Pilot Study of a Novel Arm Restraint For Critically Ill Patients
Phase: PHASE1
Conditions: Acute Respiratory Failure
Sponsor: University of Vermont

 
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Human Subjects Research Protocol  
 
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PROTOCOL SUMMARY 
 
Project Title: 
Protocol 
Version 
Date: 
Phase I Pilot Safety and Feasibility of a Novel Restraint Device for Critically Ill Patients with 
Acute Respiratory Failure 
10-31-18 
 
 
Principal Investigator:   
Renee Stapleton, MD PhD; Dale Needham, FCPA  MD  PhD 
 
NCT Number: 
NCT03621475 
 
 
 
 
Lay Language Summary:  (Please use non-technical language that would be understood by nonscientific IRB members to summarize the 
proposed research project.  The information must include: (1) a brief statement of the problem and related theory supporting the intent of 
the study, and (2) a brief but specific description of the procedure(s) involving the human subjects.  Please do not exceed one single-spaced 
8 ½ X 11” page.) 
 
The goal of this Fast-Track STTR project is to optimize and test a novel arm restraint in older critically ill 
mechanically ventilated patients that increases mobility; reduces agitation, use of sedative medications, 
and delirium; and exhibits high satisfaction and acceptability among hospital staff, family members, and 
patients.  Older mechanically ventilated patients are often immobilized with wrist restraints to prevent 
self-extubation and are sedated to reduce agitation caused by their restraints and endotracheal 
(breathing) tube. This sedation and immobility lead to complications, including delirium and muscle 
weakness, that are independently associated with long term cognitive impairment, reduced physical 
functioning, and mortality. Specifically, the incidence and duration of delirium in the ICU are strongly and 
independently associated with long-term cognitive impairment that is similar to Alzheimer’s Disease and 
Related Dementias. 
 
Healthy Design is developing the novel ExersidesTM restraint that allows arm mobility but prohibits hands 
from reaching oral/nasal endotracheal and feeding tubes or intravenous lines. Because it permits 
mobility, ExersidesTM may reduce agitation and the need for sedatives. In preliminary pilot testing, 
ExersidesTM has demonstrated very encouraging results. The objectives of this STTR Fast-Track project 
are to optimize ExersidesTM and evaluate it in a randomized controlled trial (RCT) in older critically ill 
patients at high risk for delirium and associated long-term cognitive impairment. The multidisciplinary 
investigator team has expertise in critical care, extensive experience in conducting ICU RCTs, and a 
history of successful collaboration.  
 
During Phase I, a prospective study will be performed in 8 older mechanically ventilated patients to 
demonstrate that 1) the revised ExersidesTM prototype is safe and 2) the RCT proposed in Phase II is 
feasible. The milestones to proceed to Phase II are to demonstrate that: 1) the revised ExersidesTM 
restraint has mean incidence rate <5% across 7 pre-specified safety criteria in mechanically ventilated 

 
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older patients who require restraint; and 2) the RCT in phase II is feasible by successfully enrolling 8 
ICU patients into the phase I study and completing at least 90% of all proposed outcome measures. 
 
In Phase II, a multi-site within-patient crossover RCT in older mechanically ventilated patients requiring 
restraint will be conducted to test the following outcomes in ExersidesTM versus traditional wrist restraint: 
1) Mobility assessed by actigraphy (primary outcome); 2) Agitation, delirium, and medication use 
(secondary outcomes); and 3) Satisfaction with and acceptability/perceptions of the device (secondary 
outcomes).  Successful completion of this project will result in an ExersidesTM restraint that is ready for 
final optimization in preparation for commercialization, and is suitable for larger clinical studies to 
demonstrate effectiveness reducing long-term cognitive impairment in older ICU patients. 
 
 
PURPOSE AND OBJECTIVES  
 
Purpose:  The importance of the research and the potential knowledge to be gained should be explained in detail.  Give background 
information.  
Background and Significance 
Every day, >27,000 patients are restrained in US hospitals with physical restraints in intensive care units 
(ICUs) accounting for 56% of all restraint days, and older patients being 8 times more likely to be 
restrained than younger patients.1  Hence, physical restraint is a major issue in ICUs, especially for 
older adults.  Restraints are used in an attempt to reduce dangerous self-removal of endotracheal tubes, 
feeding tubes, and intravenous (IV) catheters.2  However, existing restraint devices have major 
limitations. Especially in older patients, restraints are associated with increased agitation and delirium, 
often leading to increased use of sedative medications, with associated complications including: 
immobility, muscle weakness, pressure ulcers, falls, prolonged mechanical ventilation duration, 
nosocomial infections, increased healthcare costs, and increased mortality.1  Of particular note, older 
patients and those with Alzheimer’s Disease and Related Dementias are at particular risk of delirium in 
the ICU.1  In both younger and older patients, the duration of delirium in the ICU is strongly associated 
with post-ICU long-term cognitive impairment, with cognitive test scores similar to patients with 
Alzheimer’s Disease and Related Dementias.1  Moreover, in older adults, delirium is significantly 
associated with incident dementia (odds ratio (OR) = 8.7) in those without pre-existing cognitive 
impairment3 and with accelerated cognitive decline1 in those with pre-existing dementia, with worsening 
dementia severity (OR = 3.1) and global function (OR = 2.8).3  Hence, this Fast Track project is 
responsive to PAS-17-065 given that the ExersidesTM restraint is designed to increase mobility/activity 
and reduce sedation, delirium, and sedative medication use, thereby reducing the risk of long-term 
cognitive impairment in older critically ill patients. 
  
By 2030, more than 74 million Americans will be >60 years old.4  With the aging population, there is an 
urgent unmet public health need to develop new strategies to protect mechanically ventilated patients 
from the removal of medical devices AND from the immobility, agitation, sedating medications, and 
delirium associated with traditional wrist restraints. There is a paucity of randomized controlled trials 
(RCTs) evaluating physical restraint devices, and a consequential international call for such research, as 
per the recent Intensive Care Delirium Research Agenda, co-authored by Dr. Needham (multiple PI) and 
leading international delirium researchers.1  Moreover, the Association of Critical Care Nurses, 
American Thoracic Society, Society of Critical Care Medicine, and American College of Critical Care 
Medicine, as well as the Joint Commission and Centers for Medicare and Medicaid (CMS), have 
strongly voiced this public health need by recommending and mandating the use of ‘least restraint 
necessary’ in clinical practice.1  However, none of the currently available traditional restraint devices 
optimally meet these complex needs. 
 
The most common restraints used in ICUs are soft wrist restraints that tie to the bedside and 
substantially restrict movement at the shoulder and elbow.5 Wrist restraints can be tied more loosely, but 
this increases the risk of self-extubation and self-removal of the restraints themselves, especially when 

 
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patients are unsupervised.1  Mitt restraints also may be used, but when used without wrist restraints 
patients may press their hands (in the mitts) together around a tube or line for self-removal.  Arm boards 
and elbow immobilizers are limited by often requiring continuous supervision as patients are able to self-
remove the restraint on the opposing arm. 
 
Healthy Design Ltd. Co. is developing the 
“ExersidesTM” restraint, a novel, adjustable arm 
restraint for invasive or non-invasive mechanically 
ventilated patients.6-8 ExersidesTM is designed to 
prevent self-extubation while improving upper arm 
mobility, and reducing agitation, delirium, and the 
need for sedating medications. Unlike traditional 
wrist and mitt restraints, ExersidesTM permits arm 
movement but does not allow the hands to reach 
endotracheal and feeding tubes (Figure 1). This 
novel restraint provides the least restrictive 
restraint possible at any time in a patient’s varying 
ICU course and permits maximum mobility levels 
commensurate with patient physical and cognitive 
condition. It is adjustable for patient size and to 
readily allow varying levels of restraint by bedside 
nurses. This multi-level restraint will empower 
nurses to minimize restraint AND sedation 
simultaneously, rather than relying on sedation to 
help patients tolerate the restraint. Thus, ExersidesTM will meet current 'least restraint necessary' 
regulations and 'best practice' recommendations.  
 
Preliminary Studies and Data 
1.  A prototype of the novel ExersidesTM restraint was designed to prevent self-extubation while 
minimizing immobility, agitation, and sedation.  
Supported, in part, by a sub-award from R24HD065703, the 
prototype (shown in Figure 2) was designed to allow complete 
rotational capacity of the shoulder joint, with comfort flexion at 
the elbow, while providing a squeezable ergonomic hand grip. 
The straps that secure the hand at the grip are designed to 
avoid the anterior wrist to permit use of a radial arterial 
catheter, when clinically indicated, and render the posterior 
aspect of the hand accessible for peripheral IVs, if clinically 
indicated. The device also allows easy access to the arm for 
blood pressure cuffs and IVs. ExersidesTM telescopes to 
adjust to the variable arm length of each patient and has a 
soft outer shell for cushioning. The wrist straps do not bind 
circumferentially, as with traditional wrist restraints, to help 
prevent possible compromise in vascular circulation. Two 
attachments at the distal arm offer a resistance band tie and a 
non-flexible tie that can be affixed to a hospital bed, if desired. 
Configurations for adjustable levels of restraint are: 1) no tie for a calm patient, 2) resistance tie 
(intermediate level of restraint) for a patient with flailing arms OR for resistance exercise as might be 
supervised by a physical therapist or nurse, and 3) rigid tie for temporary tighter restraint for an agitated 
or aggressive patient or as a temporary restraint during a procedure when the arm must be immobilized.  
 
2.  An evaluation in healthy subjects demonstrated that the first ExersidesTM prototype was 
feasible to use and comfortable for subjects.  The prototype was tested in 6 registered nurse (RN) 
Figure 1. ExersidesTM restraint prototypes in use.         
A: Healthy volunteer able to move arm from the shoulder 
but the restrained hand is unable to self-extubate or 
remove the device. Adjustable levels of restraint possible 
using resistance or rigid (white) straps.  B: The 
ExersidesTM restraint (both arms) in use by an awake 
patient mechanically ventilated for acute lung injury and 
able to participate in care. 
   
              
A                                       B                       
Figure 2. Healthy volunteer wearing 
the ExersidesTM restraint.  Adjustable 
white straps (lower left) attach to bed 
and can be titrated to patient needs. 

 
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volunteers who, following consent, were videotaped and acted in both their staff role (bedside RN) and 
simulated patient role (performed in a hospital bed). In the patient role, volunteers were instructed to act 
as: 1) a calm and cooperative patient, 2) a confused patient with moving arms, and 3) an agitated 
patient. Results, summarized in Table 1, demonstrate 
high satisfaction. 
3.  A pilot study of first prototype ExersidesTM 
restraint in ICU patients demonstrated feasibility 
and potential benefit.   An IRB-approved pilot study 
was conducted in one Vermont hospital ICU, where 10 
mechanically ventilated patients were alternatingly 
assigned to wear ExersidesTM or traditional wrist 
restraints (n=5 in each group, 64±7 years old, 30% 
women). On day #3 of intubation, all patients were 
continuously videotaped for 4 consecutive hours while 
wearing their assigned device.  All 5 patients in the 
ExersidesTM group tolerated the device with no adverse 
events (defined as no self-extubation, feeding tube or 
IV dislodgement, self-removal of restraint, skin 
breakdown or bodily trauma to patient or nurse).  
Activity and agitation were qualitatively assessed by analyzing the video recording, demonstrating that 
patients were active and awake while using ExersidesTM, with rare agitation observed in the ExersidesTM 
group.  Sedation medication dosing (propofol in all patients) was measured immediately before and then 
during the 4-hour period (Table 2).  Propofol use, sedation score, time spent moving, and time spent 
interacting were all generally improved with ExersidesTM. 
 
Themes derived from qualitative feedback from patients, nurses, and occupational therapists are in 
Table 3. In the Phase I portion of this STTR, we will revise the device based on existing feedback 
(Tables 1 and 3) and provide expanded data on safety and feasibility in an independent academic 
medical center (UVM site). 
 
 
 
 
4.  Continuous actigraphy is feasible to provide an objective, quantitative measure of 
mobility/activity in critically ill patients. We published data on feasibility of 48-hour wrist actigraphy 
monitoring, using the same sensor device proposed herein, in ICU patients. Overall, 35 of 48 (73%) 
eligible subjects/proxies provided consent. Thirty four of 35 (97%) completed 48-hour actigraphy 
assessment,1  and 10 of these 34 (29%) received mechanical ventilation. In the RCT in STTR Phase II, 
we will assess the effect of ExersidesTM on activity, quantified using wrist actigraphs over 4-hour 
periods: 9am to 1pm, and 1pm to 5pm.  The actigraphs report an activity count per 30 second epoch 
and the RCT’s primary endpoint is the total activity count (from 30 second epochs) within a 4-hour 
period. Among the mechanically ventilated patients in our published study, median (25th, 75th percentile) 
4-hour total activity counts for all observed 4-hour periods were 2654 (1158, 7495), with 1pm to 5pm 
Table 1. Healthy volunteer survey (N=6) 
demonstrating high satisfaction with the 
ExersidesTM restraint 
 
Strongly Agree 
or Agree 
Neutral/Disagree/ 
Strongly disagree 
From perspective of simulated PATIENT 
Comfortable 
5 
1 
Safe 
6 
0 
Effective 
6 
0 
Preferable 
6 
0 
More humane 
6 
0 
From perspective of simulated STAFF 
Easy to don/doff 
3 
3 
Easy to change level 
5 
1 
Safe for staff 
5 
1 
Effective  
6 
0 
Preferable 
5 
1 
More humane 
6 
0 
Table 2. Patients using ExersidesTM restraint vs. traditional wrist restraints required less sedation 
and spent more time moving, and interacting during 4-hour study period 
 
Pre-study: 
Propofol dose 
(mcg/kg/hour) 
During study: 
Propofol dose 
(mcg/kg/hour) 
During study: 
SAS* 
Time spent moving 
(hours) during 4-
hour period 
Time spent interacting 
(minutes) during 4-
hour period 
Traditional wrist restraints (n=5)   
26±18 
20±12 
3.2±0.4 
0±0 
2.2±4.4 
ExersidesTM restraint (n=5) 
28±8 
11±10 
4±0.7 
2.6±1.6 
66±74 
*Sedation-Agitation Scale; 1=comatose, 4=calm and cooperative, 7=dangerously agitated 
Table 3:  Feedback on prototype from patients, nurses, and occupational therapists 
Patients 
Nurses 
Occupational therapists 
Straps pushing upward on hands 
Happy to be able to move 
Can scratch nose with arm rod 
Better to see patient awake 
Difficult to adjust hand straps 
Better for IV placement 
Grip too large 
Shoulder piece effective 
Easier to hold arm rod than arm 
More rehab done with awake patient 

 
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having lower median activity counts: 2404 (1253, 13084) vs. 9am-1pm: 2771 (849, 6830). These activity 
counts in ICU patients are very low compared with reference values of 4-hour daytime activity counts of 
~9,600 to ~48,900 in elderly nursing home patients,1 demonstrating the need for greater activity/mobility 
in this patient population, as per the objective of this proposal. 
In our pilot study (see #3 above), 3 patients wore actigraphs (2 in traditional wrist restraint group and 1 
in ExersidesTM group); thus, demonstrating that wearing actigraphs with ExersidesTM is feasible, as 
expected based on our existing expertise with actigraphy. 
 
6.  Usual care restraint and sedation practices at study sites: All 3 study sites for the RCT (Aim 3) 
use only traditional soft wrist restraints.  As per Joint Commission guidelines, a physician order is 
required for use of restraints, with renewal of order at least once every 24 hours.  Additionally, all 3 sites 
use guideline recommended practices1 for management of sedation/agitation and delirium/cognitive 
impairment in their ICUs, that include aiming for patients’ wakefulness via use of short-acting analgesics 
(e.g. fentanyl), short-acting continuous sedation (e.g. propofol) when needed, and minimized use of 
benzodiazepines.  
 
 
References. Include references to prior human or animal research and references that are relevant to the design and conduct of the study. 
REFERENCES CITED 
 
1 !!! INVALID CITATION !!! 
2 Kruger C, Mayer H, Haastert B, et al. Use of physical restraints in acute hospitals in Germany: a multi-
centre cross-sectional study. Int J Nurs Stud 2013; 50:1599-1606 
3 Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-
old: a population-based cohort study. Brain 2012; 135:2809-2816 
4 US Census Bureau, 2014 National Population Projections Tables (Rev. May 9, 2017); Table 3: 
Projections of the Population by Sex and Selected Age Groups for the United States: 2015 to 
2060. https://www.census.gov/data/tables/2014/demo/popproj/2014-summary-tables.html. 
Accessed August 30, 2017.  
5 Martin B, Mathisen L. Use of physical restraints in adult critical care: a bicultural study. Am J Crit Care 
2005; 14:133-142 
6 Pavini M, inventor. Pavini M, assignee. Protective and exercise restraint system for intubated patients. 
US Appl. No. 62/205,298. 2015 Aug 14.  
7 Pavini, M, inventor. Pavini, M, assignee. Medical protective and exercise restraint systems and 
methods. US Appl. No. 15/237,325. 2016 August 15.  
8 Pavini, M, inventor. Pavini, M, assignee.  Medical protective and exercise restraint systems and 
methods.  Int’l. Appl. No. PCT/US2016/047090. 2016 August 15.  
9 Carville K, Lewin G, Newall N, et al. STAR: a consensus for skin tear classification. Primary Intention 
2007; 15:18-28 
10 The National Pressure Ulcer Advisory Panel (NPUAP) 2016 Staging Consensus Conference on 
Pressure Injury Stages. http://www.npuap.org/resources/educational-and-clinical-
resources/npuap-pressure-injury-stages/. Accessed August 31, 2017.  
11 Katz S, Ford AB, Moskowitz RW, et al. Studies of Illness in the Aged. The Index of Adl: A 
Standardized Measure of Biological and Psychosocial Function. Jama 1963; 185:914-919 
12 Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly 
people. CMAJ 2005; 173:489-495 
13 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis 1987; 40:373-383 
14 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. 
Crit Care Med 1985; 13:818-829 
15 Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score 
to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related 
Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 
22:707-710 

 
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16 Demers L, Weiss-Lambrou R, Ska B. Development of the Quebec User Evaluation of Satisfaction 
with assistive Technology (QUEST). Assist Technol 1996; 8:3-13 
17 Demers L, Monette M, Lapierre Y, et al. Reliability, validity, and applicability of the Quebec User 
Evaluation of Satisfaction with assistive Technology (QUEST 2.0) for adults with multiple 
sclerosis. Disabil Rehabil 2002; 24:21-30 
18 Patton MQ. Qualitative Research & Evaluation Methods: Integrating Theory and Practice. 4th ed. 
Thousand Oaks, CA: Sage Publications, 2015;  
19 Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven 
methodology and workflow process for providing translational research informatics support. J 
Biomed Inform 2009; 42:377-381 
20 Nalamalapu SR, Needham DM, Stapleton RD. Patient Recruitment Rate in Multicentered 
Randomized Trials in Critical Care. Crit Care Med 2016; 44:e588-589 
 
 
 
Objectives:  Clearly state the primary and secondary objective(s) of the study. 
Phase I Specific Aims: 
1. To revise the ExersidesTM prototype based on feedback obtained from standardized patients in the 
UVM simulation center. 
2. To demonstrate that the revised ExersidesTM restraint is safe, and that conducting the proposed RCT 
(for STTR Phase II) is feasible, by performing a prospective evaluation in 8 mechanically ventilated older 
patients who require wrist restraint, including pilot testing all proposed measurements and outcomes 
planned for STTR Phase II 
 
Milestones to progress to Phase ll: (A) Demonstrate that the revised ExersidesTM prototype is safe in 
older mechanically ventilated patients who require restraint (i.e., has mean incidence <20% across pre-
defined safety criteria, including: skin breakdown and laceration, reportable injuries to patients and 
clinicians, self-removal of the restraint, and damage to ICU bed or equipment), and (B) Demonstrate 
feasibility of the RCT planned for STTR Phase II, including enrollment of 8 ICU patients and completion 
of >90% of all outcomes/measures. 
 
Phase II Specific Aims: 
3. To conduct a multi-site, within-patient crossover RCT in older mechanically ventilated patients 
requiring restraint to test the following hypotheses regarding ExersidesTM vs. traditional wrist restraints: 
a. ExersidesTM allows greater upper extremity activity, as measured by actigraphy (primary 
outcome) 
b. ExersidesTM reduces delirium, agitation, and use of sedatives, analgesics and 
antipsychotics 
c. ExersidesTM has high satisfaction, assessed via both quantitative and qualitative 
evaluations, among ICU clinicians, families and patients. 
 
 

 
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METHODS AND PROCEDURES  
 
Study Design, Procedures, and Statistical Analysis Plan (all included here for Phase I and then Phase II):  
PHASE I (small cohort study to assess feasibility and safety) 
Aim 1: To revise the ExersidesTM prototype based on pre-existing user feedback 
 
For this Aim, we and the company (Healthy Design, Ltd) will utilize the UVM Simulation Center to test 
the current device in 3 standardized patients.  During this session, comfort, safety, and satisfaction will 
be evaluated in a simulated hospital setting.  Following this session, any revision of the novel device 
needing to occur based on feedback obtained will be performed by the manufacturer before proceeding 
to Aim 2.  Prevention of safety issues listed below in Aim 2 will be addressed during device refinements 
by surveying for sharp edges or hard protrusions and adding padding, as well as ensuring that securing 
straps are appropriately positioned, wide and padded. 
 
Aim 2: To demonstrate safety of the ExersidesTM restraint and the feasibility of conducting an RCT (Aim 
3, STTR Phase II) by performing a pilot cohort study to assess the restraint in 8 older ICU patients. 
 
Study Site: UVM, a large regional hospital with extensive ICU RCT experience, is located close to 
Healthy Design, with Drs. Pavini and Stapleton having a pre-existing collaborative working relationship.  
 
Patients (n=8): We will conduct a study of 8 elderly ventilated ICU patients requiring restraint per an 
active physician order.  See inclusion and exclusion criteria below in Table 4. 
 
            Table 4:  Inclusion and Exclusion Criteria for Study Entry into STTR Phase I and Phase II Studies 
Inclusion Criteria 
Exclusion Criteria 
Rationale for Exclusion 
1. >60 years old 
2. Physician order for use of 
bilateral wrist restraints 
3. Requiring invasive or non-
invasive mechanical ventilation 
with actual or expected total 
duration of >48 hours 
4. Expected ICU stay >3 days after 
enrollment (to permit adequate 
exposure to proposed 
intervention) 
5. Not deeply sedated (Richmond 
Agitation Sedation Scale [RASS] 
score > -2)1 
1. Upper extremity impairments that prevent use of 
novel restraint device (e.g. amputation, arm injury) 
Unable to receive proposed intervention 
2. Limited mobility of either upper extremity prior to 
admission (e.g. frozen shoulder, severe arthritis) 
 
 
Inaccurate data for primary outcome 
assessment during RCT (i.e. actigraphy) 
 
 
3. Pre-existing primary systemic neuromuscular 
disease (e.g. Guillain-Barre) 
4. Neuromuscular blocker infusion (eligible once 
infusion discontinued if other inclusion criteria met) 
5. Pre-existing severe cognitive impairment or 
language barrier prohibiting outcome assessment 
Unable to perform outcome assessments 
6. Expected death or withdrawal of life-sustaining 
treatments within 6 days from enrollment 
Patients unlikely to complete proposed 
outcome assessment protocol 
7. Incarcerated 
Vulnerable population; ethical issues 
8. Severe skin breakdown on either upper extremity 
Unable to receive proposed intervention 
 
 
Consent: As most eligible patients will be unable to make decisions, written informed consent will most 
often occur via legally authorized representatives (LARs) with participant re-consent upon regaining 
capacity.  See below under section on Consent. 
 
 
Description of restraint intervention: All 8 patients will wear both the ExersidesTM and traditional wrist 
restraint devices on both arms, sequentially, over 2 study days. On Day 1, they will wear the 
ExersidesTM restraint on both arms from 9am-1pm and wrist restraints on both arms from 1pm-5pm. On 
Day 2, they will wear the restraints on both arms in the opposite order. During each 4-hour period, 
subjects will be observed by research and nursing staff, with validated and reliable hourly assessments 
of sedation/agitation (RASS) status,1 and validated and reliable delirium assessment (CAM-ICU) at the 
start and stop of each period (see Aim 3, Outcome 2 for description of RASS and CAM).1 Subjects will 
wear actigraphs on both wrists to measure mobility/activity continuously.  A digital video camera will be 
set up at the foot of the patient’s bed to continuously record his/her movements during the study 
sessions. Overnight between Days 1 and 2, subjects will resume traditional restraints, per MD order. 
Intervention ends on Day 2. Satisfaction/acceptability/perceptions of device will be assessed in nurses, 
family members, physicians, and patients as per RCT protocol (see Aim 3, Outcome 3). 
 
 
Phase I Outcomes: 

 
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1. Demonstrate that revised prototype is safe, with <20% mean incidence across 7 safety criteria in 
the 8 subjects enrolled.  Safety criteria in STTR Phase I will include: 1) clinician or patient 
laceration (Grade 2b or higher, per STAR laceration grading criteria9) from any sharp edges of 
device, 2) development of pressure ulcer from device of Stage 3 or greater per 2016 National 
Pressure Ulcer Advisory Panel Pressure Injury Stages,10 3) reportable injury (per local institutional 
standards) of patient by device, 4) reportable injury (per local institutional standards) to clinician by 
device, 5) self-removal of device, 6) damage to hospital bed rendering it non-functional, and 7) 
damage to ICU equipment (e.g. ventilator) rendering it non-functional.. 
2. Demonstrate that conducting the proposed RCT in Aim 3 is feasible, by consent/recruitment rate 
and pilot testing measures/outcomes for the RCT, via the following tasks: 
 
Consent/Recruitment:  8 patients consented and enrolled within <7 months 
 
Outcomes/measures:  At least 90% of all outcomes planned for the RCT in Aim 3 (STTR 
Phase II) will be measured in the 8 patients: 1) actigraphy counts, 2) RASS sedation/agitation 
score,1 3) CAM-ICU delirium score,1 4) medication use, 5) satisfaction/ 
acceptability/perceptions of novel restraint.  Incidence of self-extubation will also be reported 
in addition to the following measures of efficacy: 1) patient-reported satisfaction measures 
including comfortable, safe, effective, preferable and more humane; and 2) staff-reported 
satisfaction measures including easy to don/doff, easy to change level, safe for staff, effective, 
preferable and more humane.  See Aim 3 for these RCT measures. 
 
 
Data collection/management, quality assurance & analysis: See Aim 3. 
 
Sample size: N=8 was based on feasible enrollment from the single study site during the 9-month 
Phase I period (i.e., ~1 patient/month). Literature suggests that there is no advantage to including more 
than 6-10 subjects per group in a Phase I study, and most chemotherapeutic phase I studies have N=3 
per cohort.1 Thus, N=8 is adequate for the proposed Aims to prepare for the RCT in Aim 3. 
 
Phase I Study follow-up. The engineer will prepare a report on the outcomes of all assessments 
based upon STTR Phase I, and will decide (in consultation with the project leadership team) which 
device improvements/modifications will be required before use of device in Aim 3 (STTR Phase II). 
 
PHASE II (3-site RCT to compare the novel restraint to traditional wrist restraints) 
Aim 3: To conduct a multi-site, within-patient randomized crossover trial in older critically ill mechanically 
ventilated patients who require restraint, to compare the ExersidesTM restraint vs. traditional wrist restraints. 
 
Overview and Study Design Phase II. The objective of the Phase II project is to conduct an RCT to measure 
3 outcomes: 
1. Mobility/activity evaluated by actigraphy (primary outcome) 
2. Agitation, delirium, medication use (sedative, analgesic, and antipsychotic), and incidence of self-
extubation (secondary outcomes) 
3. Satisfaction with, and acceptability/perceptions of, the device by patient, family, and clinicians 
(secondary outcomes) 
 
 
Study Sites: We will recruit patients from 3 hospitals: UVM, JHU and UCLA.         
These sites were selected due to successful prior collaborations, experience in ICU RCT recruitment, 
similar sedation practice (Prelim Data 6), experience in ICU mobility/actigraphy, and similar “usual care” 
(Prelim Data 6). A study overview is in Figure 3. 

 
9 
 
 
 
Data Coordinating:  Data 
coordination will occur through 
integrated efforts between Healthy 
Design and all 3 study sites, with 
full support for design, conduct, 
monitoring, and analysis. An 
employed data coordinator will 
create a study database in RedCAP 
and will manage data from all 3 enrolling sites. Data coordination, cleaning, and subsequent analyses 
will be overseen by Drs. Colantuoni (PhD biostatistics faculty/ co-I) with Drs. Stapleton, Needham, and 
Pavini. Dr. Stapleton will oversee RCT conduct, including regulatory/ NIH reports. And employed study 
monitor will conduct site monitoring visits during the RCT. 
 
 
Study Leadership of RCT: To address leadership and communication issues, an Executive 
Committee (“EC”: Drs. Stapleton, Needham, and Pavini, along with Ms. Ardren [Project Manager, 
UVM]) will meet twice monthly by phone to discuss RCT conduct. For issues that require broader input, 
the RCT also will have a Steering Committee that includes the EC plus Drs. Kamdar (UCLA site PI), 
Colantuoni (Biostatistician), Pandian (Nurse co-investigator), Neufeld (aging/delirium co-investigator) 
that will meet monthly or as needed.  Each site-PI will supervise daily operations, along with site 
research staff supported by per-patient capitation payments. All investigators will co-author 
publications, with author order mutually agreed upon in advance.  
 
 
Patients (n=54): Eligibility criteria are identical to the cohort study in Aim 2 (Table 5). 
 
Consent: As in the study in Aim 2 (STTR Phase I), consent will most often occur via LARs with 
participant re-consent upon regaining capacity.  See below under section on Consent. 
 
Randomization: After consent, patients will be randomized (1:1) to Group A vs B (Fig. 4) via UVM’s 
web-based system (24 hrs/day), with variable-sized blocks of 2 or 4, stratified by site. 
 
Blinding: Due to the nature of restraint devices, we cannot blind patients, families, or ICU clinicians. To 
minimize bias, the primary outcome (actigraphy) will be analyzed by an outcome assessor blinded to 
patient identity or study group (Dr. McGinness) and key co-interventions will be standardized with 
planned analyses to evaluate balance between groups (see Statistical Analysis Plan). 
 
Standard ICU co-interventions for all patients: Important aspects of routine care will be standardized 
for BOTH study groups based on existing protocols at all sites, including: 1) turning by RN every 2 hr 
while in bed; 2) sedation/delirium management as per published practice guidelines (see Preliminary 
Data #6); 3) daily spontaneous breathing trials and ventilator weaning protocols, and 4) nutrition as per 
registered dietician consultation. These co-interventions are recorded electronically to easily facilitate 
the study monitoring plan. 
 
On-study data collection: Demographic, laboratory, physiological, and rehabilitation data will be 
collected (see Tables 5 and 6). 
 
Table 5:  Patient Variables -- Collected at Enrollment 
Patient Variables – collected at enrollment/baseline 
Collection Method 
Measurement Scale 
Demographic data (e.g. age, sex, race, marital status) 
Chart review 
Continuous/Binary/Categorical 
Height & weight; body mass index  
Chart review 
Continuous 
Comorbidities: Charlsona & Functional Indicesb 
Chart review 
Ordinal 
Baseline function: Katz Activities of Daily Living,11 and 
Clinical Frailty Scale12  
Proxy interview (see Outcomes 
below) 
Continuous/Ordinal 
ICU admission diagnosis (e.g. sepsis, renal failure)  
Chart review 
Categorical 
Severity of illness: APACHE IId 
Chart review 
Continuous 
Alzheimer’s disease and related dementia: IQCODE-SF 
surveye ; Delirium Risk Score 
Chart review;  
Categorical 

 
10 
 
 
 
Implementation of the RCT intervention:  
 
Study design: An innovative crossover design will allow each patient to serve as their own control 
(Figure 4), enabling us to assess both devices early in the study period while minimizing confounding 
by dynamic temporal changes in these critically ill patients, followed by a longer 4-day assessment with 
each patient wearing one device that will allow us to measure outcomes better assessed over days 
(rather than hours).  Subjects will be 1:1 randomized to either Group A or B, with both groups receiving 
both novel 
and traditional 
restraints.  On 
Days 1 and 2, 
subjects will 
wear each 
device for 4 
hours (9am-
1pm and 1pm-
5pm), during 
which time they will be observed by research and nursing personnel, with validated and reliable hourly 
assessments of sedation/agitation (RASS score).  A digital video camera will be set up at the foot of the 
patient’s bed to continuously record his/her movements during the study sessions.  Overnight between 
study Days 1-2 and 2-3, subjects will resume traditional wrist restraints, as per MD order.  No sensor or 
video data will be recorded during overnight periods when study staff are not available.  Starting on Day 
3 morning, subjects who continue to require restraints (per MD order) will be placed in either traditional 
or novel restraints device, as per their original randomization (i.e. the device worn for first 4-hr study 
period on Day 1) for up to 4 more days (i.e. until earliest of restraints no longer needed, death, or ICU 
discharge). This novel within-patient crossover design allows for increased precision with fewer 
subjects (see Sample Size) because it controls for confounding effects of patient-specific characteristics 
via each patient serving as their own control when comparing outcomes (i.e. arm activity) of the novel 
vs. traditional restraint during Days 1 and 2, along with reduced bias due to randomized allocation of 
initial study group (novel vs. traditional). Moreover, this design permits more prolonged comparison of 
novel vs. traditional device (over Days 3 to 6) to measure secondary outcomes (e.g., agitation, delirium, 
and medication use) that are more accurately evaluated over longer periods of evaluation. The 
randomization feature of this study design also controls for potential temporal differences in movement 
(e.g., patient more awake/mobile from 9am-1pm vs. 1pm-5pm). Patient eligibility criteria also help 
ensure that the study occurs when patients require restraint and are readily assessed for the primary 
and secondary outcome measures.  
 
 
Recurrence of clinical need for restraint and/or ICU readmit: If a patient ceases to need restraint 
during the 6-day study period, but then is deemed to need restraint again, the randomly allocated 
intervention will resume (up to 6-day maximum), with study ending upon ICU discharge (without re-
starting if ICU re-admit).   
aCharlson Index: a score for in-patients derived from 19 comorbidities; an increased score reflecting increased 1-year mortality.13   
bFunctional Comorbidity Index: an 18-diagnosis scale for ICU patients predicting 1-year SF-36 physical function;.1   
  
dAPACHE II:  Severity index using age, medical conditions, & acute physiology. Scores reflect increased short-term mortality.14 
eIQCODE-SF (Short Form of Informant Questionnaire of Cognitive Decline in the Elderly) is a validated proxy-based measure of baseline cognitive 
impairment commonly used in studies of hospitalized and critically ill patients1 
Table 6:  ICU-Related Variables – Collected at Enrollment and DAILY During ICU Stay 
ICU Variables – collected at enrollment and daily during ICU stay 
Collection Method 
Measurement Scale 
SOFAa organ failure score (with lab, medication and physiological data) 
Chart review 
Continuous 
Nutrition received (calories/protein) 
Chart review 
Continuous and categorical 
Exercise/rehab received as part of routine clinical care (type, duration) 
Chart review 
Continuous and categorical 
Compliance with proposed intervention regimen 
CRF review  
Continuous and categorical 
aSOFA: A validated composite score of 6 organ systems used to assess the severity of ICU organ dysfunction. 15 

 
11 
 
 
Training and quality assurance:  Training on study procedures (e.g. placement of restraints, data 
collection) will occur via Healthy Design staff traveling to each site before study start and in Year 2 of 
the RCT.  To ensure fidelity of intervention implementation, research staff will use daily checklists of key 
tasks and protocol violations will be transmitted real-time to the Clinical Data Manager. At least twice 
during the study, in-person monitoring visits to each site will occur to assess protocol compliance and 
conduct source verification.  Centrally, we will use standard data quality control procedures, including 
ongoing review of quality metrics, missing data, and data outliers.  
 
 
STTR Phase II Outcomes (see Table 7). 
Outcome 1:  Mobility evaluated by actigraphy. 
 
Primary outcome – Mobility assessed by actigraphy (Table 7). Upper extremity mobility will be 
evaluated by actigraphy. The Philips Respironics Spectrum Plus® actigraph is a commercially-available 
actigraphy device weighing 16 grams. It contains a battery-powered activity monitor and uses a highly 
sensitive accelerometer to monitor the occurrence and degree of motion. This device was chosen as it 
is widely used in research.1 Moreover, we have published on feasibility of using this device in ICU 
patients.1  We hypothesize that ExersidesTM will allow greater upper extremity mobility, as measured 
by actigraphy.  Movement recorded on the sensors will be compared with the video recordings to 
determine if the movement was purposeful or caused by agitation. 
Outcome 2:  Agitation, delirium, and medication use will be assessed as secondary outcomes. 
 
Agitation:  Agitation will be measured via RASS (Richmond Agitation Sedation Scale) score1 assessed 
by research staff every 60 minutes during the four 4-hour periods (Days 1 and 2) when subjects are 
using novel and traditional restraints, and then every 4 hours during Days 3-6 when subjects are using 
their randomly assigned device. RASS is a validated and reliable ordinal measure of sedation/agitation 
status in the ICU ranging from -5 to +4.1  All study personnel will be trained in measuring RASS score. 
We hypothesize that ExersidesTM will reduce delirium, agitation, and use of sedatives, analgesics 
and antipsychotics. 
 
Delirium:  Delirium will be measured via CAM-ICU (Confusion Assessment Method for the ICU) at its 
maximum appropriate frequency of every 4-hours during Days 1-2, and then every 12 hours during 
Days 3-6.  The CAM-ICU score is a validated and reliable binary measure of delirium status in the ICU.1  
All personnel will be trained in measuring CAM-ICU. Our group has extensive experience with CAM-
ICU.1  
 
Sedative, analgesic, and antipsychotic medication use: Throughout the 6-day study period, use and 
dose of medications will be assessed by chart review.  Medications in these categories include, but are 
not limited to, opiates, benzodiazepines, typical and atypical antipsychotics, propofol, and 
dexmedetomidine.  
Table 7:  Primary & Secondary Outcomes  of Efficacy RCT in Aim 3 
Outcome 
 
Instrument 
Scale 
Assessment Timing 
Primary Outcome 
1 
Upper extremity mobility  
Actigraphy (total activity 
counts per 4 hours) 
Continuous 
Continuously throughout study 
Secondary Outcomes 
 
 
 
2 
Sedative, analgesic, and antipsychotic 
medication dose and use 
Chart review 
Continuous 
Baseline and then daily 
Agitation  
RASS score1 
 
Video recording 
Ordinal 
 
Continuous 
Baseline, every 60 min days 1-2, 
then every 4 hours days 3-6 
All study sessions 
Delirium  
CAM-ICU score1 
Binary 
Baseline, every 4 hours days 1-2, 
then every 12 hours days 3-6 
3 
Satisfaction with novel restraint (nurses, 
family, physicians, and patients when able) 
QUEST 2.0 score16 
Ordinal 
Survey at conclusion of study 
period 
Perceptions of novel restraint (nurses, 
family, physicians, and patients when able) 
Semi-structured 
interviews and response 
to specific satisfaction 
measures in Table 1. 
Qualitative 
Daily for bedside nurses and 
conclusion of study period for 
others 

 
12 
 
Outcome 3:  Satisfaction with and acceptability/perceptions of the device  
Satisfaction and acceptability will be assessed by the Quebec User Evaluation of Satisfaction with Assistive 
Technology (QUEST 2.0) survey and by semi-structured interviews. We hypothesize that ExersidesTM will 
demonstrate high satisfaction, assessed both quantitatively and qualitatively, among ICU clinicians, families 
and patients. 
 
 
Satisfaction: The QUEST 2.0 is a valid, reliable, and widely used 12-question survey assessing 
satisfaction with technological devices.1  It is scored from 1-5, with >3.26 considered high satisfaction.  
The QUEST 2.0 has 2 subscales (satisfaction with device and with services).  Satisfaction with the 
ExersidesTM restraint will be assessed using the device subscale, which has good test-retest stability 
(ICC 0.82).17   
 
 
Acceptability/perceptions: Daily for nurses, and at the conclusion each subject’s study period for 
family members, physicians, and patients, device users will undergo semi-structured interviews (Table 
9) to assess perceived barriers and facilitators of using the novel device.  Responses will be recorded 
digitally and will 
be subject to 
open coding and 
analysis with 
grounded 
theory.18 
Patients and 
health care 
providers will also answer the same satisfaction measures as shown in Table 1. 
 
 
 
Data Collection, Management, and Quality Control for RCT 
 
A REDCap web-based database will be used for research data using unique identifiers for subjects and 
staff.19  Data collection will be protocolized, with staff trained on those protocols, and regularly 
monitored by our Clinical Data Manager (Ms. Howard) and via site monitoring visits (see Aim 3C). 
Moreover, missing or inconsistent data will be detected at data entry. Early, random audits will be 
performed shortly after start of study and every 4 months thereafter, such that a total of ~10% of all 
records will be audited by the employed data coordinator.  Additionally, Steering Committee meetings 
will each occur twice monthly (Aim 3D).  
 
Statistical Considerations for RCT 
 
Sample size:  Sample size was determined for the primary outcome, arm activity, as assessed by 
actigraphy over Days 1 and 2 (defined as total activity counts per 4-hour period: 9am-1pm and 1pm-
5pm).  Although Phase II is 24 months long, there are only 18 months for recruitment, as we need 3 
months for startup and 3 months for close out (Table 10).  Across the 3 study sites, we expect to recruit 
1 patient per site per month during the 18-months, yielding a total N=54.  Experience enrolling ICU 
patients in RCTs at each site.1 suggests that 1 patient/month/site is feasible and mirrors empirical data, 
with our analysis of 33,106 patients from 23 RCTs, demonstrating median (IQR) enrollment of 0.90 
(0.50–1.79) patients/month per site.20   
 
Assuming N=54, we calculated the treatment effect (i.e. the relative change in the median total activity) 
that can be detected with 80% power and 5% Type I error rate. We used the following assumptions 
(these data were informed by our preliminary data with modest adjustments for expected differences for 
the proposed 3-center study):  (1) 9am-1pm median total activity = 3000, (2) 1pm-5pm median total 
activity = 2700, (3) variance of Log(total activity) set conservatively to 2.5 and 6.0 for 9am-1pm and 
1pm-5pm periods, respectively, (4) Log(total activity) has 0.85 correlation within a patient over time, and 
(5) no cross-over effect of the restraints.  Using N=10,000 simulation, the 54-patient sample size can 
Table 8:  Open-ended questions for semi-structured interviews about novel restraint 
1. What did you like about the ExersidesTM restraint? And what do you NOT like about it? 
2. What did you find makes the ExersidesTM restraint is easy to use? 
And what makes it difficult to use?  
3. If you could change the ExersidesTM restraint, what would you change? 
4. Do you think that some patient movements were related to agitation instead of “normal” mobility? 
(Y/N)  If yes, how can you tell the difference? How were those movements different between 
devices? 
5. Any final thoughts or comments about the ExersidesTM restraint and usual restraint devices? 

 
13 
 
detect a 56% relative increase in median total activity comparing the novel vs. traditional restraint 
(median of 3000 vs. 4674).   
 
Statistical Analysis Plan  
a) Summary for all Aims:  All analyses will follow the intention-to-treat (ITT) principle.  A 2-tailed 
p-value <0.05 will be statistically significant.  As described in the Study Design (Section 3K), the within-
patient crossover design removes patient-specific effects from evaluation of the treatment effect.  
Potential pitfalls of this design include order effects, carryover effects, and patient dropout.  To avoid 
order effects, we randomize whether patients start the trial with the novel vs. traditional restraint (Figure 
4).  Carryover effects (i.e. one part of the study affecting subsequent parts) and drop out considerations 
are discussed further below. 
 
During the first 2 Days, the primary endpoint (activity) is measured for each period on each day, such 
that each patient will contribute 4 longitudinal measurements.  This primary endpoint is measured as 
total activity, the sum of the recorded activity counts for the corresponding period/day.  Secondary 
endpoints include agitation (normal vs. sedated/agitated as defined by RASS), delirium (positive vs. 
negative for delirium based on CAM-ICU, among patients who are not comatose [RASS -4, -5]) and 
medication use (quantified by computing the total dose of medications received within each class 
(Outcome 2) using standard equivalency conversions for drugs within each class, as done in our prior 
research.1  Analysis will include summary statistics (mean, median, standard deviation and quantiles) of 
the key co-interventions (see Aim 3I above) and the RCT endpoints (Table 8), separately for each 
period over the 2 days, stratified by treatment group.  
 
To estimate the effect of the novel restraint, a linear model will be fit for the Log(total activity) as a 
function of main terms for treatment (Group A vs. B), time period (1pm-5pm vs. 9am-1pm), and 
treatment order (BA/AB vs. AB/BA).  The natural logarithm is applied to the primary endpoint to reduce 
right skew in the distribution of total activity, with the exponentiated regression coefficient for the main 
term for treatment (A vs. B) in the linear regression model representing the relative difference in median 
total activity comparing the novel vs. traditional restraint, which will quantify the treatment effect. The 
linear model will be fit using weighted least squares to account for the correlation in the primary 
endpoint within a patient over time; the correlation structure will be specified as unstructured and allow 
for the possibility that the variance of the primary endpoint may be different in each period/day.  The 
same linear models will be applied to the continuous secondary endpoints (e.g. medication dose).  For 
the binary secondary endpoints, the effect of the novel vs. traditional restraint will be quantified using a 
longitudinal logistic regression model as a function of the same covariates (treatment, period, and 
treatment order).  The longitudinal logistic regression model will be fit using generalized estimating 
equations allowing for an unstructured within-patient correlation structure.  Activity, agitation, delirium 
and medication use will continue to be measured up to ICU discharge, death or Day 6.  Starting on Day 
3, the endpoints will be expressed as every 4-hour total activity counts, agitation assessment and total 
medication use, as well as every 12-hour delirium.  With the data starting on Day 3, we will explore the 
long-term effects of the restraints by fitting linear and logistic longitudinal regression models that include 
main terms for treatment and time and the interaction of treatment and time. Time will be modeled as a 
restricted cubic spline with degrees of freedom selected by model fit statistics. As secondary outcomes 
are hypothesis-generating, we will not correct for multiple comparisons, but will consider the number of 
comparisons when interpreting results. 
 
Subgroup analysis will be performed in eligible patients with baseline history of Alzheimer’s 
disease and related dementia. To evaluate the potential effect of time-varying patient factors (not 
strictly controlled via a within-patient crossover design – e.g. organ failure status (Table 7)) on the 
primary results, sensitivity analysis of the above regression results will be conducted by including such 
variables into regression models.  To evaluate for any sex-specific effect in this study, sex will be 
included in the regression model as a co-variate and as a statistical interaction term with the 
main term for treatment (A vs. B) to fully address NIH requirements.  
 

 
14 
 
b)  Minimizing missing data: Our primary outcome is assessed during the first 2 study days when 
missing data are uncommon in our prior studies.1   Missing data will be minimized through ongoing 
contact with participants/families and ICU nurses to increase likelihood of obtaining data.  Missing data 
will be described for all variables, and patient characteristics will be compared between those with vs. 
without missing outcomes.1  Based our preliminary data and experience with other studies using similar 
eligibility criteria, we expect <5-10% missing data due to death or other patient loss, and any missing 
will not be associated with treatment allocation; thus, no imputation will be performed and we would 
enroll up to 60 total patients, if needed, to compensate for missing data to obtain the primary outcome 
on N=54 patients. 
 
c)  Data safety monitoring board (DSMB) meetings:  The DSMB (see Data Safety document) will 
meet before the RCT (in STTR Phase II) begins, and after half of the patients have been enrolled into 
the RCT to review safety and recruitment data only.  As this is a small RCT, there will be neither interim 
analyses to evaluate efficacy nor stopping rules for efficacy or futility. 
 
 
 
 
For research involving survey, questionnaires, etc.:  Describe the setting and the mode of administering the instrument and the provisions for 
maintaining privacy and confidentiality.  Include the duration, intervals of administration, and overall length of participation. (describe and attach 
all instruments) 
 
Not applicable 
 
During both the Phase I cohort study and Phase II RCT, we will conduct qualitative assessment of the 
ExersidesTM restraint.  Family members and clinicians (e.g., nurses and physicians) caring for patients enrolled 
into the cohort study (STTR Phase I) or into the RCT (STTR Phase II) will be asked to complete satisfaction 
questionnaires (QUEST questionnaire attached), provide feedback on satisfaction measures (Table 1), and 
participate in a brief semi-structured interview (see questions in Table 8) to assess their satisfaction with, and 
perceptions of, the ExersidesTM restraint. Family members may be the Legally Authorized Representatives 
(LARs) who provide consent for the patient to participate in the RCT, but additional family members beyond the 
LARs also may be asked to participate, and they will be identified via observation of them visiting the 
consented participant while in the ICU. Only family members >18 years of age will be included. Family 
members will undergo verbal consent, and no identifiable information will be obtained from them.  Consent 
from participating medical personnel (nurses, physicians) will be inferred by their willingness to answer our 
questions, complete the survey and provide feedback.  
 
Completion of both the QUEST questionnaire, feedback questions, and the semi-structured interview will occur 
in private space near the medical ICU, and we anticipate this will take approximately 15 minutes.  These will 
only occur once toward the end of the study. 
 
 
 
Risks/Benefits:  Describe any potential or known risks.  This includes physical, psychological, social, legal or other risks.  Estimate the probability 
that given risk may occur, its severity and potential reversibility.  If the study involves a placebo or washout period, the risks related to these must be 
addressed in both the protocol and consent.  Describe the planned procedures for protecting against or minimizing potential risks and assess their 
likely effectiveness.  Where appropriate, discuss plans for ensuring necessary medical or professional intervention in the event of adverse effects to 
the subjects.   Discuss the potential benefits of the research to the subjects and others.  Discuss why the risks to the subjects are reasonable in 
relation to the anticipated benefits to subjects and others.  Discuss the importance of the knowledge gained or to be gained as a result of the 
proposed research and why the risks are reasonable in relation to the knowledge that reasonably may result.  If there are no benefits state so. 
RISKS TO HUMAN SUBJECTS 
Human Subjects Involvement, Characteristics, and Design 
This research includes 4 components where human subjects will be enrolled: 
(A) Testing the revised ExersidesTM restraint device on 3 healthy subjects (STTR Phase I); 
(B) A prospective cohort study in 8 older critically ill patients (STTR Phase I) where feasibility of doing a larger 
RCT will be demonstrated; 
(C) A multi-site randomized controlled trial (RCT in STTR Phase II) in which 54 patients will be enrolled; and 
(D) Feedback from family members and from clinicians (e.g., nurses, and physicians) caring for patients 
enrolled into either the studies in (B) or (C), from above, about their satisfaction with, and perceptions of, the 

 
15 
 
ExersidesTM restraint. 
 
Potential Risks 
There are potential risks for all participants regarding potential breach of confidentiality and invasion of privacy. 
If a critically ill patient regains decisional capacity and is approached about the study for re-consent (after a 
legal next of kin has already provided informed consent for the patient), he or she may experience stress 
and/or discomfort. 
Potential risks from the ExersidesTM restraint device are very low. Our own preliminary data demonstrate safety 
in that no adverse or severe adverse events (i.e. no self-removal of endotracheal tubes, feeding tubes, 
intravenous lines, etc.) – these preliminary data are from a pilot study that has already taken place that 
enrolled critically ill patients in a single intensive care unit. Although self-removal of tubes and lines is a risk, as 
occurs with any existing currently available restraint device, we anticipate that this risk is very low due to the 
design of the ExersidesTM restraint that intentionally was created to further reduce this risk in comparison to 
traditional restraints. Other potential risks include skin breakdown from the ExersidesTM restraint device, and a 
theoretical increased risk of increased removal of upper extremity peripheral IVs, but we did not observe any of 
these events in our pilot study. 
There are few alternative treatments to participating in this RCT. Use of the ExersidesTM restraint device is not 
standard of ICU care at any clinical center. However, this study will not alter clinical care that occurs with 
regard to other aspects of critical illness. Specifically, only patients whose physicians have already written an 
order requiring physical restraints will be considered for the study. The novel ExersidesTM restraint device will 
only be used while such an order is active, as part of routine clinical care (i.e. no patient will receive the 
ExersidesTM restraint device without a need for physical restraint as documented/ordered by the ICU 
clinicians). All study sites currently follow (and will continue to follow throughout the duration of the study) Joint 
Commission requirements for re-assessment and re-ordering restraints at least once every 24 hours. If a 
restraint is no longer required/ordered as part of routine clinical care, then use of the ExersidesTM restraint 
device will immediately stop and not re-start unless a renewal of a restraint order is done, as required by 
clinical circumstances. In no way will the study have any influence over the ordering of restraints as part of 
clinical care in the ICU. 
 
ADEQUACY OF PROTECTION AGAINST RISKS 
Recruitment and Informed Consent 
a) Critically ill older patients recruited into cohort study (STTR Phase I) and multi-site RCT (STTR Phase II) 
All patients who meet inclusion and exclusion criteria will be invited to participate in this study. Using 
observation/review of the electronic medical record and daily hospital rounds, study staff will identify 
consecutive patients admitted to the ICU who meet the basic eligibility criteria. After this initial screen for 
eligibility, study personnel will proceed as per local IRB requirements, including contacting the patient’s ICU 
physicians to confirm appropriateness for the study and obtain permission to approach the patient/legal next of 
kin for discussion of the study and to undertake the informed consent process. If the physicians agree, study 
staff will approach the patient in-person or, if the patient doesn’t have decisional capacity at the time of 
enrollment, a legal next of kin in-person (via in-person meeting). Most patients participating in this study will 
require mechanical ventilation and will therefore be receiving some amount of sedative medications at the time 
of enrollment. Hence, we anticipate that a large proportion of patients will lack the capacity to provide informed 
consent at the time of study eligibility and therefore, we expect that study staff will go through the process of 
informed consent and review the consent materials with the legal next of kin. Consent will be documented, in 
writing, on an IRB-approved consent form. No minors will be considered in the proposed research; therefore, 
parental permission and child assent is not applicable to this application. All conversations with the 
patient/legal next-of-kin regarding the study will be held in a private setting; study staff will allow for patients’ 
desire to have family present and/or to confer with family, and to make participation decisions according to his 
or her own time. Once patients who did not have decisional capacity at the time of initial consent regain that 
capacity, they will be re-consented for ongoing participation in the study. 
b) Family members, nurses and physicians caring for patients enrolled into the STTR Phase I or Phase II 
studies. All family members of patients participating in the cohort study (STTR Phase I) or the RCT (STTR 
Phase II) will be invited to provide information about their satisfaction with, and assessment/perceptions of, the 

 
16 
 
ExersidesTM restraint. Only family members >18 years of age will be included, and they will be identified by 
visiting their loved one in the ICU. After being approached by research personnel, they will undergo informed 
consent, but importantly no personal identifiable information will be obtained from them as we will only ask for 
satisfaction scores and qualitative feedback about the device. Nurses and physicians caring for the patients in 
the RCT also will be asked to complete the satisfaction questionnaire and semi-structured interview. Their 
enrollment and consent will be in accordance with institutional IRB policy. 
 
Protections against Risk 
All subjects will be informed of the research nature of the activity, including the completion of any measures 
and questionnaires, the estimated time required to complete the activities, and that participation is voluntary, 
without any compromise on the current medical care if they decline participation. All study personnel will be 
trained in the protection of human subjects and HIPAA. To protect against disclosure, all subjects will be 
assigned a unique study identification number. It is this number that will accompany study materials and data. 
The information that would allow for a link between this study ID number and the direct identifiers will be kept 
securely and separately from the datasets. All participant-identifying information will be removed from the 
dataset before analysis. Identifying information and de-identified paper study records will be kept in locked file 
cabinets and password protected computers that reside within locked offices with security personnel and other 
physical safeguards. All study databases will be maintained on password protected computers and routinely 
backed up to password protected servers. Identifying information will be deleted at the earliest possible date. 
We will keep all patient information confidential in accordance with Public Health Services Act (42 USC 299a- 
1(c)). As previously described, fetuses, neonates, minors, and prisoners are not part of this study. Pregnant 
women will also not be included as only people >60 years old will be eligible Research study staff will take 
several steps to address the risks listed above. During screening for eligible critically ill patients, attending 
physicians will have the opportunity to exclude a patient who, in the physician’s judgment, would not be an 
appropriate participant. Reasons for exclusion include (but are not limited to): legal or risk management 
concerns; psychological illness or morbidity; and cognitive limitations. A patient's decisional capacity will be 
determined by his or her treating physician using accepted standards for determining decisional capacity and 
will be confirmed, in a similar manner, by the research staff, as part of the informed consent process. For all 
participants, it will be emphasized that participation is voluntary, that all steps involved with participation are 
voluntary, and that they are allowed to decline to complete any activity or to answer any question they are 
asked. For all participants, it will be emphasized that they may withdraw from the study or any study 
procedures at any time without any loss of rights or benefits to which they are otherwise entitled and without 
losing status or standing within the institution. Healthy volunteers will receive $50 plus the cost of parking as 
compensation for their time (which is estimated as up to 3 hours). Critically ill patients and their family member 
will not receive compensation or tokens of appreciation provided for participation to minimize potential coercion 
or the appearance of coercion. 
As mentioned above, risks of the ExersidesTM restraint are very low. Nevertheless, we have taken the 
following steps and safeguards in the study protocol to minimize such risks and protect against them: 
1. Data will be kept secure and confidential 
2. Treating physicians will be allowed to exclude patients from the study 
Additionally, we will submit a plan for monitoring of adverse events to the study’s Data and Safety Monitoring 
Board (DSMB). Serious adverse events that might bear any relationship to the intervention will be reported to 
the local IRB as well as the University of Vermont Human Subjects Committee (parent site) and the DSMB, 
which may elect to restrict or cease enrollment. See Data and Safety Monitoring Plan. Furthermore, a 
medical/site monitoring plan is in place whereby a Study Monitor will visit each site at least twice during the 
study to assess protocol compliance and conduct source verification. During the site visit, case report forms will 
be reviewed for quality control. 
Finally, data presentations will include only group data and will be presented in a way that ensures individual 
participants cannot be identified. If respondents may be identified by a specific subgroup analysis due to the 
low numbers of these types of respondents (e.g., patients aged >90), these subgroup data will not be 
presented in isolation in any format.  There is a small risk of breach of confidentiality with the addition of video 
recording of subjects while in the novel and wrist restraints.  We will take steps to minimize this risk by angling 
the camera to reduce capture of medical personnel and family members who are also in the room.  A sign will 

 
17 
 
be posted on the door to alert anyone entering the room that a camera is in use.  The recordings will be 
removed from the video camera / storage card as soon as possible, and downloaded to a secure server.  We 
will encrypt the recordings for storage during the study, and require two-factor authentication for access.  The 
footage will be reviewed by authorized study staff in a timely manner and the extracted data will be identified 
only by the subject’s Study ID.  After the data is extracted, the video recordings will be destroyed. 
 
We recognize that in the current crossover design where subjects wear the device bilaterally for a 4-hour 
period on 2 consecutive days, we may encounter problems with a slow “wash out” period for sedative 
medications given before the start of a 4-hour period and thus reducing mobility during the observation period. 
This issue will be minimized because all study sites use short-acting, as-needed, bolus dosing of medications 
(Preliminary Data 6) and subjects will wear both devices in opposite order on Days 1 and 2. 
 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO HUMAN SUBJECTS AND OTHERS 
a) Healthy volunteers to test revised ExersidesTM restraint 
There will be no benefit to healthy volunteers participating in this research. However, they will contribute to new 
knowledge from which future ICU patients may benefit if our intervention is found to improve outcomes. 
b) Critically ill older patients recruited into cohort study (STTR Phase I) and multi-site RCT (STTR Phase II) 
There may be some benefit to the critically ill participants enrolled in this research, as literature suggests that 
patients who participate in clinical trials overall have improved outcomes compared to patients who do not 
participate.2,3 Individual subjects enrolled in this trial may also receive direct benefit if the intervention is found 
to improve patient outcomes such as mobility, agitation, delirium, and use of sedative medications. Currently 
there are few therapies known to improve outcomes of ICU patients.  
The objective of this proposal is to perform a multi-site RCT of a novel restraint device in older ICU patients. If 
this intervention is ultimately shown to be beneficial in future trials, it will substantially expand the 
armamentarium of the critical care clinician. Given the potential benefit that may result from this therapy in 
treating a population of elderly patients with high mortality and morbidity rate, the limited risks are reasonable. 
c) Family members, nurses and physicians caring for patients enrolled into STTR Phase I or STTR Phase II 
studies 
The patient surrogate involved in the consent process may benefit from interaction with the research team who 
can provide explanations and answer questions regarding the patient’s critical illness and issues related to 
restraint, as well as the patient’s functional status during and after hospitalization.  
When providing satisfaction and acceptability information, family members, nurses, and physicians will not 
have any direct benefit from participating in this research. However, future ICU patients may benefit if our 
intervention is found to improve outcomes. 
Contact PD/PI: Stapleton, Renee D 
Protection of Human Subjects Pg.138 
 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
Because critical illness is common and is a major cause of mortality as well as morbidity among survivors, 
developing and testing novel therapies is paramount. In this study, we propose to perform a multi-site RCT of a 
novel restraint device in older ICU patients to improve mobility, agitation, sedation, delirium, and sedative 
medication use. The information gained from this investigation may represent a major leap forward in therapy 
for older critically ill patients; thus the minimal risks to subjects are reasonable. Even if the intervention is not 
beneficial, this study is designed to provide important information that will guide future interventions. 
 
PROTECTION OF HUMAN SUBJECTS REFERENCES 
1. Truong AD, Kho ME, Brower RG, Feldman DR, Colantuoni E, Needham DM. Effects of neuromuscular 
electrical stimulation on cytokines in peripheral blood for healthy participants: a prospective, single-blinded 
Study. Clin Physiol Funct Imaging 2017;37:255-262. 
2. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? 
Evidence for a “trial effect.” J Clin Epidemiol 2001;54:217-224. 
3. Peppercorn JM, Weeks JC, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within 
and outside clinical trials: conceptual framework and structured review. Lancet 2004;363:263–270. 

 
18 
 
Therapeutic Alternatives:  List the therapeutic alternatives that are reasonably available that may be of benefit to the potential subject and include 
in the consent form as well. 
 
Not Applicable 
There are few alternative treatments to participating in this RCT.  The standard of care at all participating 
centers is a traditional soft wrist restraint. Use of the ExersidesTM restraint device is not standard of ICU care at 
any clinical center. However, this study will not alter clinical care that occurs with regard to other aspects of 
critical illness. Specifically, only patients whose physicians have already written an order requiring physical 
restraints will be considered for the study.  
Data Safety and Monitoring:  The specific design of a Data and Safety Monitoring Plan (DSMP) for a protocol may vary extensively depending on 
the potential risks, size, and complexity of the research study.  For a minimal risk study, a DSMP could be as simple as a description of the Principal 
Investigator’s plan for monitoring the data and performance of safety reviews or it could be as complex as the initiation of an external, independent 
Data Safety and Monitoring Board (DSMB). The UVM/UVM Medical Center process for review of adverse events should be included in the DSMP.   
 
DATA SAFETY MONITORING PLAN 
The  STTR Phase I Cohort Study will be monitored locally by the Principle Investigator who will assess 
participant safety, efficacy of the study intervention, benefit/risk, recruitment of participants, adequacy of 
measured and collected data, and adherence to the protocol.  At the conclusion of the Phase I cohort study, 
we will convene a Data and Safety Monitoring Board (DSMB) that will oversee the RCT in STTR Phase II. 
Below, we outline the responsibilities, membership, and organization of the DSMB: 
 
1. Responsibility: As per NIH policy, the responsibility of the DSMB will be to advise and make 
recommendations regarding participant safety; efficacy of the study intervention; benefit/risk ratio of 
procedures and participant burden; selection, retention, and recruitment of participants; adherence to protocol 
requirements; data and statistical analysis plan; adequacy of measured and collected data; and possible 
amendments to the study protocol and consent forms. As this proposal includes a small clinical trial, the main 
charge of the DSMB will to focus on safety, and there will be no stopping rules for efficacy or futility. 
 
2. Membership: We will convene 4 independent voting members (3 members will constitute a quorum) who are 
not study investigators, and have no financial, scientific, or other conflict of interest with the trial. All members 
will provide written documentation of competing interests. We will include expertise in the following fields: 2 
members from key subject areas involved in the research (clinical experts in critical care medicine, mobility 
and/or delirium/cognitive impairment), 1 from biostatistics, and 1 from clinical investigation/ trials. The group will 
designate a chair and an executive secretary from the group membership; the chair will be responsible for 
overseeing meetings, developing agendas, generating reports, and being the contact person for the DSMB. 
Because committee members will likely be located at various sites, the committee meetings may be conducted 
by teleconference. 
 
3. Organization: The group will meet during the course of the trial as follows 
a. Meeting coordination: All meetings will occur in 3 parts: 
i.  An open meeting with principal investigators, project coordinators, and statistician to review 
accrual 
and outcomes as per below. 
ii.  A partially closed meeting with the DSMB and study statistician only to review the study 
outcomes 
per below. 
iii.  A closed session for DSMB members only to discuss oversight issues, emerging results, 
comments, and recommendations, which will be discussed until consensus among members. The 
chair would reserve the right to break a tie, if needed. 
  
b. RCT in STTR Phase II 
i. Initial meeting for RCT 
1. Protocol, consent, and data quality review: The DSMB will meet again before start of 
the RCT in Phase II. They will review data from Phase I. They will also review the entire 
IRB-approved RCT protocol with regard to participant safety, recruitment, randomization, 
intervention, data management, quality control, and statistical analysis. Additionally, they 

 
19 
 
will review the informed consent documents for applicability and readability, and 
standard operating procedures for data management and control. 
2. Safety review: The DSMB will review information for recruitment, subject retention, 
protocol adherence, intervention effects, gender and minority inclusion, and participant 
safety. The DSMB will review, discuss, and approve the plan for identifying, assessing, 
and transmitting serious adverse event (SAE) and adverse (AE) information to the 
DSMB. 
3. The DSMB will also approve the DSMB Charter and review any conflicts of interest 
that have  bene disclosed. 
4. Recommendations: Voting in closed session, the DSMB can recommend that the trial 
continue with no modifications, continue with modifications, or stop for safety concerns. 
The chair or designate will summarize major points of discussion, decisions, actions, and 
reasons, and additional information needed for future meetings. The report will be 
provided to study’s Principal Investigators for submission to the study sites’ IRBs. 
ii. Interim meetings: 
Meetings will occur after 1/2 (n=27) of the total participant sample (n=54) have completed all 
study procedures. Ad hoc meetings can be requested by the PI or DSMB if an unanticipated 
safety signal is identified. The DSMB will evaluate all of the items outlined above in the safety 
review (3b(ii)). Recommendations from the DSMB will also be summarized as outlined above 
(3b(iii)).  During this interim meeting, the DSMB will review data for recruitment, randomization, 
subject retention, protocol adherence, intervention effects, gender and minority inclusion, and 
participant safety. The DSMB will receive cumulative data, including safety events that are 
reported to the IRB (as described below) and major clinical outcome variables prepared by the 
trial biostatistician. They may perform its own statistical analysis of these data and can request 
additional data if necessary. All data will initially be provided to the DSMB without indication of 
treatment group allocation. 
 
Safety monitoring also will occur via the PIs and co-Is being involved in the conduct of the clinical trials 
including supervising the screening for patient eligibility. The PIs will have knowledge of any adverse events 
that may arise and will report them according to IRB and NIH/NIA guidelines and to the description provided 
below. All potential participants will be provided contact information for the IRB of record (University of 
Vermont, Johns Hopkins University, University of California) to register complaints or other problems. The 
DSMB will modify or stop the study if any such complaints represent a legitimate concern about the study 
procedures or methods. The design of the proposed studies and the proposed ExersidesTM restraint 
intervention are not complex and have very low potential risk to the patient. Our preliminary data demonstrate 
that the ExersidesTM restraint is safe, as we experienced no adverse events in the pilot study already 
completed with the prototype device. The physical restraint device proposed for this trial is a Class I medical 
device under US Food & Drug Administration regulation 21 C.F.R. § 880.6760 subject to general controls and 
is exempt from Federal Drug Administration (FDA) approval. The relatively low risks will be further minimized 
as described in the above Human Subjects section entitled “Protection Against Risks.”  
Confidentiality of participants’ data will be protected by having all identifying participant-information removed 
from databases before analysis. Electronic data storage will be password protected with daily back-up and 
storage. Only research associates who directly interact with research subjects will have access to participant 
identifying information. All filing cabinets and storage facilities that contain sensitive patient information will be 
locked when not used. All computers and storage cabinets will be located within secure office locations. 
 
 
Adverse Event and Unanticipated Problem (UAP) Reporting:  Describe how events and UAPs will be evaluated and reported to the 
IRB.  All protocols should specify that, in the absence of more stringent reporting requirements, the guidelines established in the 
Committees on Human Research “Adverse Event and Unanticipated Problems Reporting Policy” will be followed.  The UVM/UVM 
Medical Center process for review of adverse events and UAPs to subjects or others should be included in the DSMP.   
 
1. Events of Interest 
The novel restraint device being tested in the FREEDOM Trial is considered so low-risk that it is exempt 

 
20 
 
from FDA IDE regulations.  Nevertheless, participants will be monitored for medical events of interest 
including skin laceration, upper extremity joint pain, and equipment damage that may not be serious but 
may be related to the novel restraint intervention.  These data will be collected daily while the subject is on 
study (through day 3 for the pilot study and day 7 for the RCT).  These data will be recorded in the 
electronic database. 
 
 
2. Adverse Event (AE) Reporting 
Given the high acuity of diseases and morbidity related to critical illness in the patient population under 
study (over age 60 years old receiving invasive or non-invasive mechanical ventilation and requiring 
restraint), it is difficult to identify an adverse event (AE) within the constellation of symptoms related to the 
normal evolution of critical illness.  Therefore, expected AEs (e.g. abnormal laboratory values, aberrant 
physiology such as fever or tachycardia or hypotension, etc.) consistent with the underlying 
pathophysiology or progression of underlying illness will neither be collected nor reported.   Only AEs that 
are both unexpected and felt to be related (to any degree) to the novel restraint device will be collected and 
reported, the majority of which will be considered “events of interest” as above.  The investigator will use 
his/her judgment to determine whether an AE is considered to be definitely related, probably related, 
possibly related, unlikely related, or not related (see table below in 5.a.).  These unexpected and related (to 
any degree) AEs will be documented in the participant medical record and/or study file.  It is the 
responsibility of the investigator to review all documentation (e.g. hospital progress notes, laboratory 
results, diagnostic reports, etc.) regarding each event.  This reporting process is outlined below. 
 
 
3. Serious Adverse Event (SAE) Reporting 
Similar to AEs, given the high acuity of diseases and morbidity related to critical illness in the patient 
population under study (over age 65 years old receiving invasive or non-invasive mechanical ventilation 
and requiring restraint), it is difficult to identify an SAE within the constellation of symptoms related to the 
normal evolution of critical illness.  Only ‘unexpected’ SAEs (inconsistent with underlying pathophysiology 
or progression of underlying disease) will be collected and reported.  Expected SAEs will not be reported 
(see description below).  The investigator will use his/her judgment in determining whether an event is 
considered to be reportable per guidelines.  SAEs will be documented in the participant medical record 
and/or study file.  It is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory results, diagnostic reports, etc.) regarding each event.  This reporting process is 
outlined below. 
 
3.A.  DEFINITION OF SERIOUS ADVERSE EVENTS (SAES) 
An event will be considered an SAE if it meets any one or more of the following criteria:   
A. Results in death 
B. Is life-threatening - an event where a participant is at risk of death at the time of the event. It 
does not refer to an event that hypothetically might have caused death if it was more severe. 
C. Prolongation of hospitalization - any substantial extension of an inpatient hospitalization beyond 
the stay anticipated/required in relation to participant’s condition prior to the SAE, as 
determined by the investigator or treating physician. 
D. Results in Disability or Incapacity - is defined as a substantial disruption of a person's ability to 
conduct normal life functions. 
E. Led to fetal distress, fetal death or a congenital abnormality or birth defect 
F. Important medical event - are those that may not be immediately life-threatening, but may 
jeopardize the participant and may require intervention to prevent one of the other serious 
outcomes listed above. 
 
3.B.  EXPECTED SAES 
As the patient population under study are hospitalized and critically ill at baseline, care must be taken to 
determine if an event is outside of what would be expected given the degree and nature of the critical 

 
21 
 
illness prior to the serious adverse event.  In the population under study, some examples of potential 
expected SAEs include:  
 
Abnormalities in oxygenation and/or ventilation expected for the degree of injuries sustained. 
 
Fluctuations in hemodynamic measures expected for the degree of injuries sustained. 
 
Agitation and/or pain responses expected for the degree of injuries sustained. 
 
Complications directly related to sustained injuries. 
 
Use of medications, blood products, support devices and other therapies expected for the degree 
of injuries sustained.  
 
3.c.  Expected Deaths 
Importantly, as approximately 15-25% of participants will die from their critical illness, we anticipate that 
deaths in this study will be expected and occur as a result of the patients’ underlying illness, with 
associated mortality data recorded in the CRF.  Please note that reporting an expected death as an SAE 
via the electronic database report form is not required.  However, it is left to each individual site to 
determine whether it meets local requirements for reporting to the IRB.  Unexpected deaths should be 
reported as described below. 
 
3.D.  UNEXPECTED SAES 
All unexpected SAEs must be reported to the PIs and Project Manager using the appropriate form as 
outlined below.  
 
3.e.  Definition of Unexpected SAE 
Any SAE occurring in a subject participating in this Trial where the nature, severity, or frequency of the 
event is not consistent with the expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event (e.g. sudden death from MI in a person with ARDS and sepsis without 
known heart disease). 
 
4. Reporting Period 
Participants should be monitored for related AEs (to any degree) and unexpected SAEs from the time of 
randomization until the day after the on-study period is complete (study day 7 for multi-site RCT as 
participants will be on study for maximum of 6 days, or 24 hours after removal of restraint device under 
study, whichever is earlier).   
 
 
5. Reporting Timelines 
Related AEs (to any degree – definitely, probably, possibly, or unlikely) and unexpected SAEs should be 
reported to the PIs and Project Manager (Dr Stapleton, Dr. Needham, and Ms. Ardren) within 24h of 
knowledge of the occurrence of the event.  The site is expected to notify the PIs or Project Manager by 
phone or email and complete the Related AE and Unexpected SAE report form to submit the initial report, 
as well as any follow-up reports. 
 
5.a.  Initial Report 
If the investigator does not have all information regarding an unexpected SAE, he/she will not wait to 
receive additional information before notifying the PIs and Project Manager of the event and completing 
the appropriate report.   
 
Initial reports, at a minimum, should include the following information: 
 
Date (if available, time) of event onset 
 
Individual reporting the event (i.e. investigator, sub-investigator) 
 
Assessment of causality (i.e. relationship of event to participation in the study)  
 
As much information regarding the event as possible (i.e. if the event is still ongoing and the 
participant is still undergoing investigations and/or treatments, any preliminary information) 

 
22 
 
 
Assessment of Causality 
The investigator is responsible for assessing the relationship of all unexpected SAEs to study 
participation.  The following categories should be used to make the causality determination.   
Definitely related 
Suggests that a temporal sequence of this SAE is associated with 
study participation, and there is no doubt that the event is 
associated with participation in this study. 
Probably related 
Suggests that a reasonable temporal sequence of this SAE with 
study participation exists and the association of the event with 
participation in the study seems likely. 
Possibly related 
Suggests that the association of this SAE with study participation is 
unknown and the event is not reasonably supported by other 
conditions. 
Unlikely related 
A serious adverse event that is more likely due to other causes 
than study participation. 
Not related 
A serious adverse event that is clearly due to extraneous causes 
(disease, environment, etc.) and does not meet the criteria for a 
study participation relationship listed under possibly, probably, or 
definitely related. 
 
There may be instances when an event has occurred and the investigator has minimal information at 
hand to include in the initial SAE report to the central study team.  In these cases, it is important that the 
investigator make an assessment using their best judgement or opinion at the time of the initial report.  
The investigator would then reassess when the necessary information becomes available and may opt 
to update their causality assessment. 
 
5.b.  Follow-up 
After the initial report, the investigator is required to monitor and treat the participant until the event is 
resolved, stabilizes, or otherwise explained.  New or updated information will be recorded until the event 
information is considered complete. 
 
5.c.  Expedited Reporting 
Safety events that fulfill the following criteria require specific expedited reporting timelines to the DSMB 
And NIA:  Unexpected SAE and definitely related, probably related, possibly related, or unlikely related 
to study participation. 
 
Once the site submits the event report to the PIs and Project Manager, the SC will review the report and 
determine whether it meets the criteria for expedited reporting.  If the unexpected SAE is considered 
definitely related, probably related, possibly related, or unlikely related to study participation, the study 
leadership will generate an expedited event report that will be submitted to the DSMB and the NIA within 
3 working days of receiving the site’s report. 
 
5.c.  General Event Reporting to the Safety Officer and the DSMB 
Any safety event that is an unexpected SAE and related (to any degree) to study participation will be 
reported to the DSMB and to the Safety Officer in expedited fashion, as described above in 5.c. 
 
 
 
Withdrawal Procedures:  Define the precise criteria for withdrawing subjects from the study.   Include a description of study requirements for when 
a subject withdraws him or herself from the study (if applicable). 
Once patients who did not have decisional capacity at the time of initial consent regain that capacity, they will 
be re-consented for ongoing participation in the study. A patient's decisional capacity will be determined by his 
or her treating physician using accepted standards for determining decisional capacity and will be confirmed, in 

 
23 
 
a similar manner, by the research staff, as part of the informed consent process. For all participants, it will be 
emphasized that participation is voluntary, that all steps involved with participation are voluntary, and that they 
are allowed to decline to complete any activity or to answer any question they are asked. For all participants, it 
will be emphasized that they may withdraw from the study or any study procedures at any time without any loss 
of rights or benefits to which they are otherwise entitled and without losing status or standing within the 
institution. 
Sources of Materials:  Identify sources of research material obtained from individually identifiable human subjects in the form of specimens, records 
or data.  Indicate whether the material or data will be obtained specifically for research purposes or whether use will be made of existing specimens, 
records or data. 
Sources of Materials 
Via electronic and physical safeguards, all data will be secure in accordance with the Office of Management 
and Budget, and accessible only to those directly involved with this project. Throughout the study, research 
staff will have access to individually identifiable information available in the medical record. Patient identifying 
information only will be known to the research team members who are required to directly interact with the 
participant. All research staff who are not directly involved with patient evaluation (e.g. Data Manager and 
Analyst) will not have access to the linkage between the unique ID number and participant-identifying 
information. 
a) Critically ill older patients recruited into cohort study in STTR Phase I and multi-site RCT in STTR 
Phase II : Screening data to identify eligible critically ill older patients will be viewed from the medical 
record. Data collected for these studies will come from patient or proxy interviews, chart review, clinical 
assessment and physical examination (using validated and reliable measurement instruments). At 
enrollment and during their ICU stay, research personnel will collect data, such as comorbid conditions, 
demographic information, physical functioning, severity of illness, and organ failure data. Research staff 
will also assess agitation/sedation, delirium, sedative medications received as part of clinical care, with 
these assessments done in person via direct observation/interaction or by medical record review. 
Additionally, we will also collect information from satisfaction questionnaires and semi-structured 
interviews, which will be done in person. 
b) Family members, nurses and physicians caring for patients enrolled into Phase I or Phase II studies 
: Information collected from satisfaction questionnaires and semi-structured interviews will be done in 
person. 
 
 
DRUG AND DEVICE INFORMATION  
 
 
Investigators are encouraged to consult the UVM Medical Center Investigational Pharmacy Drug Service (847-4863) prior to finalizing study 
drug/substance procedures. 
 
Drug (s) 
X 
Not applicable 
Drug name – generic followed by brand name and common abbreviations. Availability – Source and pharmacology; vial or product sizes and 
supplier.  If a placebo will be used, identify its contents and source. (attach investigational drug brochure) 
 
Preparation:  Reconstitution instructions; preparation of a sterile product, compounded dosage form; mixing guidelines, including fluid and volume 
required.  Identify who will prepare. 
 
Storage and stability – for both intact and mixed products.   
 
Administration – Describe acceptable routes and methods of administration and any associated risks of administration. 
 
Toxicity – Accurate but concise listings of major toxicities.  Rare toxicities, which may be severe, should be included by indicated incidence.  Also 
adverse interactions with other drugs used in the protocol regimen as well as specific foods should be noted.  Address significant drug or drug/food 
interactions in the consent form as well.  List all with above details. 
 
Is it FDA approved: (include FDA IND Number) 
1.  in the dosage form specified?  If no, provide justification for proposed use and source of the study drug in that form. 
 
2.  for the route of administration specified?  If no, provide justification for route and describe the method to accomplish. 
 

 
24 
 
3.  for the intended action? 
 
 
Device (s) 
 
Not applicable 
Device name and indications (attach investigational device brochure) 
ExersidesTM Restraint 
Is it FDA approved: (include FDA IDE Number) 
1.  for indication specified? If no, provide justification for proposed use and source of the device. 
The device is 510k exempt and IDE exempt. 
Risk assessment (non-significant/significant risk) - PI or sponsor needs to assess risk of a device based upon the use of the device with human 
subjects in a research environment.   
Risk assessment is deemed to be non-significant and potential risks from the ExersidesTM restraint device are 
considered to be very low. Our own preliminary data demonstrate safety in that no adverse or severe adverse 
events (i.e. no self-removal of endotracheal tubes, feeding tubes, intravenous lines, etc.) – these preliminary 
data are from a pilot study that has already taken place that enrolled critically ill patients in a single intensive 
care unit. Although self-removal of tubes and lines is a risk, as occurs with any existing currently available 
restraint device, we anticipate that this risk is very low due to the design of the ExersidesTM restraint that 
intentionally was created to further reduce this risk in comparison to traditional restraints. Other potential risks 
include skin breakdown from the ExersidesTM restraint device, and a theoretical increased risk of increased 
removal of upper extremity peripheral IVs, but we did not observe any of these events in our pilot study. 
 
 
 
SUBJECT CHARACTERISTICS, IDENTIFICATION AND RECRUITMENT  
 
Subject Selection:  Provide rationale for subject selection in terms of the scientific objectives and proposed study design. 
Critically ill older patients recruited into cohort study in STTR Phase I  and multisite 
RCT in STTR Phase II  Eligible patients will be those who are 60 years of age or older, requiring invasive or 
non-invasive mechanical ventilation with actual or expected duration of mechanical ventilation >48 hours, 
cared for in an ICU with an expected ICU length of stay of >3 days after enrollment, and who are not deeply 
sedated (i.e. have a Richmond Agitation Sedation Scale (RASS) score > -2). No individuals 65 years and older 
will be excluded from the proposed study based on sex, race, or ethnicity. We anticipate that enrolled patients 
will have a wide range of health status, including potentially ranging from no prior comorbid disease and high 
prior health status to patients with many comorbidities and low prior health status. 
Patients will be excluded if they meet any of the following criteria: 
1. Upper extremity impairments that prevent use of novel restraint device (e.g. amputation, arm injury) 
2. Severe skin breakdown preventing securing of ExersidesTM restraint 
3. Limited mobility of either upper extremity prior to admission (e.g. frozen shoulder, severe arthritis) 
4. Pre-existing primary systemic neuromuscular disease (e.g. Guillain Barre) 
5. Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion criteria met) 
6. Pre-existing severe cognitive impairment or language barrier prohibiting outcome assessment 
7. Expected death or withdrawal of life-sustaining treatments within 6 days from enrollment 
8. Treating clinicians disagree with participation 
9. Incarcerated 
 
Subject selection aligns with the project’s goal of studying intubated senior patients requiring restraint. 
 
Vulnerable Populations:  Explain the rationale for involvement of special classes of subjects, if any.  Discuss what procedures or practices will be 
used in the protocol to minimize their susceptibility to undue influences and unnecessary risk (physical, psychological, etc.).  
X 
Not applicable 
 
 
 
Number of Subjects:  What is the anticipated number of subjects to be enrolled at UVM/UVM Medical Center and in the case of a multi-center study, 
with UVM/UVM Medical Center as the lead, the total number of subjects for the entire study. 
Phase I study: 8;       Phase II study: 54 
 

 
25 
 
Inclusion/Exclusion Criteria:  Eligibility and ineligibility criteria should be specific. Describe how eligibility will be determined and by whom.  
Changes to the eligibility criteria at a later phase of the research have the potential to invalidate the research. 
Table 5: Inclusion and Exclusion Criteria for Study Entry into STTR Phase I and Phase II Studies 
Inclusion Criteria 
                            Exclusion Criteria                               
Rationale for Exclusion 
1. >65 years old 
2. Physician order for use of 
bilateral wrist restraints 
3. Requiring invasive or non-invasive 
mechanical ventilation with actual 
or expected total duration of >48 
hours 
4. Expected ICU stay >3 days after 
enrollment (to permit adequate 
exposure to proposed intervention) 
5. Not deeply sedated (Richmond 
Agitation Sedation Scale [RASS] 
score > -2)186 
1. Upper extremity impairments that prevent use of novel 
restraint device (e.g. amputation, arm injury) 
Unable to receive proposed intervention 
2. Limited mobility of either upper extremity prior to 
admission (e.g. frozen shoulder, severe arthritis) 
Inaccurate data for primary outcome 
assessment during RCT (i.e. actigraphy) 
3. Pre-existing primary systemic neuromuscular disease 
(e.g. Guillain Barre) 
4. Neuromuscular blocker infusion (eligible once infusion 
discontinued if other inclusion criteria met) 
5. Pre-existing severe cognitive impairment or 
language barrier prohibiting outcome assessment 
Unable to perform outcome assessments 
6. Expected death or withdrawal of life-sustaining treatments 
within 6 days from enrollment 
Patients unlikely to complete proposed 
outcome assessment protocol 
7. Incarcerated 
Vulnerable population; ethical issues 
8. Severe skin breakdown on either upper extremity       
Unable to receive proposed intervention   
Using the electronic medical record and daily ICU rounds, study staff will identify consecutive patients admitted 
to the ICU who meet eligibility criteria. After this initial screen for eligibility, study personnel will contact the 
patient’s ICU physician to confirm appropriateness for the study.  The PI will confirm that a patient is eligible for 
the study prior to enrollment and this will be documented on a case report form.  
Inclusion of Minorities and Women:  Describe efforts to include minorities and women.  If either minorities or women are excluded, include a 
justification for the exclusion.  
INCLUSION OF WOMEN AND MINORITIES 
Targeted/planned distribution and rationale: 
Persons of either sex and of all race and ethnicity categories, who meet the eligibility criteria, will be eligible to 
enroll in the clinical study. The eligibility criteria do not exclude any specific sex, race or ethnic category. More 
specifically, no individual will be excluded from this study based on sex or race/ethnicity. Based on past similar 
studies at all study sites, we estimate the proportion of women among patients in the proposed study will be 
approximately 40-50% and reflects the population of critically ill patients. We anticipate that minority 
representation of the patient sample will reflect the demographics in the regions where each of the 3 study 
sites is located (Vermont/Upstate New York; Baltimore, Maryland; and Los Angeles, California) (see Table 1). 
 
Please see our Planned Enrollment Table for details. Overall, we estimate that approximately 35% of the 
study population will be comprised of racial or ethnic minorities. Based on existing data, we do not expect 
differences in our outcomes due to minority status but we are collecting sex/gender and race/ethnicity data and 
will include them as covariates in our multivariate analyses if needed. 
 
Table1: Race/ethnicity in Vermont, Washington, and South Carolina (%)* 
Race/Ethnicity 
Vermont 
Baltimore, 
MD 
Los Angeles, 
CA 
Total for Critically Ill Patients 
Enrolled in this Research 
White/Caucasian 
94.9 
29.6 
71.0 
65.2 
Black/African-American 
1.3 
63.7 
9.1 
24.7 
Native American/Alaskan Native 
0.4 
0.4 
1.5 
0.8 
Asian 
1.8 
2.3 
15.1 
6.4 
Native Hawaiian/Pacific Islander 
<0.1 
<0.1 
0.4 
0.1 
Two or more races 
1.9 
2.1 
3.0 
2.3 
Hispanic (separate data category) 
1.9 
4.2 
48.5 
18.2 
* https://www.census.gov/quickfacts/fact/table/US/PST045216 
Inclusion of Children: Describe efforts to include children.  Inclusion is required unless a clear and compelling rationale shows that inclusion is 
inappropriate with respect to the health of the subjects or that inclusion is inappropriate for the purpose of the study.  If children are included, the 
description of the plan should include a rationale for selecting or excluding a specific age range of children.  When included, the plan must also 
describe the expertise of the investigative team in working with children, the appropriateness of the available facilities to accommodate children, and 
the inclusion of a sufficient number of children to contribute to a meaningful analysis relative to the purpose of the study.  If children are excluded 
then provide appropriate justification. Provide target accrual for this population. 
INCLUSION OF CHILDREN 

 
26 
 
The Program Announcement (PAS-17-065) to which this proposal is responding to is to “conduct research 
leading to the development of innovative products and/or services that may advance progress in preventing 
and treating Alzheimer's disease (AD) and Alzheimer's-disease-related dementias (ADRD).” Hence, we are 
specifically including only patients ≥65 years old in the proposed study, as previously discussed with a program 
officer at the National Institute on Aging. This population (i.e. adult >65 years old) is suitable to the topic of this 
study since the prevalence of restraint use and the risk of ICU-associated delirium and long-term cognitive 
impairment are much higher in older than in younger patients (see Significance section within the proposal). 
Study subjects will therefore not include children, as defined by NIH, since the target area of investigation 
involves older critically ill adults. Children have unique age-related mobility and cognitive development issues 
that would need separate study from the proposed research. Moreover, the developing brain of children makes 
them markedly different from the target patient population needed for investigating ADRD issues for this 
Program Announcement and the Aims of the proposed study. 
For protocols including the use of an investigational drug, indicate whether women of childbearing potential have been included and, if not, include 
appropriate justification. 
N/A 
If HIV testing is included specifically for research purposes explain how the test results will be protected against unauthorized disclosure.  Include if 
the subjects are to be informed of the test results.  If yes, include the process and provision for counseling.  If no, a rationale for not informing the 
subjects should be included.   
X 
Not applicable 
 
 
Recruitment:  Describe plans for identifying and recruitment of subjects.  All recruitment materials (flyers, ads, letters, etc) need to be IRB approved 
prior to use.   
Using the electronic medical record and daily ICU rounds, study staff will identify consecutive patients admitted 
to the ICU who meet eligibility criteria. After this initial screen for eligibility, study personnel will contact the 
patient’s ICU physician to confirm appropriateness for the study and permission to contact patient/proxy for 
discussion of study and informed consent process in compliance with local IRB procedures. If the physicians 
agree, study staff will contact the patient in-person; if the patient does not have decision-making capacity at the 
time of enrollment, a legal next of kin in-person will be approached for informed consent. If patients regain 
capacity, patients will be asked to re-consent for continued participation. 
 
 
FINANCIAL CONSIDERATIONS  
 
Expense to Subject:  If the investigation involves the possibility of added expense to the subject (longer hospitalization, extra studies, etc.) 
indicate in detail how this will be handled. In cases where the FDA has authorized the drug or device company to charge the patient for the 
experimental drug or device, a copy of the authorization letter from the FDA or sponsor must accompany the application. Final approval 
will not be granted until the IRB receives this documentation. 
 
There are very limited circumstances under which study participants may be responsible (either directly or via their insurance) for covering 
some study-related expenses. If the study participant or their insurer(s) will be billed for any portion of the research study, provide a 
justification as to why this is appropriate and acceptable. For example, if the study involves treatment that is documented standard of care 
and not investigational, state so. In these cases, the protocol and the consent should clearly define what is standard of care and what is 
research. 
There is no charge to patients. 
Payment for participation:  Describe all plans to pay subjects, either in cash, a gift or gift certificate. Please note that all payments must be 
prorated throughout the life of the study. The IRB will not approve a study where there is only a lump sum payment at the end of the study 
because this can be considered coercive. The amount of payment must be justified. Clarify if subjects will be reimbursed for travel or other 
expenses. 
X 
Not applicable 
 
 
Collaborating Sites.  When research involving human subjects will take place at collaborating sites or other performance sites when 
UVM/UVM Medical Center is the lead site, the principal investigator must provide in this section a list of the collaborating sites and their 
Federalwide Assurance numbers when applicable.  (agreements may be necessary) 
 
Not applicable 
 
Johns Hopkins University, FWA00005834 
University of California Los Angeles, FWA00004642 
Rutland Regional Medical Center, FWA00003554 
 
 

 
27 
 
 
INFORMED CONSENT  
 
Consent Procedures:  Describe the consent procedures to be followed, including the circumstances under which consent will be obtained, 
who will seek it, and the methods of documenting consent.  Specify the form(s) that will be used e.g. consent (if multiple forms explain and 
place identifier on each form), assent form and/or HIPAA authorization (if PHI is included).  These form(s) must accompany the protocol as 
an appendix or attachment.   
 
Note:  Only those individuals authorized to solicit consent may sign the consent form confirming that the prospective subject was provided 
the necessary information and that any questions asked were answered. 
As most eligible patients will be unable to make decisions, written informed consent will most often occur 
via legally authorized representatives (LARs) with participant re-consent upon regaining capacity.  
All patients who meet inclusion and exclusion criteria will be invited to participate in this study. Using 
observation/review of the electronic medical record and daily hospital rounds, study staff will identify 
consecutive patients admitted to the ICU who meet the basic eligibility criteria. In order to conduct the 
screening, the research team will obtain: 1) an IRB waiver of consent for screening; 2) an IRB waiver 
of HIPAA authorization; and 3) all necessary institutional confidentiality agreements. After this initial 
screen for eligibility, study personnel will proceed as per local IRB requirements, including contacting 
the patient’s ICU physicians to confirm appropriateness for the study and obtain permission to approach 
the patient/legal next of kin for discussion of the study and to undertake the informed consent process. If 
the physicians agree, study staff will approach the patient in-person or, if the patient doesn’t have 
decisional capacity at the time of enrollment, a legal next of kin in-person (via in-person meeting). 
Most patients participating in this study will require mechanical ventilation and will therefore be receiving 
some amount of sedative medications at the time of enrollment. Hence, we anticipate that a large 
proportion of patients will lack the capacity to provide informed consent at the time of study eligibility and 
therefore, we expect that study staff will go through the process of informed consent and review the 
consent materials with the legal next of kin. Consent will be documented, in writing, on an IRB-approved 
consent form. No minors will be considered in the proposed research; therefore, parental permission and 
child assent is not applicable to this application. All conversations with the patient/legal next-of-kin 
regarding the study will be held in a private setting; study staff will allow for patients’ desire to have family 
present and/or to confer with family, and to make participation decisions according to his or her own time. 
Once patients who did not have decisional capacity at the time of initial consent regain that capacity, they 
will be re-consented for ongoing participation in the study. 
 
Family members may be the Legally Authorized Representatives (LARs) who provide consent for the 
patient to participate in the RCT, but additional family members beyond the LARs also may be asked to 
participate, and they will be identified via observation of them visiting the consented participant while in 
the ICU. Only family members >18 years of age will be included. Family members will undergo informed 
consent, but no identifiable information will be obtained from them. Nurses and physicians caring for the 
patients in the RCT (study (C) from above) also will be asked to complete the satisfaction questionnaire 
and semi structured interview with their enrollment and consent in accordance with institutional IRB 
policy.  
Information Withheld From Subjects:  Will any information about the research purpose and design be withheld from potential or 
participating subjects?  If so, explain and justify the non-disclosure and describe plans for post-study debriefing.   
X 
Not applicable 
 
 
 
 
Attach full grant application, including budget information and/or any contract or draft contract 
associated with this application.  
 
All materials must be submitted electronically to the IRB via InfoEd. Proper security access is needed to 
make electronic submissions. Visit the InfoEd Resource Materials page for more information.