Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05665764 |
| Other study ID # |
D4414-P |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2023 |
| Est. completion date |
June 30, 2025 |
Study information
| Verified date |
July 2023 |
| Source |
VA Office of Research and Development |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Veterans with traumatic brain injury (TBI) frequently experience insomnia, which is linked
with delayed TBI recovery, more severe functional impairment, and exacerbation of disabling
TBI after-effects such as depression, chronic pain, and fatigue. Current research suggests
that TBI can impact numerous systems involved in sleep, suggesting that insomnia can have
various causes and that a "one-size-fits-all" approach to treatment is likely inadequate. As
such, it is necessary to determine which Veterans may benefit from standard evidence-based
treatments, such as Cognitive Behavior Therapy for Insomnia, and which may require enhanced
treatments targeting specific underlying mechanisms.
An emerging body of evidence has established a link between circadian rhythm disruption and
post-TBI insomnia. A mismatch between circadian and desired sleep timing (i.e., "circadian
misalignment") is common following TBI, as evidenced by disruptions of key circadian rhythms
involved in sleep regulation (e.g., melatonin production), as well as the onset of circadian
rhythm sleep-wake disorders. Importantly, circadian-driven sleep disturbances require
specialized treatments that target circadian rhythms (i.e., "chronotherapies"), such as timed
sleep windows or enhanced light exposure, as standard treatment approaches can fail to
address or even exacerbate the underlying circadian misalignment. Thus, circadian
misalignment represents a novel and modifiable treatment target and has the potential to
improve functional outcomes in Veterans with TBI and insomnia.
Detection of circadian misalignment and optimal use of chronotherapies require the ability to
measure circadian phase (i.e., timing of the central circadian clock). However, current sleep
medicine in TBI is hampered by a lack of pragmatic options for measuring circadian phase.
This is because laboratory dim light melatonin onset (DLMO), the gold standard measure of
circadian phase, is time and cost prohibitive, requiring specialized sample (e.g., saliva)
collection facilities and placing substantial burden on the patient. Recently, novel methods
of DLMO measurement have been developed that may enhance the accessibility and practicality
of circadian phase assessment, although, as of yet, they have not been used in Veterans with
TBI. The proposed single-arm, longitudinal study seeks to evaluate the feasibility of two
methods of measuring DLMO in the home environment of Veterans with TBI and insomnia: 1)
direct measurement of self-collected salivary melatonin; and 2) indirect estimation of DLMO
using activity and light-exposure data collected through actigraphy. Additionally, this study
seeks to explore the relationships between circadian misalignment, sleep disturbance, and
functional impairment in Veterans with TBI.
The specific aims of this study are to: Aim 1) evaluate the feasibility of two methods of
home DLMO measurement (i.e., self-collected salivary melatonin and actigraphy data) in
Veterans with TBI and insomnia; and Aim 2) examine associations between circadian
misalignment (i.e., the difference in timing between DLMO and attempted sleep onset), sleep
disturbance, and functional impairment. Veterans with TBI and insomnia will be asked to wear
a wrist-based actigraphy device for one week, which will collect data on light exposure and
sleep-wake states. They will then be asked to self-collect seven hourly saliva samples under
dim light conditions in their own home and mail them to a testing facility using a provided
pre-paid shipping label. Saliva samples will be used to directly measure DLMO and actigraphy
data will be used to indirectly estimate DLMO using established mathematical models of the
human circadian pacemaker. Evaluating the feasibility of home DLMO measurement is a crucial
first step for enhancing precision sleep medicine for Veterans with TBI and insomnia.
Findings will inform the development and testing of tailored sleep interventions for use with
this patient population.
Description:
Background and Significance:
Insomnia is a pervasive problem among Veterans with traumatic brain injury (TBI). Veterans
with TBI frequently experience sleep disturbances following their injury. Insomnia, an
impairing disorder characterized by difficulty initiating or maintaining sleep, is the most
common sleep disturbance reported following TBI. Indeed, Veterans with TBI are 50% more
likely to develop future insomnia compared to their non-injured peers.
The development of insomnia following TBI can delay recovery and contribute to functional
impairments. Compared to TBI patients with normal sleep, those with insomnia have up to
eightfold greater odds of functional impairment in the six months after injury. Post-TBI,
United States (U.S.) Veterans who had poor sleep were more likely to report pain was
interfering with their lives, have diminished health-related quality of life, and perform
worse on neurobehavioral measures. A large-sample study found that insomnia was associated
with decreased life satisfaction both immediately following TBI and one-year post-injury.
Furthermore, insomnia is strongly associated with, and can exacerbate, other TBI sequelae
such as depression, chronic pain, and fatigue, which can further delay rehabilitation and
recovery from TBI.
Mechanisms underlying insomnia in TBI are heterogeneous, indicating that a
"one-size-fits-all" approach to treatment is likely inadequate. While the precise mechanisms
that underlie insomnia after TBI remain unknown, the extant research suggests that TBI can
impact numerous systems that regulate sleep and wake states. Insomnia can result from damage
to specific brain regions involved in sleep initiation (e.g., basal forebrain). Widespread
brain damage, such as diffuse axonal injury, can disturb sleep through disruption of neuronal
signaling, buildup of cellular waste byproducts, and toxic metabolic cascades. Perturbation
of hormonal systems are also associated with insomnia following brain injury. Moreover,
physical and psychological sequelae of TBI, such as pain, depression, or posttraumatic stress
disorder (PTSD), can contribute to insomnia. Therefore, it is necessary to differentiate
Veterans who may benefit from standard evidence-based treatments, such as Cognitive
Behavioral Therapy for Insomnia (CBTI), and those who may require enhanced treatments
targeting specific underlying mechanisms.
One distinct, but understudied, causal mechanism implicated in post-TBI insomnia is
disruption to the circadian system. Circadian rhythms are changes in biochemical,
physiological, or behavioral processes that repeat over the course of approximately 24 hours
and are responsive to external cues such as light exposure. A mismatch between circadian and
desired sleep timing (i.e., "circadian misalignment") can disturb sleep, manifesting as
insomnia or circadian rhythm sleep-wake disorders (CRSDs) like delayed or advanced sleep
phase disorders. Following TBI, circadian misalignment is common, as seen in perturbations of
key circadian rhythms involved in sleep regulation (e.g., melatonin production), as well as
the manifestation of CSRDs. This may be because TBI dysregulates the expression of circadian
clock genes, which in turn is correlated with disruption of day/night activity rhythms.
Another potential pathway linking TBI to circadian misalignment is the immune system, which
communicates bidirectionally with the circadian system and is activated following TBI.
Post-TBI inflammation may induce circadian desynchrony-a lack of temporal coordination across
tissues, organs, and molecular processes-thus impairing homeostatic control and driving a
pathological feedback loop of further inflammation, circadian misalignment, and resulting
sequelae. Indeed, many impairments that arise from TBI, including sleep-wake disturbances,
are also observed in cases of circadian desynchronization, further implicating circadian
misalignment in TBI symptomatology.
Accurate detection, and subsequent correction, of circadian misalignment represents a unique,
novel, and modifiable treatment target that has the potential to improve the efficacy of
circadian-targeted treatments ("chronotherapies") and functional outcomes for Veterans with
TBI and insomnia. Failure to detect circadian misalignment underlying insomnia can lead to a
choice of an ineffective intervention. Treating circadian-driven sleep disturbances requires
specialized treatment approaches, such as timed exposure to light and darkness or melatonin
supplementation, that aim to modify the timing or signaling strength of the individual's
internal biological clock. By acting upon this clock, chronotherapies can adjust the timing
of sleep-wake cycles and consolidate irregular or fragmented sleep. However, appropriate and
efficacious administration of chronotherapies requires an understanding of the precise timing
of the individual's biological clock (i.e., circadian phase), as the potency of these
interventions vary across the internal day and night and can range from salubrious to
ineffective or even harmful. For example, when unguided by circadian phase, standard sleep
interventions, like sleep restriction therapy (the main component of CBTI), may fail to
address underlying circadian misalignment or may even exacerbate it. Additionally, the degree
of side effects associated with acute sleep restriction, such as impaired attention, daytime
sleepiness, disrupted mood, and dysregulated autonomic function, depend upon the individual's
circadian phase prior to the start of the intervention. Thus, accurate measurement of
circadian misalignment would not only allow providers to identify when an empirically
supported chronotherapy (alone or in combination with other sleep interventions) may be
indicated, but it could also help providers optimize the delivery of chronotherapies for
insomnia and monitor changes to circadian phase, thereby improving treatment response.
Sleep medicine for TBI is hampered by a lack of pragmatic options for measuring circadian
phase. Time of dim light melatonin onset (DLMO) is currently considered the "gold standard"
for measuring circadian phase and is an important tool for identifying circadian misalignment
in insomnia. However, laboratory measurement of DLMO is time and cost prohibitive, as
patients must report to the collection facility 6-8 hours before their typical bedtime,
remain in supervised dim-light conditions, and give frequent samples (e.g., saliva) until
their bedtime or later. Such requirements make the routine measurement of DLMO in clinical
settings impractical. Indeed, lack of testing for objective markers of circadian phase like
DLMO has been recently highlighted as a significant gap in the identification of circadian
misalignment when diagnosing and treating sleep disorders. Alternatives to laboratory DLMO
that allow healthcare providers to pragmatically and accurately measure circadian phase are
needed to advance precision sleep medicine in TBI.
Novel methods of DLMO measurement have been developed that may enhance the accessibility and
practicality of circadian phase assessment; however, their feasibility for Veterans with TBI
and insomnia remains unknown. In the past decade, two new approaches for measuring DLMO at
home have emerged. The first involves directly testing for DLMO in self-collected saliva
samples. Although similar to laboratory DLMO measurement, in that Veterans are still required
to collect frequent saliva samples under dim light conditions, self-collected saliva allows
Veterans to remain in the comfort of their own homes during the collection procedures. This
approach could increase uptake of DLMO measurement by clinicians, as it would circumvent the
need for a referral to another facility or service. Initial research has shown that obtaining
DLMO from self-collected saliva is viable for over 85% of participants, suggesting that
patients are able to adhere to collection procedures. The second novel approach involves
indirectly measuring DLMO from the patient's daily activity levels and light exposure. By
employing established mathematical models of the human circadian pacemaker, DLMO can be
estimated based on the amount and timing of light exposure throughout the day, as well as the
timing of sleep. Excitingly, the data needed for indirect DLMO measurement can be acquired
passively via wearable sensor technology, such as a wrist-worn actigraphy device, meaning
that circadian phase can be assessed with minimal patient burden. Previous research has
achieved high rates of data acquisition using this approach and successfully estimated DLMO
with as little as a few days of actigraphy data. More important, both home DLMO approaches
have been validated against laboratory DLMO in healthy participants and participants with
disordered sleep, suggesting that they can measure circadian phase with enough accuracy to be
used in clinical practice.
While these initial findings are promising, additional work is needed before they can be
applied to the care of insomnia in Veterans with TBI. Potential barriers inherent to each
home DLMO method may limit successful measurement of circadian phase. For example, the
requirements of home saliva collection, such as avoiding light exposure and providing samples
at prespecified times, may be difficult for Veterans experiencing TBI symptoms like cognitive
impairment. Similar difficulties may be encountered when using actigraphy, as Veterans may
inadvertently cover the light sensor with clothing or forget to wear the device continuously
over the assessment period. Establishing the feasibility of home DLMO methods in Veterans
with TBI and insomnia is a vital first step for their implementation in clinical care.
Significance. In summary, there is a crucial need for circadian phase assessment to be made a
routine part of insomnia care for Veterans with TBI, yet the primary way of doing so,
laboratory DLMO, is rarely used due to its high level of burden. This project will address
the above gap by evaluating the feasibility of two pragmatic methods for measuring circadian
phase via DLMO in the home environment: direct measurement of DLMO through self-collected
saliva and indirect measurement of DLMO via activity and light exposure data. Additionally,
this study will be the first direct exploration of the hypothesized relationships between
circadian misalignment, functional impairment, and sleep disturbance in Veterans with TBI.
Thus, findings from this study may inform the development and testing of tailored sleep
interventions for Veterans with TBI, with the goal of enhancing functional outcomes by
restoring synchrony between biological timing and psychosocial demands. For example, accurate
and accessible measurement of circadian phase will allow providers to: 1) detect underlying
circadian misalignment in insomnia that would otherwise go unnoticed; 2) provide Veterans
with TBI with an appropriate evidence-based sleep intervention (i.e., chronotherapy or
standard care); and 3) monitor treatment response and adjust accordingly. Finally, this
research has broad implications for a range of populations seeking rehabilitative care,
including those with a history of stroke, spinal cord injury, and serious mental illness.
Description of Population to be Enrolled:
Potential participants will be all willing and eligible U.S. military Veterans aged 18-64
from the following populations: 1) those seeking outpatient services at the Rocky Mountain
Regional Veterans Affairs (VA) Medical Center; and 2) those in existing clinical and research
databases (e.g., the Rocky Mountain Mental Illness Research, Education and Clinical Center
[RM MIRECC] research database).
Study Design and Research Methods:
Recruitment. Multiple means will be used to inform potential participants (i.e., Veterans
with TBI and insomnia receiving care in the Veterans Health Administration) about this
research project. This includes letters, flyers, social media, advertisements, presentations,
and/or involving professionals treating Veterans. The RM MIRECC recruitment team will assist.
Screening. A research team member will explain the procedures to interested participants (via
phone or video conference) and complete the screening checklist. If applicable, primary
caregivers will be invited to attend screening and subsequent sessions. Those who pass
screening will be scheduled for in-person eligibility evaluation and Consent/Baseline.
Eligibility, Consent, and Baseline Assessment. Informed consent will be obtained from
interested participants who pass the initial screening (and caregivers, if applicable, to
obtain collateral data). Eligibility criteria will be established via administration of the
OSU TBI-ID, SCISD-R, and SCID. Following confirmation of eligibility, a member of the
research team will administer other measures via the Research Electronic Data Capture
(REDCap) survey system. Actigraphy and home saliva collection dates will be scheduled. At
this time, a Preparation call will also be scheduled to take place the day before saliva
collection.
Practice Training Session. Following baseline assessment (during the same visit), a practice
session will take place, so the participant can learn to use the actigraphy device and the
home saliva collection kit (Salimetrics, CA, USA), both of which will be given to the
participant at the end of the session along with instructional handouts. At the end of the
practice session, a brief skills check (e.g., simulating saliva collection procedures) will
be conducted to address any remaining difficulties in understanding the study tasks.
Furthermore, the practice session will be piloted with the first four study participants and
adjustments to the protocol will be made as needed. A step-by-step video on how to complete
saliva collection will also be created for this study and hosted on a study website. Based on
study findings, teaching resources will be made public for use by other clinicians and
researchers. Participants will be provided with locations of return FedEx facilities (for
returning saliva samples) closest to their home. Time to complete Baseline procedures and the
practice session will be 2.5 hours.
Collection of Actigraphy and Sleep Diaries. For the week prior to their home salivary
melatonin collection, participants will be asked to wear an actigraphy device continuously on
their non-dominant wrist. They will be instructed to leave the device uncovered, such as by
clothing, to allow the light sensor to function properly. Participants will also be asked to
complete a daily sleep diary (5 minutes). They will receive a REDCap email link each morning
for electronic data submission. A research team member will provide instructions on how to
enter sleep diary data. During the week of sleep diary collection, participants will receive
follow-up reminders (either by phone or email) if diary responses are not entered during the
day. Participants will not be required to change their daily routines in any other way.
Home Saliva Collection. Pre-collection/Preparation Appointment. The day before saliva
collection, participants will be called to remind them of the process. The research team
member will go over each step, ensure participants have the correct collection times
recorded, and answer any questions. The saliva kit contains all necessary materials for the
storage and shipping of specimens (e.g., 7 pre-labeled cryovials). Along with the saliva kit,
participants will be provided with a nightlight to facilitate collection, as well as a
handout to guide them through the collection process based on the Salimetrics DLMO Profile
Saliva Collection protocol. Participants will be asked to avoid alcohol and caffeine for 24
hours prior to saliva collection and to avoid pitted fruit and bananas during the day of
collection. The provided handout will also include self-reported checks for methods adherence
(e.g., avoiding food, caffeine), which will supplement the objective light adherence check
(see next section).
Collection Day. At 5.5 hours prior to their typical self-reported bedtime, participants will
be asked to reduce all sources of light as much as possible. Participants will be asked to
remain in dim light (e.g., 40-watt lightbulb exposure or lower, closed blinds) and to reduce
all electronic screen brightness as much as possible during the saliva collection process, as
light exposure can inhibit melatonin production. The nightlight will be provided to assist in
dimming the home. As an adherence check, light exposure during saliva collection will
continue to be measured using the already provided actigraphy device. Participants will also
be asked to refrain from napping, eating major meals, or brushing teeth during the collection
period but will be allowed to consume light snacks. Saliva collection will then begin 5 hours
prior to the participant's typical bedtime. Collection will take place each hour until 7
samples have been obtained (5 hours prior to bedtime until 1 hour after typical bedtime). For
the 10 minutes prior to each collection, participants will be asked to refrain from eating
any food or drinks other than water and to rinse their mouths with water. At the collection
time, participants will be asked to provide passive drool using the labeled cryovial and
record the collection time. They will be asked to store each saliva sample in the fridge or
freezer when actively collecting saliva and then store all saliva samples in the freezer once
collection is finished, until they are ready to drop the samples off at a FedEx shipping
location for overnight shipping using the prepared shipping label. At this point,
participants will also return the actigraphy device either in person or via a prepared
shipping label. DLMO timing will be determined by Salimetrics laboratory services.
Qualitative Interview. A brief qualitative interview will be administered to participants
(and caregivers, when applicable), including those who discontinue the study early (if
possible). This will provide data regarding user experience with the DLMO methods, including
potential facilitators and barriers.
Data Analysis Plan:
Aim 1. Each home DLMO measurement method will be evaluated separately and considered feasible
if 70% participants provide adequate data for measurement of DLMO.
Aim 2. Linear regressions will be conducted to explore the association between circadian
misalignment (independent variable) and either functional impairment or sleep disturbance
(dependent variables). Functional impairment will be assessed using the WHODAS 2.0 summary
score. Sleep disturbance will be assessed using the PROMIS sleep disturbance total score.
Circadian misalignment will be defined as the difference in time between DLMO and the average
sleep diary-based bedtime. Values for circadian misalignment will be calculated for each home
DLMO method and evaluated in four separate statistical models. Covariates for all models will
include age, gender, depressive symptom severity, and PTSD symptom severity.
