Conditions: Spinal Cord Injury Respiratory Muscle Weakness
Keywords: Tetraplegia High Paraplegia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
Spinal cord injury (SCI), especially involving the cervical and upper thoracic segments, can significantly compromise respiratory muscle function. Respiratory complications can ensue, including lung collapse and pneumonia, which are the primary cause for mortality in association with traumatic SCI both during the acute and chronic phases post-injury. Lesions at the level of the cervical or high thoracic spinal cord result in respiratory muscle weakness, which is associated with ineffective cough, mucus retention, and mucus plugging. Despite the fact that pulmonary complications are a major cause of morbidity and mortality in this population, there is a paucity of effective interventions in the SCI population known to improve respiratory muscle strength with pharmacologic interventions receiving little to no attention. The current objective of this study is to determine the effectiveness of 16 weeks of sustained release oral Albuterol to; (1) improve respiratory muscular strength, and (2) improve cough effectiveness.

Detailed description:
Although the past 40 years has witnessed a substantial improvement in the acute and chronic management of persons with SCI, mortality remains high during the first year post-injury, and pulmonary complications including pneumonia, lung collapse (atelectasis), respiratory failure, and thromboembolism are the predominant cause. The propensity for pulmonary complications among subjects with SCI stems from paralysis of respiratory muscles. Injury to the cervical and upper thoracic cord significantly compromises function of the diaphragm, intercostal muscles, accessory respiratory muscles, and abdominal muscles. Respiratory muscle dysfunction is manifest as diminution in lung volumes, reduction in maximal static inspiratory and expiratory mouth pressures (MIP and MEP, respectively), and reduction in peak cough pressure and flow. Cough effectiveness is contingent upon both inspiratory and expiratory muscle strength; increasing the pressure-generating capacity of the inspiratory and expiratory muscles in persons with tetraplegia and high paraplegia may, therefore, translate to improved cough effectiveness and reduction in the propensity for atelectasis and, possibly, pneumonia.

Respiratory muscle training, often utilizing simple hand-held portable resistive or threshold training devices, appears to have marginal effects on vital capacity and maximal static mouth inspiratory and expiratory pressures (MIP and MEP, respectively), although data is inconclusive. Pharmacologic interventions to improve respiratory muscle strength have received little attention in the SCI population. Studies involving oral beta-2 adrenergic agonists, which have been shown to elicit anabolic effects on skeletal muscle in young men and an increase in muscle strength among patients with facioscapulohumeral muscular dystrophy, have also demonstrated salutary effects in persons with SCI. There are many foreseeable advantages of a pharmacologic approach to improve respiratory muscle strength in persons with SCI. For instance, RMT can be physically demanding and time consuming, compliance can be an issue, and sustainable improvements have not been realized. The intent in the present proposal is to enroll a targeted cohort of 24 comparatively weaker subjects with tetraplegia and high paraplegia in a randomized, double-blind, placebo-controlled, parallel group trial to assess the effects of an oral beta-2 agonist upon respiratory muscle strength and cough effectiveness.

Arms:
arm 1: Subjects will receive 16 weeks of active medication. arm 2: Subjects will receive 16 weeks of placebo medication.

Interventions: intervention 1: Oral Albuterol Extended Release intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive extended release Albuterol, 4mg twice daily for the first week. The remaining 15 weeks subjects will receive extended release Albuterol, 8mg twice daily. intervention 2: Subjects will receive placebo tablets twice daily for 16 weeks.

Protocol document:
Prot_SAP_000.pdf: 
Revised: March 2017 TC 
The Effect of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
Background and Significance: 
With an estimated 12,000 incident cases per year, spinal cord injury (SCI) now affects over 300,000 
Americans, approximately 52% of whom have injury at the cervical level (tetraplegia) [1].  Although the past 40 
years has witnessed a substantial improvement in the acute and chronic management of persons with SCI, 
mortality remains high during the first year post-injury, and pulmonary complications including pneumonia, lung 
collapse (atelectasis), respiratory failure, and thromboembolism are the predominant cause [2,3]. History has 
also seen a shift in the principal cause of mortality during the chronic phase of SCI (> 1 year post-injury); 
mortality related to urosepsis and renal failure has now been supplanted by pulmonary complications, 
particularly pneumonia [2].  Thus, pulmonary complications are now the primary cause for premature mortality 
in the SCI population regardless of time post-injury [2,3]. 
The propensity for pulmonary complications among subjects with SCI stems from paralysis of 
respiratory muscles.  Injury to the cervical and upper thoracic cord significantly compromises function of the 
diaphragm, intercostal muscles, accessory respiratory muscles, and abdominal muscles.  Respiratory muscle 
dysfunction is manifest as diminution in lung volumes, reduction in maximal static inspiratory and expiratory 
mouth pressures (MIP and MEP, respectively), and reduction in peak cough pressure and flow [4].  In a cross 
sectional analysis of two large outpatient populations with SCI, the forced vital capacity (FVC), or the volume of 
air forcibly exhaled during a maximal expiratory maneuver, varied inversely with level of lesion; injury levels T6 
and above were associated with FVC values below the predicted limits of normal, falling to approximately 50% 
of predicted at the highest injury levels [5]. Reduced volume and ineffective cough predispose to airway 
closure and atelectasis, secretion retention, and pneumonia.  Residual function of the diaphragm, the principal 
muscle of inspiration innervated by phrenic nerve roots C3 to C5, is required for unassisted breathing.  
Excluding C1 and C2 motor complete injuries, most subjects with tetraplegia achieve spontaneous ventilation 
due to a functioning diaphragm despite intercostal and abdominal muscle paralysis.  However, muscle 
paralysis impairs integrated thoracic expansion during inspiration via alterations in the mechanical properties of 
the lungs and chest wall, specifically paradoxical downward displacement of the upper rib cage during 
inspiration [6] and reduced lung and chest wall compliance [7].  These changes in turn are associated with 
reduction in lung volumes [8,9] and in maximal static mouth pressures (MIP and MEP) [6,7].  Reduced 
inspiratory capacity directly affects expulsive cough pressure generation and may limit the ability to sigh 
deeply, both of which may predispose to retained secretions, atelectasis, and increased pneumonia risk [4,10].  
Expiratory muscle function is more severely compromised than inspiratory muscle function with higher 
level SCI given more widespread paralysis of expiratory muscles, principally the expiratory intercostals and 
abdominal musculature.  Residual expiratory muscle function required for forceful expiration (as during 
exercise) and for effective cough has been attributed to the clavicular portion of the m. pectoralis major 
innervated by nerve fibers originating in the fifth through seventh cervical segments [11] and to the m. 
latissimus dorsi [12].  In patients with neuromuscular disease, conditions often associated with chronic disease 
progression, diaphragmatic function as reflected by MIP is usually well maintained until late in the disease 
course, which explains why reduction in MEP compared to MIP has been found to be a more sensitive 
indicator of progressive respiratory impairment [13].  However, in traumatic cervical SCI, characterized by 
simultaneous disruption of inspiratory and expiratory muscle function at time of injury, assessment of MIP may 
confer greater predictive value.  Kang et al. found among subjects with tetraplegia that MIP correlated better 
than MEP with pulmonary function parameters requiring active expiratory effort such as FVC and peak cough 
flow [14].  Thus, significant decreases in MIP as compared to MEP might better identify individuals with 
tetraplegia and high paraplegia who are at highest risk for pulmonary complications; impaired inspiratory 
muscle strength results in further impairment of already significantly compromised expiratory muscle function 
and cough effectiveness.  Indeed, deeper inspiration (greater inspiratory capacity) accompanied by higher MIP 
is associated with expansion of more distal airways (preventing atelectasis), improvement in expiratory muscle 
function (better length-tension relationships), and increases in lung elastic recoil pressure [15-17].  Further, in 
our experience, subjects with high level SCI generally have comparatively lower percent predicted MEP as 
compared to MIP, again suggesting that deterioration in MIP has greater discriminatory power than subtler 
decreases in an already depressed MEP for identifying individuals at greatest risk for future pulmonary 
complications. 
Respiratory muscle atrophy and subsequent impaired function are not only the result of muscle 
paralysis, but also stem from inactivity and deconditioning of residual and neurologically intact respiratory 
June 2, 2016
NCT02508311


Revised: March 2017 TC 
muscles.  Numerous interventional studies in persons with tetraplegia have investigated whether inspiratory 
and expiratory resistive or threshold training, involving relatively inexpensive portable devices, are effective for 
improving respiratory muscle strength.  Most studies have been uncontrolled and not comparable due to 
diverse protocols, heterogeneity of subject characteristics, or differences in training techniques [18, 19].  Since 
2006, there have been three systematic reviews of respiratory muscle training (RMT) in persons with SCI, and 
similar conclusions have been drawn; although there is a suggestion that RMT can result in increases in vital 
capacity and static mouth pressures, the effect size is small, and the data inconclusive[18-20].  Further, there 
is no evidence of carryover beyond the training period [21]. Insufficient data exists to make conclusions 
regarding the effects of RMT upon endurance, quality of life, exercise performance, or pulmonary 
complications [18, 19].  In two of the better designed trials, repetitive training of the clavicular portion of the 
pectoralis major via isometric exercise for 6 weeks among subjects with tetraplegia resulted in improvements in 
expiratory muscle strength [22], and a novel approach using non-resistive normocapnic hyperpnea training 
resulted in significant improvement in respiratory muscle strength and endurance [23].  A systematic review 
and meta-analysis found a lack of sufficient evidence to either support or discourage use of an abdominal 
binder to improve respiratory function in SCI [24].  Lastly, interventions to improve inspiratory muscle function 
via diaphragmatic or phrenic nerve stimulation, or to improve expiratory muscle function and cough strength via 
magnetic or electrical stimulation can prove highly efficacious, but are often invasive and reserved for highly 
selected individuals [25].   
Pharmacologic interventions to improve respiratory muscle strength have received little attention in the 
SCI population.  A randomized trial with crossover demonstrated that oral theophylline for 6 weeks did not 
improve pulmonary function in persons with SCI [26].  Studies involving oral beta-2 adrenergic agonists, 
however, which have been shown to elicit anabolic effects on skeletal muscle in young men [27] and an 
increase in muscle strength among patients with facioscapulohumeral muscular dystrophy [28], have also 
demonstrated salutary effects in persons with SCI.  One small study showed that administration of an oral 
beta-2 agonist to subjects with tetraplegia amplified total work output during functional electronic stimulation of 
leg muscles [29]. In a separate study, it was demonstrated that administration of an oral beta-2 agonist in 
persons with tetraplegia improved forearm muscle size and strength [30]. On the basis of these reports, we 
performed preliminary experiments and now have compelling data that lends support to the efficacy of beta-2 
agonists for improving respiratory muscle strength in persons with SCI.  Salmeterol (Serevent ©) is a long-
acting inhaled beta-2 adrenergic agonist approved as a bronchodilator for maintenance management of 
obstructive lung disease; this agent also exhibits systemic absorption following inhalation [31].  We performed 
a randomized, double-blind, placebo-controlled, crossover trial of inhaled salmeterol in eleven persons with 
chronic stable tetraplegia, and found significant improvements compared to matching placebo in lung volumes 
[FVC, FEV1, expiratory reserve volume (ERV)] and static mouth pressures (MIP and MEP) after 4 weeks of 
twice daily administration suggesting improvement in lung function and respiratory muscle strength (see Table 
in Preliminary Studies section) [32].  The medication was well tolerated, and no adverse events were reported. 
As a follow-up, we recently completed a randomized, double-blind, placebo-controlled, parallel group trial in 30 
persons with tetraplegia and high paraplegia (15 subjects each in the active drug and placebo groups) who 
were administered an oral beta-2 agonist (albuterol repetabs 4 mg twice daily) versus matching placebo over 
12 weeks (data not published). Significant improvements were noted in MIP among subjects who received 
active drug compared to placebo, and improvements in MEP trended toward significance.  Also, it was noted 
that the greatest increases in MIP were in subjects with the lowest MIP at baseline, suggesting that the 
weakest individuals targeted by a baseline MIP of < 90 cmH2O would stand to derive the greatest benefit in 
terms of improvement in respiratory muscle strength and potentially reduction in pulmonary complications. 
There are many foreseeable advantages of a pharmacologic approach to improve respiratory muscle 
strength in persons with SCI.  For instance, RMT can be physically demanding and time consuming, 
compliance can be an issue, and sustainable improvements have not been realized [21, 23]. Perhaps more 
importantly, in our experience the weakest individuals with SCI who are at greatest risk for recurrent pulmonary 
complications are the least likely to engage in effort-related protocols.  Indeed, our research subjects are often 
more independent and generally healthier and more willing to engage in research than their weaker 
counterparts.  If we witness what we have documented thus far, we anticipate that most of these issues will be 
of limited concern given the ease of implementation of this oral medication, the minimal side effects 
encountered, the minimal time commitment or need for ancillary assistance, and the potential for sustainable 
effects on respiratory muscle function.  Further, it is foreseeable that combination modalities (i.e. 
pharmacologic and respiratory muscle training regimens) would be possible in motivated individuals.  The 


Revised: March 2017 TC 
ultimate challenge, which remains to be investigated, is whether improvement in respiratory muscle strength 
and cough effectiveness translates to a decrease in respiratory complications. 
Our intent in the present proposal is to enroll a targeted cohort of 24 comparatively weaker subjects 
with tetraplegia and high paraplegia in a randomized, double-blind, placebo-controlled, parallel group trial to 
assess the effects of an oral beta-2 agonist upon respiratory muscle strength and cough effectiveness.  Based 
upon the findings from our recent study (please see “Preliminary Studies”), we have chosen a MIP of < 90 
cmH2O as a criterion for study inclusion. Use of MIP as the preferred surrogate of underlying respiratory 
muscle strength in persons with SCI has been previously reported [14].  Individuals will be randomized equally 
(12 in each group) to receive oral albuterol versus matching placebo for 16 weeks (initial 4 weeks at previous 
dose of 4 mg twice daily, then in the absence of significant side effects, increased to 8 mg twice daily for the 
final 12 weeks).  If we identify as we anticipate significant improvements in indices of respiratory muscle 
strength in the active study group after 16 weeks, we intend to repeat testing two weeks later to see if 
improvements are sustainable.  Positive results would dictate the need to pursue a multicenter trial to see if 
pulmonary complications are reduced, thus making a significant impact on the welfare of this at risk population. 
B. Preliminary Studies 
Independent of effects upon respiratory muscle strength, we found that administration of the inhaled 
beta-2 adrenergic agonist, metaproterenol sulfate, to subjects with chronic stable tetraplegia resulted in a 
significant increase (>12% and 200 ml) in the forced expiratory volume in one second (FEV1) in 14 of 34 (41%) 
subjects [33].  We hypothesized that the previously unrecognized airflow obstruction unmasked by 
bronchodilator administration among subjects with tetraplegia was due to autonomic imbalance; sympathetic 
(bronchodilating) innervation to the lungs is interrupted, whereas parasympathetic (bronchoconstrictive) 
neurotransmission carried by vagal nerve fibers remains intact.  Support came from a subsequent investigation 
that employed  body plethysmography to measure specific airway conductance (sGAW), a more sensitive 
indicator of airway caliber and bronchodilation than the FEV1, among subjects with tetraplegia and low 
paraplegia (injury below T5) [34]. In subjects with tetraplegia but not paraplegia, we found baseline sGAW to 
be reduced consistent with resting airway narrowing, and witnessed significant increases in sGAW consistent 
with bronchodilation following inhalation of metaproterenol sulfate.  These findings are important to the present 
proposal insofar as bronchodilation induced by beta-2 agonists can help prevent atelectasis and enhance lung 
volumes independent of anabolic effects, thereby potentially conferring added benefits.  
We performed a preliminary study to evaluate the potential role of a long-acting beta-2 agonist in 
tetraplegia [32]. Eleven subjects with tetraplegia completed a randomized, double blind, placebo-controlled 
crossover study. All received placebo or the long-acting beta-2 agonist salmeterol (50ug twice a day from a 
Diskus inhaler) for 4 weeks with a 4-week washout period. Salmeterol is known to be rapidly absorbed into the 
systemic circulation following inhalation [31]. Results obtained during the 4th week of salmeterol or placebo 
administration, regardless of the order of administration, are shown in the following table: 
Table 1 
Baseline 
Placebo 
Salmeterol 
Total lung capacity (TLC) (L) 
5.20±0.47 
5.11±0.48 
5.32±0.32 
Force vital capacity (FVC) (L) 
3.11±0.38 
3.22±0.41 
3.36±0.52*§ 
Forced expiratory volume in 1 sec (FEV1) (L) 
2.40±0.51 
2.52±0.49 
2.74±0.52*§ 
Expiratory reserve volume (ERV) (L) 
0.51±0.20 
0.55±0.17 
0.60±0.20● 
Residual volume (RV) (L) 
2.11±0.45 
.89±0.41 
1.98±0.44 
Maximum inspiratory pressure (MIP) (cmH20) 
72.50±18.6 
73.9±21.5 
81.6±20.8*§ 
Maximum expiratory pressure (MEP)(cmH20) 
40.9±16.6 
45.9±19.2 
51.3±20.0*§         
data are mean±SD; *p<0.01 versus baseline; §p<0.05 versus placebo; ●p<0.05 versus baseline; L=liters 


Revised: March 2017 TC 
 
 
 
 
Patients receiving salmeterol had significant 
improvement in FVC, FEV1, MIP, and MEP 
compared 
to 
placebo 
and 
baseline. 
Expiratory reserve volume improved during 
administration of salmeterol compared to 
baseline (Table 1, Figure 1). Because 
spirometric parameters improved consistent 
with bronchodilation, it cannot be stated for 
certain that improvement in MIP and MEP 
represented an increase in respiratory 
muscle strength because both parameters 
are highly dependent upon the lung volume 
at which they are measured. However, by 
considering 
MIP 
and 
MEP 
values 
in 
relationship to whether salmeterol was given 
first or second, it appeared that improvement 
in MIP and MEP among those given 
salmeterol first was sustained through the 
washout period and into the placebo period (Figure 1), suggesting that sustained increase in MIP and MEP 
was due to improvement in respiratory muscle strength. Also, a significant increase in the ERV suggested that 
salmeterol improved expiratory muscle strength (Table 1) [33]. 
 
To pursue this question further, we recently completed a randomized, double-blind, placebo-controlled, 
parallel group trial in 30 persons with tetraplegia and high paraplegia (injury T6 and above). Fifteen subjects 
each in the active drug and placebo arms were randomized to receive an oral beta-2 agonist (albuterol 
repetabs 4 mg twice daily) versus matching placebo across 12 weeks (data not published).  For post-
intervention testing, we waited the equivalent of 5 half-lives of the drug to eliminate acute bronchodilator 
effects; any improvements in pulmonary function were therefore deemed secondary to increases in respiratory 
muscle strength.  We found a statistically significant increase in MIP among subjects who received active drug 
versus placebo (%change = 22.7 ± 19.6 vs. 7.5 ± 17.0; p=0.03).  The corresponding change in MEP (active 
drug versus placebo) trended toward significance (%change= 18.5 ± 29.1 vs. -0.2 ±19.8; p=0.06) [Figures 2a 
and 2b].   In the subset of individuals who received active drug (n=15), a statistically significant inverse 
correlation was found between baseline MIP and change in MIP (r2= -0.326; p=0.03), with a trend toward an 
inverse correlation between baseline MEP and change in MEP [(r2= 0.181; p=0.11) [Figures 2c & 2d].  These 
findings suggest that those with the lowest baseline mouth pressures tended to have the greatest improvement 
in respiratory muscle strength after receiving oral albuterol (see shaded boxes, Figures 2c & 2d).  Thus, 
administration of an oral beta-2 agonist appeared to elicit the greatest effect on respiratory muscle strength in 
the weakest individuals, thereby targeting those persons who conceivably stand to derive the greatest benefit.  
Upon further inspection, a cutoff baseline MIP value of 90 cmH2O identified subjects below which appeared to 
have the greatest responses to administration of active drug, while those with more “normal” MIP values above 
this threshold exhibited little improvement.  Similar findings were noted with regard to MEP, but did not reach 
statistical significance. Albuterol was also very well tolerated with minimal side effects; one subject in the active 
drug group withdrew because of jitteriness. 
  
 
 
 
 
 
 
Figure 1: Percent change from baseline in MIP and MEP during 
phase 1 and phase 2.  *p <0.05 for percent change from baseline. 
a) 
b) 
c) 
d) 


Revised: March 2017 TC 
 
Figure 2: Oral Beta-2 versus Placebo for a) % change in MIP from FRC, b) % change in MEP from TLC, c) % change 
versus baseline MIP in active; and d) % change versus baseline MEP in active. 
 
 
C. Research Design and Methods: 
PROPOSED STUDY:  This prospective interventional study will be performed at the National Center of 
Excellence for Medical Consequences of Spinal Cord Injury located at James J. Peters Veterans Affairs 
Medical Center (JJPVAMC), Bronx, NY. Prior to patient recruitment, approval by the local Institutional Review 
Board and Research and Development Committee will be obtained. Written informed consent will be obtained 
from all participants prior to the screening. An oral beta-2 agonist, or placebo, will be administered to subjects 
with tetraplegia and high paraplegia; the study will be prospective, double-blind with placebo.  Subjects will be 
selected who have no history of asthma, allergies, hypertension or cardiovascular disease. Also excluded will 
be those already using beta-2 adrenergic agonists, corticosteroids, or antidepressants. Twenty-four patients 
with tetraplegia (C3-C8) and high paraplegia (T1-T6) who have baseline MIP < 90 cmH2O if male or MIP < 65 
cmH2O if female, will be studied. Participants with SCI will be selected from the approximately 120 individuals 
with SCI who undergo annual pulmonary function testing at our facility.  These tests are routinely performed in 
our pulmonary function lab and interpreted by the principal investigator (~ 120 per year).  We estimate that 
65% of these subjects will have tetraplegia or high paraplegia (~ 78 subjects), and of these ~ 50% will have a 
MIP < 90 and 65 cmH2O leaving 39 subjects for enrollment; assuming an attrition rate of 30%, this leaves 27 
subjects, more than the 24 anticipated, to complete the trial.  Based on power analysis (provided below), we 
need 12 subjects in each group (albuterol vs. placebo) to have a power of 81% at the alpha of 5%.  Subjects 
will be divided into two groups of twelve, randomized equally to receive sustained-release albuterol repetabs 
versus matching placebo over a 16 week period. For the first week, the dosage of albuterol shall be 4 mg every 
12 hours as in the previous trial, then in the absence of untoward side effects, increased to 8 mg every 12 
hours for the remaining 15 weeks. The study drug/placebo will be dispensed by the VA Research Pharmacy on 
the subject’s first visit and provided at no cost; both study investigators and subjects will be blinded as to study 
drug. Spirometric parameters, lung volume parameters, diaphragmatic thickness, maximal mouth inspiratory 
and expiratory pressures (MIP and MEP, respectively), simultaneously obtained esophageal pressure 
measurements (E-MIP, E-MEP), cough esophageal pressures (C-ESO) will be measured as described below 
at baseline, after 16 weeks and again at 18 weeks.   The flow chart below highlights the test schedule: 
Table 2: Procedures To Be 
Performed. 
Baseline 
Drug or 
Placebo 
Post 
Residual 
 
Week: 0 
Week: 1-16 
Week: 16 
Week: 18 
Pulmonary Function Test and 
Lung Volumes  
X 
 
X 
X 
Respiratory Muscle Strength 
Testing 
X 
 
X 
X 
Diaphragmatic Ultrasound 
X 
 
X 
X 
Pulmonary Questionnaire 
X 
 
X 
X 
Take Daily Medication 
 
X 
 
 
TLC 
 
 
r2= -0.326; 
p=0.03 
r2= -0.181; 
p=0.11 


Revised: March 2017 TC 
Weekly Home Pulmonary 
Function Test 
 
X 
 
 
Weekly Self-Symptom Survey 
 
X 
 
 
Bi-Weekly Phone Interview 
 
X 
 
 
 
Pulmonary Function Testing and Lung Volumes: 
Pulmonary Function Test: While seated in the chair and after a mouth piece and nose clip are applied, the 
subject will be asked to breathe normally for 3 to 6 breaths.  They will then be instructed to forcibly inhale until 
their lungs are filled.  After a brief pause, they will then be instructed to forcibly exhale the air in their lungs and 
hold the maneuver for approximately 6 seconds. After a brief rest, the maneuver will be repeated a minimum of 
three times to ensure reliability.   
Static Lung Volumes: The volume of air in the lungs will be assessed using the nitrogen washout technique.  
The nitrogen washout technique, which takes about five minutes to perform, will begin while a subject is seated 
in his/her wheelchair and after a mouth piece and nose-clips have been applied.  The subject will then be 
asked to breathe room air into and out of the mouthpiece for 3-6 breaths.  The air exhaled, which normally 
contains mostly nitrogen, will be collected and analyzed by a machine called a metabolic cart.  Once a subject 
has completed the 3-6 breaths, he/she will be asked to take a slow deep breath in and to exhale until he/she 
feels that the lungs are empty, after which the subject returns to a normal breathing pattern.  Following an 
additional 3-6 regular breaths, the metabolic cart will begin delivering 100% oxygen through the mouthpiece.  
The subject will continue to inhale 100% oxygen while taking normal breaths until oxygen is the only gas 
measurable in his/her exhaled air.  After a brief rest, the maneuver will be repeated a minimum of two times to 
ensure reliability.   
Respiratory Muscle Strength Testing:  Maximal inspiratory pressure (MIP) from functional residual capacity 
(FRC), and maximal expiratory pressure (MEP) from TLC will be performed with a flanged mouthpiece 
according to established protocols using a modification of the Black and Hyatt technique [36]. For simultaneous 
measurement of transesophageal pressures, subjects will be asked to swallow a small balloon-tipped catheter 
connected to a computer. The balloon will be inserted into one nostril and into the esophagus after numbing 
medicine (4% lidocaine) has been applied to the nasal passages, throat, and to the tube itself in order to make 
swallowing the balloon easier. Then, pressures at the mouth and at the balloon will be recorded simultaneously 
by having the subject blow in and out as strongly as possible through a mouthpiece connected to a recording 
device. The subject will repeat these maneuvers a maximum of five times, and then be asked to perform 5 to 
10 cough maneuvers of varying intensities while pressure at the esophageal balloon is recorded. The principal 
investigator’s team has ample experience in esophageal manometry.  
Diaphragmatic Ultrasound: A 7.5 MHz ultrasound (Acuson 128 XP/10, Mount View, Ca) linear transducer 
probe will be used to obtain 2D images (cross sectional view of the structure) of the diaphragm at the zone of 
apposition (ZOA) of the right hemithorax. All subjects will be seated comfortably in their wheel chairs during 
imaging. The diaphragm will be visualized in the right mid-axillary line at the levels of 8th or 9th intercostal space 
depending on a clarity and parallelism of visualized structures (pleura, diaphragm muscle and peritoneum). 
The diaphragm muscle in the ZOA is represented as a non-echogenic central structure bordered by two 
echogenic lines representing pleural and peritoneal membranes. Subjects will be asked to perform breathing 
through a flow volume meter (Carefusion, Yorba Linda, Ca) and to perform maneuvers of maximal inspiration 
and expiration. They will be asked to maintain an active respiratory effort in maximal inspiration and expiration 
for 1-2 seconds to prevent closure of the glottis and relaxation of the diaphragm and to provide a better 
visualization of the diaphragm in those positions. Continuous recording of the images will be obtained through 
at least 5 breathing cycles (maximal expiration to maximal inspiration). Simultaneous recording of time points 
and lung volumes will be obtained. All recordings will be done by the single experienced investigator. 
Retrograde analysis of the recordings will be done and freeze frame control will be used during replay 
alongside time records to precisely determine the end inspiration and end expiration. Diaphragm thickness 
(Tdi) will be measured as a distance between the midpoints of the pleural and peritoneal membranes at the 
end of inspiratory volume (EIV) and end of expiratory volume (EEV). The diaphragm thickness will be reported 
to the nearest 0.1mm which is within the range of accuracy of the transducer. The change in 
transdiaphragmatic index (Tdi) during inspiration (shortening of diaphragm), will be calculated and reported as 
the difference between Tdi at EEV and EIV, respectively.   
Randomization: An independent investigator (unaffiliated with the pulmonary program and the present study) 
will generate a counter-balanced randomization table for enrolled participants.  The randomization table will 


Revised: March 2017 TC 
account for equal sample sizes in the placebo and active drug group, and will be forwarded to the research 
pharmacy wherein the appropriate allocation of placebo/active drug will be dispensed and serve as the official 
study record. 
Weekly Home Pulmonary Function Assessment: As a part of monitoring respiratory function, all subjects 
will be asked to perform weekly spirometry measurements using a portable spirometer [Microlife Digital Peak 
Flow & FEV1 Meter (Micorlife Corporation, Dunedin, FL)]. This device will allow subjects to check and record 
peak flow and other relevant parameters of a forced expiration. Subjects will be given detailed instructions and 
a demonstration on a first visit to ensure their understanding of the device and the maneuvers they will need to 
perform. Upon turning on the device, subjects will be prompted to take a maximal breath in and then to exhale 
forcefully through a mouthpiece. Subjects will be instructed to close their lips around the mouthpiece to prevent 
air leak that could affect the measurement. The device will automatically record the results, and the dates and 
times of recording. All participants will be asked to perform three consecutive maneuvers preferably upon 
awakening in the morning. 
Weekly Self-symptom Survey: Subjects will be asked to fill out a questionnaire [37] regarding their symptoms 
on a weekly basis, the responses for which will be entered into a master database on each visit.  
Bi-weekly phone interview: A member of the investigative team will contact the subject over the phone on a 
biweekly basis to speak about any symptoms or changes in lung function that the subject may be experiencing 
or have experienced since a previous discussion.  The phone interview will only last a few minutes.  The 
subject will be reminded that they are allowed to contact a member of the study team at any point should they 
have a question or emergency. 
D. Data and Statistical Analysis: The study design consists of two between factors (Treatment and SCI groups) 
and two within factors (Time).  A mixed ANOVA will be used to determine main and interaction effects. 
Analyses will permit us to determine the effect of the drug treatment alone.  We are expecting large effect sizes 
(d >0.80) for percentage increases in MIP among subjects receiving active drug versus placebo (see 
preliminary data above), therefore, the power is greater than 0.95 at alpha <0.05.  Allowing for a 12 subject 
dropout, our power is still better than 0.85. 
E. Expected Results and Benefits: We anticipate that administration of a beta-2 adrenergic agonist to a 
targeted cohort of individuals with tetraplegia and high paraplegia who have significantly reduced MIP at 
baseline shall result in significant improvements in surrogate indices of respiratory muscle strength and 
decreased work of breathing.  It is also possible that anabolic effects might be sustained on follow-up testing 2 
weeks after stopping test medication. Findings that a beta-2 adrenergic agonist improves inspiratory and 
expiratory muscle strength would have significant therapeutic implications by increasing cough effectiveness to 
help prevent mucus retention and atelectasis.  Salutary effects would provide a rationale for a larger scale 
multicenter trial to assess if administration of beta-2 agonists is associated with a reduction in pulmonary 
complications, a major cause of morbidity and mortality in this population. 
 
Human Subjects Involvement and Characteristics  
Subjects will be enrolled at the James J. Peters VA Medical Center for both the screening phase and the 
intervention phase. We estimate that a total of approximately 40 subjects will be recruited for the screening 
phase with about 24-27 meeting inclusion criteria and completing the study. All subjects will be studied at the 
James J Peters VA Medical Center within the Center of Excellence for the Medical Consequences of SCI. 
Subjects will be recruited from individuals that undergo annual pulmonary function testing within our Center 
(approximately 120 annually), of whom ~ 65% are anticipated to have cervical or high thoracic injury, and 50% 
of these also with reduced MIP (< 90 cmH2O).  
 
Identify the criteria for inclusion or exclusion of any subpopulation.  
Subjects with Spinal Cord Injury will be recruited according to the following: 
 Inclusion criteria: 
1. Chronological age between 18-80 years,   
2. Subjects with Tetraplegia (Level of SCI C3-8); All ASIA Levels  
3. Subjects with High Paraplegia (Level of SCI T1-T6); All ASIA Levels  
4. Duration of injury ≥ 1 year, 
5. Maximal inspiratory pressure < 90 cmH2O (Men) 
6. Maximal inspiratory pressure <65 cmH2O (Women) 
 


Revised: March 2017 TC 
 
Exclusion criteria: 
1. Smoking, active or history of smoking within the past year  
2. Ventilator dependence  
3. Any history of blast injuries to the chest, 
4. Active respiratory disease or recent (within 3 months) respiratory infections 
5. Use of medications known to alter airway caliber (i.e. beta 2 agonists or anticholinergic agents)  
6. Pregnancy  
7. Lack of mental capacity to give informed consent 
           8. Use of oral or inhaled corticosteroid agents 
           9. History of epilepsy or seizure disorder 
           10. Subjects already using beta-2 adrenergic agonists 
           11. Hypertension or cardiovascular disease 
           12. History of asthma or significant extrinsic allergies 
           13. MAOI use in prior 14 days 
           14. Hypersensitivity to albuterol or any of its constituents 
           15. Antidepressant use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revised: March 2017 TC 
1. 
Center, T.N.S.C.I.S. Spinal Cord Injury Facts and Figures at a Glance. [Online] 2012; 2012:[Available 
from: https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/Facts%202013.pdf. 
2. 
DeVivo, M.J., Discharge disposition from model spinal cord injury care system rehabilitation programs. 
Arch Phys Med Rehabil, 1999. 80(7): p. 785-90. 
3. 
DeVivo, M.J., K.J. Black, and S.L. Stover, Causes of death during the first 12 years after spinal cord 
injury. Arch Phys Med Rehabil, 1993. 74(3): p. 248-54. 
4. 
Schilero, G.J., et al., Pulmonary function and spinal cord injury. Respir Physiol Neurobiol, 2009. 166(3): 
p. 129-41. 
5. 
Linn, W.S., et al., Forced vital capacity in two large outpatient populations with chronic spinal cord 
injury. Spinal Cord, 2001. 39(5): p. 263-8. 
6. 
De Troyer, A., M. Estenne, and W. Vincken, Rib cage motion and muscle use in high tetraplegics. Am 
Rev Respir Dis, 1986. 133(6): p. 1115-9. 
7. 
Estenne, M. and A. De Troyer, The effects of tetraplegia on chest wall statics. Am Rev Respir Dis, 
1986. 134(1): p. 121-4. 
8. 
Anke, A., et al., Lung volumes in tetraplegic patients according to cervical spinal cord injury level. 
Scand J Rehabil Med, 1993. 25(2): p. 73-7. 
9. 
Tow, A.M., D.E. Graves, and R.E. Carter, Vital capacity in tetraplegics twenty years and beyond. Spinal 
Cord, 2001. 39(3): p. 139-44. 
10. 
Bhaskar, K.R., et al., Bronchial mucus hypersecretion in acute quadriplegia. Macromolecular yields and 
glycoconjugate composition. Am Rev Respir Dis, 1991. 143(3): p. 640-8. 
11. 
De Troyer, A., M. Estenne, and A. Heilporn, Mechanism of active expiration in tetraplegic subjects. N 
Engl J Med, 1986. 314(12): p. 740-4. 
12. 
Fujiwara, T., Y. Hara, and N. Chino, Expiratory function in complete tetraplegics: study of spirometry, 
maximal expiratory pressure, and muscle activity of pectoralis major and latissimus dorsi muscles. Am 
J Phys Med Rehabil, 1999. 78(5): p. 464-9. 
13. 
Schramm, C.M., Current concepts of respiratory complications of neuromuscular disease in children. 
Curr Opin Pediatr, 2000. 12(3): p. 203-7. 
14. 
Kang, S.W., et al., Relationship between inspiratory muscle strength and cough capacity in cervical 
spinal cord injured patients. Spinal Cord, 2006. 44(4): p. 242-8. 
15. 
McCool, F.D. and G.E. Tzelepis, Inspiratory muscle training in the patient with neuromuscular disease. 
Phys Ther, 1995. 75(11): p. 1006-14. 
16. 
Hadjikoutis, S., C.M. Wiles, and R. Eccles, Cough in motor neuron disease: a review of mechanisms. 
QJM, 1999. 92(9): p. 487-94. 
17. 
McCool, F.D. and D.E. Leith, Pathophysiology of cough. Clin Chest Med, 1987. 8(2): p. 189-95. 
18. 
Van Houtte, S., Y. Vanlandewijck, and R. Gosselink, Respiratory muscle training in persons with spinal 
cord injury: a systematic review. Respir Med, 2006. 100(11): p. 1886-95. 


Revised: March 2017 TC 
19. 
Sheel, A.W., et al., Effects of exercise training and inspiratory muscle training in spinal cord injury: a 
systematic review. J Spinal Cord Med, 2008. 31(5): p. 500-8. 
20. 
Berlowitz, D.J. and J. Tamplin, Respiratory muscle training for cervical spinal cord injury. Cochrane 
Database Syst Rev. 7: p. CD008507. 
21. 
Rutchik, A., et al., Resistive inspiratory muscle training in subjects with chronic cervical spinal cord 
injury. Arch Phys Med Rehabil, 1998. 79(3): p. 293-7. 
22. 
Estenne, M., et al., The effect of pectoralis muscle training in tetraplegic subjects. Am Rev Respir Dis, 
1989. 139(5): p. 1218-22. 
23. 
Van Houtte, S., et al., Patients with acute spinal cord injury benefit from normocapnic hyperpnoea 
training. J Rehabil Med, 2008. 40(2): p. 119-25. 
24. 
Wadsworth, B.M., et al., Abdominal binder use in people with spinal cord injuries: a systematic review 
and meta-analysis. Spinal Cord, 2009. 47(4): p. 274-85. 
25. 
DiMarco, A.F., Restoration of respiratory muscle function following spinal cord injury. Review of 
electrical and magnetic stimulation techniques. Respir Physiol Neurobiol, 2005. 147(2-3): p. 273-87. 
26. 
Tzelepis, G.E., et al., Effects of theophylline on pulmonary function in patients with traumatic 
tetraplegia. J Spinal Cord Med, 2006. 29(3): p. 227-33. 
27. 
Martineau, L., et al., Salbutamol, a beta 2-adrenoceptor agonist, increases skeletal muscle strength in 
young men. Clin Sci (Lond), 1992. 83(5): p. 615-21. 
28. 
Kissel, J.T., et al., Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. 
Neurology, 1998. 50(5): p. 1402-6. 
29. 
Murphy, R.J., et al., Salbutamol effect in spinal cord injured individuals undergoing functional electrical 
stimulation training. Arch Phys Med Rehabil, 1999. 80(10): p. 1264-7. 
30. 
Signorile, J.F., et al., Increased muscle strength in paralyzed patients after spinal cord injury: effect of 
beta-2 adrenergic agonist. Arch Phys Med Rehabil, 1995. 76(1): p. 55-8. 
31. 
Bennett, J.A., T.W. Harrison, and A.E. Tattersfield, The contribution of the swallowed fraction of an 
inhaled dose of salmeterol to it systemic effects. Eur Respir J, 1999. 13(2): p. 445-8. 
32. 
Grimm, D.R., et al., Salmeterol improves pulmonary function in persons with tetraplegia. Lung, 2006. 
184(6): p. 335-9. 
33. 
Spungen, A.M., et al., Pulmonary obstruction in individuals with cervical spinal cord lesions unmasked 
by bronchodilator administration. Paraplegia, 1993. 31(6): p. 404-7. 
34. 
Schilero, G.J., et al., Bronchodilator responses to metaproterenol sulfate among subjects with spinal 
cord injury. J Rehabil Res Dev, 2004. 41(1): p. 59-64. 
35. 
Stocks, J., et al., Plethysmographic measurements of lung volume and airway resistance. ERS/ATS 
Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/ 
American Thoracic Society. Eur Respir J, 2001. 17(2): p. 302-12. 
36. 
Black, L.F. and R.E. Hyatt, Maximal respiratory pressures: normal values and relationship to age and 
sex. Am Rev Respir Dis, 1969. 99(5): p. 696-702. 


Revised: March 2017 TC 
37. 
Spungen, A.M., et al., Self-reported prevalence of pulmonary symptoms in subjects with spinal cord 
injury. Spinal Cord, 1997. 35(10): p. 652-7. 
 
 

ICF_001.pdf: 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   2    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
the Department of Veterans Affairs Rehabilitation Research and Development Service Merit SPiRE 
award number B1910-P.  
 
2. 
Description of the Study Including Procedures to be Used: 
If you consent to participate in this research study, you will be asked to perform the procedures listed 
below. All procedures are done for research purposes only. If you consent to participate, you will be 
randomly assigned to receive either a sustained-release (medication released for 12 hours) albuterol 
tablet (8mg) or a placebo (non-active) pill.  Regardless of which group you are in, you will be required to 
take a pill two (2) times per day for the duration of the study.  Your involvement in the study will last 18 
weeks.  You will be tested in the research center on three (3) occasions; the onset of the study 
(baseline visit or week 0), after taking the medication for sixteen weeks (4 months) (Post vsit) and again 
2 weeks after completion of the study drug (residual visit or week 18).  The week 16 test will occur 2 to 
7 days after you take the last dose of study drug.   You will be one of approximately 24 individuals to 
participate in this study.  On test days, you will be asked to perform the following: pulmonary function 
tests and lung volume assessments, respiratory muscle strength testing, and an ultrasound to 
determine the size and strength of your diaphragm. During the course of the study (4 months at home) 
you will be asked to complete the following: take pill daily, weekly home pulmonary function test, weekly 
symptom survey, and complete a bi-weekly phone interview with a member of the investigative team. 
The following table depicts these commitments: 
 
Table 2: Procedures To Be Performed 
Baseline 
Drug or 
Placebo 
Post 
Residual 
 
Week: 0 
Week: 1-16 
Week: 16 
Week: 18 
Pulmonary Function Test and Lung 
Volumes  
X 
 
X 
X 
Respiratory Muscle Strength Testing 
X 
 
X 
X 
Diaphragmatic Ultrasound 
X 
 
X 
X 
Pulmonary Questionnaire 
X 
 
X 
X 
Take Daily Medication 
 
X 
 
 
Weekly Home Pulmonary Function Test 
 
X 
 
 
Weekly Self-Symptom Survey 
 
X 
 
 
Bi-Weekly Phone Interview 
 
X 
 
 
 
Pulmonary Function Test and Lung Volumes:   
Pulmonary Function Test: 
To determine how your lungs are working, a lung function test called spirometry will be completed.  
While seated in your wheelchair and after a mouth piece and nose clip are applied, you will be asked to 
breathe normally for 3 to 6 breaths.  You will then be instructed to forcibly inhale until your lungs are 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   3    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
filled.  After a brief pause, you will then be instructed to forcibly exhale the air in your lungs for at least 6 
seconds. After a brief rest, we will repeat this maneuver a minimum of three and maximum of five times 
to ensure that we are obtaining consistent values.    
 
Lung Volumes:  
The total volume of air in your lungs will be assessed using the nitrogen washout technique.  The 
nitrogen washout technique, which takes about five minutes to perform, will begin while you are seated 
in your wheelchair and after a mouth piece and nose-clips have been applied.  You will then be asked 
to breathe room air as you normally do, into and out of the mouthpiece for 3 to 6 breaths.  The air you 
exhale, which normally contains mostly of nitrogen, will be collected and analyzed by a machine called 
a metabolic cart.  Once you have completed the 3 to 6 breaths you will be asked to take a slow deep 
breath in and to exhale until you feel that your lungs are empty, after which you will return to your 
normal breathing pattern.  Following an additional 3 to 6 regular breaths, the metabolic cart will begin 
delivering 100% oxygen through the mouthpiece.  You will continue to inhale 100% oxygen while taking 
normal breaths until oxygen is the only gas measurable in your exhaled air.   
 
Respiratory Muscle Strength Testing:   
You will be asked to swallow a small balloon attached to a tube connected to a computer. The balloon 
will be inserted by a study physician into one nostril after numbing medicine (4% lidocaine) has been 
applied to your nasal passages, throat, and to the balloon tube in order to make swallowing the balloon 
easier.  Then, pressures at the mouth and around the balloon will be measured simultaneously by 
having you blow in and out as strongly as possible through a mouthpiece connected to a recording 
device. You will repeat these maneuvers a maximum of five times. You will then be asked to perform 5 
to 10 cough maneuvers of varying intensities while pressure around the balloon is recorded.   
 
Ultrasound of your Diaphragm:   
Ultrasound will be performed while you are seated in your chair and breathing into a mouthpiece 
connected to a recording device.  The ultrasound device will be placed on the side of your chest, about 
half-way up your ribcage, and you will be asked to inhale and exhale maximally for at least 5 breaths 
during which a continuous recording of ultrasound images will be obtained. 
 
Study Drug or Placebo:   
You will be randomly assigned (as in a coin flip) to receive either a sustained-release (medication 
released for 12 hours) albuterol tablet (4 mg/tablet per oral for the first week (7 days), then 8 mg/tablet 
the remaining 15 weeks, if no drug related adverse events occur during week 1) or an identically 
appearing placebo (non-active) pill.  Regardless of which group you are in, you will be required to take 
one pill two (2) times per day (one in the morning and one at night) for the 16 weeks of the study.  The 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   4    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
study drug/pill will be dispensed to you by the VA Research Pharmacy on your first visit and provided to 
you at no cost. 
 
Weekly Home Pulmonary Function Test:  
You will be provided with a small-automated handheld device which will be used to assess your 
pulmonary function on a weekly basis.  You will perform three maneuvers to assess your expiratory 
muscle strength.  To perform each maneuver, you will inhale until your lungs are filled, pause a moment 
and place the mouthpiece end of the device in your mouth and then forcibly exhale until your lungs are 
empty.  The device will then prompt you to answer a few questions.  The investigative team will provide 
a demonstration for you on how to use the device.  
 
Weekly self-symptom survey:  
You will be provided with a binder which contains a sheet of paper for each of the 12 weeks in the total 
study.  Each sheet of paper will contain a short survey of questions designed to assess respiratory 
symptoms (questions related to how you are breathing).  You will complete one survey per week for 12 
weeks. 
 
Bi-weekly phone interview:  
A member of the investigative team will contact you over the phone on a biweekly basis to speak about 
any symptoms that you may be experiencing or have experienced since a previous discussion.  The 
phone interview will only last a few minutes.  Keep in mind that you are allowed to contact a member of 
the study team at any point should you have a question or emergency. 
 
Pregnancy Test:  
If you are female with child bearing potential you will be asked to complete a pregnancy test to ensure 
that you are not pregnant.  You will have the choice to provide urine sample or a blood sample to 
complete this test.  If you choose to give urine you will be asked to fill a urine sample cup which will be 
used to assess pregnancy. If you choose to give a blood sample, you will have a total of 5 ml (1 
teaspoon) blood drawn from a vein inside your elbow to confirm that you are not pregnant.  If the test 
shows that you are pregnant then you will be withdrawn from the study. 
 
3. 
Description of any Procedures that may Result in Discomfort or Inconvenience 
Respiratory Muscle Strength Testing: 
There will be a slight discomfort or inconvenience associated with measurement of mouth pressures. 
The nasal catheter does not cause discomfort. The swallowing of the stomach balloon tube passed 
through a nostril may result in mild, transient discomfort and may cause gagging, coughing and nose 
and throat irritation.  There is a small chance that the balloon catheter could cause injury to your 
esophagus (swallowing tube) or to the nostril.  A pulmonary doctor will be present during the entire 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   5    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
study and will assist with insertion of the balloon tube. If you are unable to swallow the balloon tube the 
study will be terminated.  
 
Study drug or placebo:   
There will be no discomfort associated with taking the pill.  You may experience the following potential 
side-effects including but not limited to (all are mild and resolve quickly upon drug discontinuation): 
• 
Tremors 
• 
Muscle cramps and/or musculoskeletal pain 
• 
Insomnia 
• 
Nervousness 
• 
Headache 
• 
Tachycardia 
• 
Palpitations 
• 
Nausea and vomiting 
 
Pregnancy Test (Blood Collection):  
You understand that a routine blood sample will be drawn from a vein inside your elbow and this can be 
associated with mild discomfort due to the blood draw. The risks of a blood draw include the possibility 
of a bruise or infection at the site of skin puncture, temporary faintness and rarely, actual fainting (a 
temporary loss of consciousness due to reflex swelling of blood vessels that results in a rapid fall in 
blood pressure).  
 
“Since this research may have unknown effects on an unborn child and should not be done during 
pregnancy, it is necessary for a pregnancy test to be done first.  To your knowledge you are not 
pregnant at the present time. You also agree to avoid becoming pregnant (use contraceptives, take 
precautions against becoming pregnant, etc.) during this study.” 
 
4. 
Expected Risks of Study: 
Respiratory muscle strength testing:  
There may be some discomfort while the stomach balloon is being swallowed. Discomfort will be 
minimized by use of a topical anesthetic agent. Performing maximal mouth pressures does not present 
any serious risks, however you may experience lightheadedness after inhaling and exhaling as strongly 
as possible. 
 
Study drug or placebo:   
You may experience the following potential side-effects including but not limited to (all are mild and 
resolve quickly upon drug discontinuation): 
• 
Tremors 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   6    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
• 
Muscle cramps and/or musculoskeletal pain 
• 
Insomnia 
• 
Nervousness 
• 
Headache 
• 
Tachycardia 
• 
Palpitations 
• 
Nausea and vomiting 
 
Blood Collection:  
The risks of blood draw include the possibility of a bruise or infection at the site of skin puncture, 
temporary faintness and rarely temporary loss of consciousness due to vasomotor instability (i.e., the 
blood vessels reflexively swell resulting in a fall in blood pressure which is commonly called “vasovagal 
episode”). 
 
There also may be risks and discomforts that cannot be foreseen. 
 
5. 
Expected Benefits of the Study: 
There are possible benefits by taking part in this study such as gains in your pulmonary function and 
expiratory muscle strength. There may be no direct benefit to you from this study. But, any information 
we get from this study will help others. 
 
6. 
Other Treatments Available: 
This is a research study; your participation is voluntary.  Should you desire additional treatment options, 
you should contact your primary physician to discuss. 
 
7. 
Use of Research Results: 
We (I) will let you and your physician know of any significant new findings made during this study 
which may affect your willingness to participate in this study. All research material generated from this 
study will remain in the possession of Gregory Schilero, MD and his study team at the JJP VAMC. 
 
Your research records will be maintained according to the requirements of the JJP VAMC as follows: 
Data Collection, Storage, and Transfer:  
• 
Your coded electronic data will be collected on VA computers that are not connected to the 
internet.  
• 
Your coded electronic data without your name, or other identifying information, will be stored on 
secured networks, behind electronic security systems, in access-restricted folders. 
• 
Hard copies of your data will be stored in a locked file cabinet behind 2 locked doors. 
 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   7    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
Access to the research materials generated from the study will be restricted to Gregory Schilero, MD 
and his study team. Your medical records will be maintained according to this medical center’s 
requirements and all research investigator files will be destroyed six years after the end of the fiscal 
year when the research project has been completed per Records Schedule DAA-0015-2015-004-
0032, Section 7.6 Research Investigator Files. If results of this study are reported in medical journals 
or at meetings, you will not be identified by name, by recognizable photograph, or by any other 
means without your specific consent.  No information by which you can be identified will be released 
or published unless required by law. In order to comply with federal regulations, research records 
identifying you may be reviewed by the following: 
Authorized representatives of the JJPVAMC (e.g. Institutional Review Board, Research 
Compliance Officer) and VA, including the Office of Research Oversight (ORO), Federal Agencies 
such as the Government Accounting Office (GAO), VA Office of Inspector General (OIG), and 
Office for Human Research Protections (OHRP) may have access to your research records. If this 
research involves articles regulated by the FDA, the FDA may choose to inspect and copy 
research records that identify individual research subjects. 
 
Clinical Trials:  
Because this research involves articles regulated by the FDA, the FDA may choose to inspect and 
copy medical or research records that identify individual research subjects. A description of this 
clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This website 
will not include a summary of the results. You can search this website at any time. 
 
8. 
Special Circumstances: 
If you are a patient, a copy of this consent form will be placed in your medical record. 
 
9. 
Compensation and/or Treatment in the Event of Injury: 
The VA must provide necessary medical treatment to a research subject injured by participation in a 
research project approved by a VA R&D Committee and conducted under the supervision of one or 
more VA employees.  Further information about compensation and medical treatment may be obtained 
from the medical administration service at this VA medical center. 
 
10.  Voluntary Participation: 
You are not required to take part in this study; your participation is entirely voluntary you can refuse to 
participate in this study or withdraw your participation in this study after you consent without penalty or 
loss of VA or other benefits to which you are entitled. 
 
 
 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   8    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
11. Termination of Participation: 
You are not required to take part in this study; your participation is entirely voluntary you can refuse to 
participate in this study or withdraw your participation in this study after you consent without penalty or 
loss of VA or other benefits to which you are entitled.  You may be withdrawn from participation by the 
investigative team without your consent if you are unable to complete the study requirements in a timely 
manner, or if the investigators have reasonable cause. 
 
12. Costs and Reimbursements: 
As a veteran or non- veteran, you will not be charged for any treatments or procedures that are part of 
this study. For veterans who are required to pay co-payments for medical care and services provided 
by VA, these co-payments will continue to apply for medical care and services provided by VA that are 
not part of this study. You will receive $300 for completing the 16 week study and an additional $75 
dollars for the third and final visit at week 18. For completing the study in its entirety you will receive a 
total $375. Payment will be in the form of an electronic deposit check approximately 6-8 weeks 
following study completion due to the administrative processing time. 
 
13.  Contact Person(s): 
To obtain answers to questions about the research, report or seek treatment for a research-related 
injury, or to voice concerns or complaints about the research contact Gregory Schilero, M.D. at the 
following: 
• 
During the Day: Gregory Schilero, MD 718-584-9000, ext. 6701 
• 
After Hours: Gregory Schilero, MD, cell (914-374-0811) 
 
To voice concerns or complaints about the research from someone outside of the research team, 
contact the following: I understand that should I wish to discuss my participation in this study with any 
other doctor or layperson, I can contact Mary Sano, Ph.D. ACOS-R&D Program by requesting an 
appointment at (718) 741-4228 hospital extension 4228, first floor in the research building, room 1F-01 
If I have questions, concerns and/or complaints concerning the research study, I can ask one of the 
researchers listed above or contact Dr. Sano.  Medical problems during the course of the study should 
be addressed to the investigator at the phone listed above. If I have problems, concerns, and questions 
about the research and research subject’s rights, I can contact Dr. Sano, who is not affiliated with this 
research study, to obtain information or to offer input. 
 
RESEARCH SUBJECTS' RIGHTS: I have read or have had read to me all of the above.  
Dr. Schilero or his delegate has explained the study to me and answered all of my questions. I have 
been told of the risks or discomforts and possible benefits of the study. I have been told of other 
choices of treatment available to me. 
 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   9    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
I understand that I do not have to take part in this study, and my refusal to participate will 
involve no penalty or loss of rights to which I am entitled. I may withdraw from this study at any 
time without penalty or loss of VA or other benefits to which I am entitled. 
 
The results of this study may be published, but my records will not be revealed unless required by law. 
This study has been explained to me. I have had a chance to ask questions. I voluntarily consent to 
participate in this study.  I will receive a signed copy of this consent form. 
 
 
 
 
Subject Signature 
 
Date 
 
Time 
 
 
 
 
 
 
Person Obtaining Informed Consent  
(Print Name)  
(Investigator or Delegate as indicated on 
Assurance Page) 
 
Signature of Person 
Obtaining Informed  
Consent 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
VA RESEARCH CONSENT FORM 
 
      
 
Version Date: May 2016  
Page:   10    of  10 
Subject Name:  
Informed Consent Date:  
Principal Investigator: Gregory Schilero, MD 
VAMC:  James J Peters 
Title of Study: The Effects of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI 
 
SCH-15-011 Amend V.4   5-10-2016 
VA   Department of Veterans 
Affairs 
 
VERBAL CONSENT IF THE PARTICIPANT LACKS UPPER LIMB FUNCTION TO 
COMFORTABLY WRITE 
 
________________________________ is unable to sign the consent form due to impaired 
arm function. I certify that I have carefully explained the purpose and nature of this research to 
him/her in appropriate language and he/she has had an opportunity to discuss it with me in 
detail. I have answered all of his/her questions and he/she has consented to participate in this 
research. I, therefore, am signing the consent form to document that he/she has given his/her 
consent to participate in this research study. 
 
Person Obtaining Consent: 
 
Name: ________________________________ 
 
Signature: ______________________________ 
 
Date: ________________________ 
 
 
Witness Name: __________________________ 
 
Signature: ______________________________ 
 
Date: ______________________