and results
in lacerations, contusions, hematomas and shearing injuries of the brain; and (2) secondary
brain injury begins immediately after the primary brain injury and results from the cellular
mediation of neuroinflammation.15,16 The principal injury of mild TBI is diffuse axonal
injury from shearing forces that is not usually identified by CT brain scan.17-20 Secondary
brain injury activates multiple cellular pathways that are initially adaptive, but become
pathological with overexpression and persistence.21-23 The biochemical consequences of these
responses develop over a period of hours with the accumulation of arachidonic acid from
cellular membrane stores and the induction of cyclooxygenase-2 (COX-2) gene expression and
enzyme activity.15,16 Arachidonic acid is then converted to detrimental vasoactive
prostanglandins and free radicals by COX-2 enzyme leading to neuronal cell death (Figure 1
see appendix). Neural COX-2 enzyme activity remains elevated for 1 to 3 days.24 Severity of
neuronal injury is correlated to COX-2 overexpression which results in a "vicious cycle" of
neuroinflammation when secondary injury propagates further COX-2 activity.15,16
Potential Effect of COX-2 Inhibition. If COX-2 overexpression causes neuronal cell damage
after brain injury, then COX-2 inhibition may provide neuroprotective effects through two
important mechanisms: (1) by reducing detrimental vasoactive prostanglandins and free radical
synthesis; and (2) shunting of arachidonic acid down alternate pathways that produce
beneficial eicosanoids.15 These cellular mechanisms are based on findings from several animal
studies over the past 30 years that strongly suggest potential beneficial effects of NSAID
inhibition of the COX-2 enzyme as a treatment for TBI-activated neuroinflammation.25-35
Although these studies examined different NSAID COX-2 kinhibitors and utilized different
animal models of TBI, they found an overall consensus of beneficial effects (i.e., reduced
prostaglandin synthesis, reduced brain edema, improvement in cognitive and motor function,
improvements in memory, and reduced mortality) suggesting COX-2 inhibition may have effects
beyond analgesia in patients with mild TBI. In fact, COX-2 inhibition has been shown to be
beneficial for animal models for other types of brain insults including ischemic brain
injury.36-40
If we identify a beneficial effect of ibuprofen for patients with mild TBI that is confirmed
with validation studies, then new standards and guidelines will be developed to improve the
ED management of this common form of brain injury. Future studies will be conducted to
elaborate the effects of ibuprofen and other NSAIDS on both the short-term and long-term
complications of mild TBI and possible other forms of TBI. Discovery of a beneficial effect
of NSAIDs for mild TBI could be especially useful for combat-related and sports-related brain
injuries.
STUDY DESIGN
Study subjects will be identified and enrolled in the emergency department. They will be
followed for a 7 to 14 day period only. The proposed project will be completed over a
one-year period with tasks and milestones as follows: Month 1 - develop protocol, create data
collection instrument and codebook, test and modify instrument, create electronic database,
and train assistants; Months 2 and 10 - identify and enroll eligible study subjects in the ED
setting, create database, enter and edit data; and Months 11 and 12 - analyze data and
interpret findings, prepare and submit papers to journals.
Study Design and Participants. We will conduct a double-blinded RCT to compare the effects of
ibuprofen versus acetaminophen on the incidence of post-concussion symptoms measured 7 to 14
days after mild TBI.
Treatment Variable. The treatment variable will be equipotent oral doses of either ibuprofen
(800 mg TID) or acetaminophen (1000 mg TID). Ibuprofen is a nonselective NSAID that inhibits
both COX-1 and COX-2 isoenzymes. COX-2 inhibition prevents arachidonic acid from converting
to vasoactive prostaglandins and reactive oxygen species in brain cell. The analgesic,
antipyretic, and antiinflammatory activity of ibuprofen operates mainly through inhibition of
COX-2.55,56 Acetaminophen is a poor inhibitor of both COX isoenzymes in the CNS and has
significantly weaker antiinflammatory effects than NSAIDs. Acetaminophen does not inhibit COX
in peripheral tissues and is less effective in the presence of peroxides.57,58 Both ibuprofen
and acetaminophen are frequently prescribed for headache pain related to mild TBI in the ED
and other primary care settings and have excellent safety profiles for short-term use. In
fact, both ibuprofen and acetaminophen have been used for the antipyretic treatment of
children with severe traumatic brain injury.59 Subjects will receive the first medication
dose in the ED and will be given the remaining 5 doses to take over 48 hours as outpatients.
This time period was selected based on animal models identifying maximum COX-2 activity. Both
medications will be identically prepared to prevent subjects from identifying the type of
treatment regimen. Treatment assignment will be randomized by the NMH research pharmacy and
blinded to both the patients and the investigators. Standard methods for blinding will be
implemented by using tablets that are identical in size, shape, color and taste for both
ibuprofen and acetaminophen.
Data Collection and Variable Measurement. Information concerning the outcome and secondary
study variables will be obtained by research assistants using standardized data collection
instruments. Follow up outcome assessment will be conducted through telephone interviews at 7
to 14 days after head injury. We will implement best practice methods for accurate and
complete data collection, including the following: (1) training assistants in data collection
methods; (2) blinding assistants to the subjects' treatment assignment; and (3) conducting
meetings with assistants to review data collection processes and difficulties. Subjects with
persistent mild TBI symptoms at time of follow up will be referred to the Rehabilitation
Institute of Chicago Concussion Clinic for further treatment.
Research Location. Northwestern Memorial Hospital is a state-of-the art, two million square
foot, 873-bed tertiary teaching hospital in downtown Chicago that is the primary teaching
hospital affiliated with the Northwestern University Feinberg School of Medicine. The
Northwestern Memorial Hospital Emergency Department is an urban, academic, 56 bed, Level I
trauma center with an annual patient volume of over 85,000 patients per year or approximately
230 patients per day. The Emergency Department is staffed exclusively by board-certified
emergency medicine physicians that also supervise the care of 48 residents and four fellows.
The reported demographic distribution of the overall Emergency Department patient population
is as follows: 7% Hispanic; 2% Asian; 35% Black; and 63% White.
SATATISTICAL ANALYSES
Data Analyses Plan. We will conduct all statistical analyses based on the American
Statistical Association Ethical Guidelines for Statistical Practice67,68 and include the
following:
1. Univariate Analyses. We will first conduct univariate analyses to assess potential
demographic and clinical differences between the two treatment groups. We will also use
ANOVA to compare the effects of ibuprofen versus acetaminophen treatment on the
incidence of mild TBI symptoms using continuous measures of pain scores and Neural-QOL
measures of pain and cognitive function.
2. Multivariate Analyses. We will use log binomial regression modeling to adjust for
potential residual confounding to estimate the effects of ibuprofen versus acetaminophen
on the incidence of mild TBI symptoms. We will also conduct survival analyses using
Kaplan-Meier graphs and Cox proportional hazards regression modeling to estimate
adjusted hazards ratios for the effects of ibuprofen versus acetaminophen on the main
outcomes of mild TBI symptoms. We will also conduct likelihood ratio and goodness-of-fit
tests to identify and include specific covariates for the regression models and
diagnostic methods to evaluate overall model fit and plausibility of model assumptions.
3. Advanced Methods for Causal Inference. We will use advanced statistical methods to allow
assessment of causation: (1) instrumental variables to estimate the effects of ibuprofen
versus acetaminophen with potential treatment regimen noncompliance by using treatment
randomization as a perfect instrument;69,70 (2) marginal structural modeling to account
for time-varying confounders and to assess for direct versus indirect effects in the
presence of intermediate factors.71-74
Sample Size Estimation. Sample size estimation is especially challenging because there are no
prior human studies measuring the effect of COX-2 inhibition on the incidence of mild TBI
symptoms. Notwithstanding this limitation, we will use the presence of headache pain at 7 to
14 days as a binary outcome. Sample size estimation is based on the following: (1) 40%
expected frequency of headache pain in the ibuprofen group versus 60% expected frequency in
the acetaminophen group; (2) the use of two-sided tests performed at a significance level of
0.05; (3) a power of 0.80 to detect a true difference in headache pain between subjects
receiving ibuprofen versus acetaminophen; and (4) one to one distribution of study subjects
receiving ibuprofen versus acetaminophen. With these assumptions, the estimated number of
study subjects needed to statistically assess ibuprofen versus acetaminophen for the
treatment of mild TBI is a total of 214 subjects.60 Our plan to enroll over 400 subjects will
provide an adequate sample size to conduct our statistical analyses. The Northwestern
Memorial Hospital Emergency Department provides care to about 2,000 head injured patients
with mild TBI each year.
