Clinical trial NCT02597478
Conditions: Advanced Cancers
Keywords: Advanced Cancers Fentanyl Sublingual Spray Fentanyl SL Spray FSS Questionnaires Surveys Mental Abilities Test Phone Call Shuttle Walk Test
Sponsor: M.D. Anderson Cancer Center
Start date: 2016-01-04; Completion date: 2021-01-27
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if fentanyl can help shortness of breath in cancer patients. Researchers also want to learn if the study drug can help to improve your physical function.

Detailed description:
If you agree to take part in this study, the study staff will collect information from your medical record about your age, sex, race, and disease type, as well as how well you are able to perform the normal activities of daily living, any drugs you are taking, and any possible causes of shortness of breath.

Study Groups:

You will be randomly assigned (as in the flip of a coin) to receive either low-dose or high-dose fentanyl spray. This is done because no one knows if one study group is better, the same, or worse than the other group.

Study Visit:

During your study visit, you will complete 2 questionnaires about any breathing problems or other symptoms you may be having. It should take about 10 minutes total to complete these questionnaires.

You will blow into a device called a spirometer a few times to measure your lung function. You will also be asked to inhale into another device called a negative inspiratory force meter (NIF). This device measures the volume of air that can be inhaled after normal breathing.

The study staff will then record your vital signs (heart rate, breathing rate, blood pressure, and your blood-oxygen level). Your blood-oxygen level will be measured with a device that will be clipped gently onto your fingertip). You will then be asked how hard it is to catch your breath and to rate your level of tiredness.

When instructed, you will walk back and forth between 2 cones in an indoor hallway for up to 12 minutes. This is called the Shuttle Walk Test. The purpose of this timed test is to see how far and fast you can walk without stopping for a rest. You will be asked to pivot briskly around the cones and continue back the other way. You may stop this test at any time if you feel you cannot continue.

After that, you will sit down and rest for up to 1 hour. During this time, the study drug will be prepared, and you may be asked at different times how hard it is to catch your breath.

After the rest period, you will be given the fentanyl to spray into your mouth and under your tongue. About 10 minutes later, you will be asked about any side effects you may be having.

At that point, you will perform a second Shuttle Walk Test. Then the study staff will ask you again about any side effects you may be having, your level of tiredness, and how hard it is to catch your breath. Your vital signs will also be measured. The total distance you walked will also be recorded.

After each walk test, you will also be asked to complete 4 tests of your mental abilities, including finger tapping, simple math questions (addition, subtraction, multiplication, division), recall of numbers, and recall of objects. It should take 15 minutes total to complete these tests.

At the end of the study visit, you will be asked which dose level of the study drug you think you received (high-dose or low-dose). You will also complete a questionnaire about how the study drug may have helped you and how satisfied you are with the study. It should take about 5 minutes to complete the questionnaire.

At the end of the study, if you think that taking fentanyl helped to improve your breathing, your doctor will be told, so that you and your doctor may discuss if fentanyl would be helpful to you in the future.

Length of Study:

Your active participation in this study is over after you complete the last questionnaire. You will be taken off study if intolerable side effects occur or if you are unable to follow study directions.

Follow-Up:

Fourteen (14) days after your study visit you will be called by the study staff and asked how you are feeling and about any side effects you may be having. This call should last about 10 minutes.

This is an investigational study. Fentanyl is FDA approved and commercially available for the treatment of pain. Its use to control shortness of breath is investigational.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Questionnaires completed at baseline and at end of study visit. Participant performs Shuttle Walk Test before and after receiving low-dose Fentanyl sublingual spray. Four mental ability tests completed after each walk test. Low-dose Fentanyl sprayed into mouth and under tongue one hour after first Shuttle Walk Test. arm 2: Questionnaires completed at baseline and at end of study visit. Participant performs Shuttle Walk Test before and after receiving high-dose Fentanyl sublingual spray. Four mental ability tests completed after each walk test. High-dose Fentanyl sprayed into mouth and under tongue one hour after first Shuttle Walk Test.
Interventions: intervention 1: Fentanyl Sublingual Spray intervention 2: Shuttle Walk Test intervention 3: Questionnaires intervention 4: Mental Ability Tests intervention 5: Phone Call
Intervention descriptions: intervention 1: Low-dose Fentanyl Goup: 15-25% of the morphine equivalent daily dose (MEDD) sprayed into mouth and under tongue one hour after first Shuttle Walk Test.

High-Dose Fentanyl Group: 35-45% of the morphine equivalent daily dose (MEDD) sprayed into mouth and under tongue one hour after first Shuttle Walk Test. intervention 2: Participants walk back and forth between 2 cones in an indoor hallway for up to 12 minutes. After one hour Fentanyl Spray delivered, then second walk test performed. intervention 3: Questionnaire completed about any breathing problems or other symptoms participant may be having at baseline. End of study questionnaire asks which dose level of study drug participant thinks they received. Participant also completes a questionnaire about how study drug may have helped them and how satisfied they are with the study. It should take about 5 minutes to complete the questionnaire. intervention 4: After each walk test, participant completes 4 tests of their mental abilities. It should take 15 minutes total to complete these tests. intervention 5: Thirty days study visit participant called by study staff. This call should last about 10 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
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A Preliminary Study of Prophylactic Fentanyl Sublingual Spray (FSS) for 
Exercise-Induced Breakthrough Dyspnea
Principal investigator: Dr. David Hui
Supportive Care Co-investigator: Dr. Eduardo Bruera
Collaborators: Dr. Larry Driver, Ms. Diane Liu
Table of Contents
A. Study Objectives...............................................................................................2
B. Background.......................................................................................................2
C. Experimental Approach ....................................................................................2
D. Statistical Analysis..........................................................................................12
E. Data Confidentiality Procedures......................................................................13
F. References......................................................................................................14


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A. Study Objectives
Primary objective:
To determine the effect of prophylactic fentanyl sublingual spray (FSS, 15-25% and 
35-45% proportional doses) on the intensity of exercise-induced dyspnea (modified 
Borg scale) between the first and second shuttle walk tests. We aim to estimate the 
effect size for both FSS arms to inform a larger, adequately powered confirmatory 
randomized controlled trial.
Secondary objectives
A.2. To determine the effect of prophylactic FSS (15-25% and 35-45% proportional 
doses) on walk distance and adverse effects between the first and second shuttle 
walk tests. We hypothesize that FSS is superior to no FSS in increasing walk distance 
and has limited side effects in opioid tolerant individuals.
A.3. To compare the intensity of exercise-induced breakthrough dyspnea between 
high (35-45% proportional dose) and low (15-25% proportional dose) doses of 
prophylactic FSS.  We hypothesize that higher doses of FSS is superior to lower doses 
FSS in reducing dyspnea at the end of the shuttle walk test.
B. Background
Dyspnea is a subjective awareness of difficulty breathing, which may be associated 
with the distressing sensation of suffocation. It is one of the most common and most 
feared symptoms among cancer patients, occurring in up to 70% of patients in the last 6 
weeks of life 1,2. Dyspnea is associated with fatigue, anxiety, decreased function and 
quality of life, and increased mortality 3,4.
In a study examining 70 patients with dyspnea, 43 (61%) reported breakthrough 
(episodic or incidental) dyspnea only, 13 (19%) had constant dyspnea only, and 14 
(20%) experienced both constant and breakthrough dyspnea.  A substantial proportion 
of the patients with breakthrough dyspnea (18/57, 32%) presented with 5 or more 
episodes per day, and the majority of episodes lasted <10 minutes 5. Breakthrough 
dyspnea is particularly challenging to treat because of its transient and episodic nature.
Exercise-induced dyspnea (or shortness of breath on exertion) is a subtype of 
breakthrough dyspnea. Breakthrough dyspnea has 4 major triggers: exertion, emotional 
changes, the environment (e.g. altitude, smog), and spontaneous/idiopathic. Because 
many cancer patients experience severe shortness of breath with activities (i.e. 
walking), they have to limit their function significantly. In a recent study conducted by 
our group, we found that a vast majority of patients (81%) had breakthrough dyspnea. 
Specifically, dyspnea affects patients’ general activity, walking ability, normal work, 
sleep, mood, relations with others and enjoyment of life 5.
The current management of dyspnea involves treatment of any reversible causes and 
supportive measures to minimize the sensation of dyspnea, such as oxygen, opioids, 
bronchodilators, and corticosteroids 1,6,7. A majority of the studies on cancer-related 
dyspnea so far focused on patients with dyspnea at rest. In a cross-over randomized 
controlled trial, Bruera et al. compared subcutaneous morphine and placebo in 10 


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patients with advanced cancer who had dyspnea at rest.  Subcutaneous morphine was 
found to be superior to placebo for relief of dyspnea 8.  This finding was replicated by 
Mazzocato et al. in another randomized controlled trial with similar design 9.  A 
Cochrane meta-analysis also showed a statistically significant positive effect of opioids 
on the sensation of breathlessness (p=0.0008), supporting the use of oral or parenteral 
opioids for treatment of dyspnea in patients with advanced disease 7,10. Several other 
systematic reviews have confirmed this finding 1,11.
Treatment options for breakthrough dyspnea. Although systemic opioids are 
established for management of dyspnea at rest, there are currently no definitive 
evidence-based options for breakthrough dyspnea. In a case series, Bruera et al. 
reported the use of rescue morphine given subcutaneously for 312 episodes of 
breakthrough dyspnea in 45 cancer patients.  After 30 minutes, 90% reported no to mild 
dyspnea 8. Based on this study, most clinicians use a dose similar to the rescue opioid 
dose for breakthrough pain (i.e. 10-20% of total daily dose) to manage breakthrough 
dyspnea. However, a more recent double-blind randomized controlled trial comparing 
systemic hydromorphone
(oral or subcutaneous (SC)), nebulized fentanyl, and 
nebulized saline for breakthrough dyspnea found no significant difference in dyspnea 
relief at 10 minutes between the treatment arms 12.  One of the reasons may be due to 
the short duration for the primary endpoint (10 minutes) and the fact that the 
investigators used mostly oral hydromorphone, which reaches peak concentration only 
45-60 minutes later. We recently completed a preliminary study examining the role of 
subcutaneous fentanyl for breakthrough dyspnea, and found a significant improvement 
in both dyspnea scores and walk distance before and after the study 13. To date, the 
evidence for opioid use for breakthrough dyspnea in cancer patients remains limited 
(Table 1). A recent review on the role of opioids in breakthrough dyspnea supported a 
promising therapeutic effect in cancer and non-cancer settings 14. Further research is 
necessary to improve the management of this distressing and debilitating symptom.
Table 1. Studies of Opioids for Breakthrough Dyspnea in Cancer Patients
Study
Methodology and  
patients
Agent and dose
Outcome
Bruera et al. 
Ann Intern Med 
1993 8
Prospective case 
series (45 cancer 
pts)
SC morphine
312 doses given 
(same dose as pain 
breakthrough)
After 30 minutes, 90% 
reported no-mild dyspnea; 
5% mod-severe dyspnea
Benitez-
Rosario et al. 
JPSM 2005 15
Retrospective case 
series (4 cancer pts)
OTFC 
800mg/1200mcg
60mg/800mcg
120mg/600mcg
15mg/400mcg
RR decreased
Dyspnea decreased by 90-
100% in 20-60 minutes
Sitte et al. 
JPSM 2008 16
Retrospective case 
series (1 cancer pt, 2 
heart failure pts)
Intranasal fentanyl
1/6 of MEDD
RR decreased, improved O2
saturation in all 3 patients
Dyspnea scores not reported
Gauna et al. 
JPM 2008 17
Prospective case 
series (2 COPD pts, 
2 cancer pts) 10 
episodes
OTFC 
30mg/200mcg
720mg/400mcg
20mg/200mcg
RR decreased
Dyspnea decreased by 90-
100% in 20-60 minutes


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24mg/200mcg
Charles et al. 
JPSM 2008 12
Prospective, double 
blind crossover RCT 
(20 cancer pts)
Systemic (mostly 
oral) hydromorphone
Nebulized 
hydromorphone
Nebulized saline
Dyspnea decreased similarly 
in all 3 arms (1.0, 0.9, 0.8)
Hui et al. JPSM 
2014 13
Prospective, double 
blind crossover RCT 
(20 cancer pts)
Subcutaneous 
fentanyl Nebulized 
hydromorphone
Nebulized saline
Dyspnea and walk distance 
significantly improved in the 
fentanyl arm
Abbreviations: 
RR=respiratory 
rate, 
OTFC=oral 
transmucosal 
fentanyl 
citrate,
SC=subcutaneous
The role of rapid onset opioids. The episodic and transient nature of breakthrough 
dyspnea makes fast onset opioids an attractive option. Administration of opioids 
intravenously or subcutaneously can allow rapid delivery of the drug, although many 
patients do not have access to these routes at home. Fentanyl is a highly lipophilic 
compound.  Over the past decade, there has been active development of fentanyl, 
including delivery by the transmucosal (oral transmucosal fentanyl citrate [OTFC], 
Actiq), buccal (Fentora), intranasal (Lazanda, Instanyl) and sublingual (Subsys, Abstral) 
formulations 18-20 These fentanyl formulations have been successfully used to manage 
breakthrough pain 21-28, although their role in breakthrough dyspnea has only been 
reported in a handful of studies.   Two small retrospective case series reported on the 
use of transmucosal and intranasal fentanyl 15,16 and one prospective series examined 
the use of OTFC 17 suggest significant improvement in breakthrough dyspnea with 
these agents. Randomized controlled trials are urgently needed to confirm these 
findings with rapid onset opioids, which could potentially open up a new therapeutic 
indication for these medications.
Fentanyl sublingual spray (FSS) is a particularly attractive option for breakthrough 
dyspnea. It was approved by the US Food and Drugs Administration in 2012 for “the 
management of breakthrough pain in adult cancer patients who are already receiving 
and who are tolerant to around-the-clock opioid therapy for their underlying persistent 
cancer pain”, and represents an alternative delivery system for fentanyl that also utilizes 
a transmucosal route like OTFC. A pharmacokinetic study examining 5 different doses 
of FSS (100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg) in healthy volunteers 
demonstrated that fentanyl enters the systemic circulation rapidly, achieving 27%, 61%, 
87% and close to 100% of maximal plasma concentration (Cmax) within 5, 10, 20 and 
30 minutes, respectively 29. In a separate crossover study comparing FSS 400 mcg, 
OTFC 400 mcg and intravenous fentanyl 100 mcg in healthy volunteers, FSS had a 
greater bioavailability (76% vs. 51%) and achieved a higher Cmax than OTFC (0.81 
mg/ml vs. 0.61 ng/ml). Similar to the previous study, the mean plasma concentrations 
were 19% and 54% of Cmax within 5 and 10 minutes 30.  In a double-blind, randomized 
placebo controlled trial, FSS provided greater and more rapid pain relief, and 
significantly reduces pain compared to placebo at 5, 30 and 60 minutes 28. The most 
common adverse effects included nausea (7%), hyperhidrosis (5%) and peripheral 
edema (5%).


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Significance. We expect to advance the understanding of how FSS can be used to 
treat exertional dyspnea in cancer patients. The effective management of dyspnea may 
ultimately help alleviate this devastating symptom. A better fundamental understanding 
of how this intervention improves physiologic parameters could also shed light on the 
pathophysiologic characteristics of dyspnea and allow us to devise new and more 
effective treatments.
This contribution will be significant because it 
represents a key step in a continuum of 
research that is expected to lead to the 
optimization of FSS to relieve exertional 
dyspnea in cancer patients and to improve 
their
function and quality of life. If the 
preliminary results from this randomized trial
demonstrate a significant effect with FSS, the 
next step will be to conduct a larger, multi-
institutional randomized controlled trial that is 
adequately powered. Further confirmation of 
FSS’s efficacy would pave the way for using 
this medication for a novel indication. The 
proposed study has the potential to greatly 
improve patients’ symptom burden, function 
and quality of life, and shift the paradigm for 
symptom research.
C. Experimental Approach
C.1. Overall Study design. This is an 
investigator-initiated 
study 
supported 
by 
Insys Therapeutics Ltd. We propose a 2-arm, 
double-blind, parallel randomized controlled 
trial of FSS
for cancer patients with 
breakthrough dyspnea (Figure 1).  The main 
goal of this study is to determine the effect size of FSS on dyspnea (at two different 
doses) to inform a larger, adequately powered confirmatory randomized controlled trial.  
After study consent, eligible patients will be asked to complete a number of surveys and 
a shuttle walk test at baseline, rest until they return to baseline dyspnea, and then do 
another shuttle walk test after they have been given FSS prophylactically.
Based on our experience conducting symptom control trials, this study will take each 
patient approximately 2 hours to complete in a single visit.  We believe this study design 
is feasible and would not add undue burden for patients. Patients will be compensated 
with a $50 gift card and a $15 parking voucher for their time and effort after they have 
completed the study assessments.
C.2. Eligibility Criteria. The eligibility criteria are shown in Table 2.


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* To minimize study burden for participation in this 2-hour study, extra bloodwork will not 
be drawn unless the patient already has the above lab abnormalities documented and 
need to be corrected. 
C.3. Study screening. A 2 step consent process will be used.  First, a verbal consent 
will be obtained by the study staff to proceed with screening of potential participants for 
eligibility and to characterize their dyspnea using the dyspnea survey and the cancer 
dyspnea scale. Outpatients may be contacted by phone within 1 week prior to their 
scheduled clinic visit to inform them of this study so they can make necessary 
arrangements if interested in participating. Eligible patients will then be formally enrolled 
onto the study after they have signed the informed consent indicating a willingness to 
participate in the trial.  The number of patients screened, approached, eligible, and
enrolled will be documented.  Reasons for refusal for eligible patients will also be 
captured.
C.4. Randomization. Patient randomization will be conducted through the Clinical Trial 
Conduct
(CTC)
website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct), 
which is maintained by the Department of Biostatistics at MD Anderson Cancer Center. 
The trial statistician will train the users (pharmacists or research nurses) in the use of 
this website for randomizing patients. The methodology to replace a patient who does 
Table 2. Study Eligibility Criteria
Inclusion Criteria
1.
Diagnosis of cancer with evidence of active disease
2.
Breakthrough dyspnea, defined as dyspnea with an average intensity level  over the past 7 
days of at least 3/10 on a  numeric rating scale upon significant exertion or continuous 
dyspnea </=7/10 with worsening upon significant exertion
3.
Outpatient at MD Anderson Cancer Center seen by the Supportive Care Service, Thoracic 
Medical Oncology, Cancer Pain Clinic, or Cardiopulmonary clinic
4.
Ambulatory and able to walk with or without walking aid 
5.
On strong opioids with morphine equivalent daily dose of 80-500 mg  for at least one week, 
with stable (i.e. +/- 30%) regular dose over the last 24 hours
6.
Karnofsky performance status >/=50%
7.
Age 18 or older 
8.
Able to complete study assessments
Exclusion Criteria
1.
Dyspnea at rest >/=7/10 at the time of enrollment
2.
Supplemental oxygen requirement >6 L per minute
3.
Delirium (i.e. Memorial delirium rating scale >13)
4.
History of unstable angina or myocardial infarction 1 month prior to study enrollment
5. Resting heart rate >120 at the time of study enrollment
6. Systolic pressure >180 mmHg or diastolic pressure >100 mmHg at the time of study 
enrollment
7.
History of active opioid abuse within the past 12 months
8.
History of allergy to fentanyl
9.
Severe anemia (Hb <7g/L) if documented in the last month and not corrected prior to study 
enrollment*
10. Diagnosis of acute pulmonary embolism within past 2 weeks
11. Diagnosis of pulmonary hypertension
12. Unwilling to provide informed consent


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not take the study medication is as follows:  In CTC, edit the patient to be replaced 
modifying MRN within the specific patient’s stratum.  Then add a history of the changes 
made to the Notes section. Randomization will be 1:1 between the two study arms with 
permuted blocks, and stratified by baseline level of dyspnea modified Borg scale at rest 
at the time of enrollment (i.e. 0-3, 4-6).
C.5. Blinding. Both the patient and the research staff conducting the assessment will 
be blinded to the treatment assignment.  FSS will be dispensed by Dispensing 
Pharmacy at MD Anderson.  Only research nurse administering the medication will be 
aware of the study dose, and will be instructed not to share that information with the 
patient and other research staff.  Further to that, we will check the blinding from patients 
and study staff at the end of study. 
C.6. Research staff. An orientation will be held with research staff involved in this study 
to introduce them with the study design and to standardize the provision of each 
intervention.
C.7. Study Interventions. The commercial supply of study medication will be provided 
by Insys Therapeutics Ltd.  We will use a one time prophylactic FSS dose equivalent to
either 15-25% or 35-45% of MEDD 10 minutes prior to the second shuttle walk test.  
FSS was FDA approved in 2012 for “For the management of breakthrough pain in adult
cancer patients who are already receiving and who are tolerant to around-the-clock 
opioid therapy for their underlying persistent cancer pain.”  
Immediately upon patient enrollment, the study physician will be notified and will 
determine the morphine equivalent daily dose (MEDD) in real time using standardized 
equianalgesic ratios.  Based on clinical practice and similarly to the dose used for 
breakthrough pain, we will use an FSS dose equivalent to 15-25% or 35-45% of MEDD 
(Table 3).  The study medication will be provided by Dispensing Pharmacy and will then 
be administered 10 minutes before the second shuttle walk test.  We estimated the FSS
dose based on the following assumptions: 
A one time rescue dose 15-45% of the MEDD is safe and effective for relief of 
dyspnea
FSS has approximately 70% oral bioavailability 30
Table 3. Proportional Dosing of FSS for patients randomized to the two study 
arms
High dose (target 35-45% MEDD)
Low dose (target 15-25% MEDD)
MEDD 
(mg/day)
FSS 
dose*
% of 
MEDD -
low
% of 
MEDD -
high
MEDD 
(mg/day)
FSS 
dose*
% of 
MEDD -
low
% of 
MEDD -
high
80-100
200
35.0
43.2
80-130
100
13.5
21.6
101-150
300
35.0
52.0
131-210
200
16.7
26.7
151-200
400
35.0
46.4
211-280
300
18.8
24.9
201-250
500
35.0
43.5
281-450
400
15.6
24.9
251-300
600
35.0
41.8
451-500
600
21.0
23.3
301-400
800
35.0
46.5


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401-500
1000
35.0
43.6
* FSS comes in 100 mcg, 200 mcg, 400 mcg, 600 mcg and 800 mcg.  A combination of 
these products would allow us to deliver the desired dose.
The following instructions will be given to the patient:
1. Swallow any saliva in your mouth.
2. Hold the medication spray unit upright using your index and middle fingers and 
thumb.
3. Point the nozzle into your mouth and under your tongue. 
4. Squeeze your fingers and thumb together to spray the medication under your 
tongue.
5. Hold the medicine under your tongue for 30-60 seconds. Do not spit out any 
medicine. Do not rinse your mouth.
6. The spray unit will remain locked after use.
C.8. Medication use during study. To minimize the co-intervention effect on dyspnea, 
patients will be advised to avoid using breakthrough opioids (for any reason) or 
bronchodilators for at least 2 hours prior to and during the study.
C.9. The Shuttle walk test is an externally paced test, and has been found to be high 
reproducible for inducing breathlessness in patients with advanced cancer
31-33.
Furthermore, the shuttle walk test was reported to be equivalent or better than 6 minute 
walk test in detecting a clinical response 34-36.
Shuttle walk tests will be conducted 
according to published procedures 31-33. The first shuttle walk test is designed to provide 
important information regarding a patient’s level of dyspnea on exertion, and to facilitate 
intra-individual comparison since there is significant variability in the expression of 
dyspnea among patients. The second shuttle walk test will be conducted 10 minutes 
after study medication has been administered.
The research staff conducting the walk test must be certified in cardiopulmonary 
resuscitation with a minimum of Basic Life Support by an American Health Association–
approved cardiopulmonary resuscitation course. Walking aid is allowed as long as 
patients keep them the same as before enrollment and during the entire study.
The shuttle walking test requires the patient to walk up and down a 10 m course. The 
course will be identified by two cones inset 0.5 m from either end to avoid the need for 
abrupt changes in direction. The speed at which the patient walks will be dictated by an 
audio signal played on a tape cassette. The start of the test will be indicated by a triple 
bleep. Thereafter the tape will emit a single bleep at regular intervals, at which point the 
subject will attempt to be at the opposite end of the course-that is, by the time the 
patient heard the signal he should be turning round the cone to proceed back down the 
course. After a minute on the same level, the subject will proceed to the next level with 
the speed of walking increased by 0.167 m/s (or 10 m/min). A change of speed to the 
next level will be indicated by a triple bleep from the tape recorder (Table 4).
To help the patient to establish the routine of the test and the first, very slow, speed of 
walking, the operator will walk alongside for the first minute. The patient will have 20


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seconds to complete each of the three shuttles in the first minute. After this first minute 
patients will pace themselves to coordinate their walking speed with the timed signals. 
When patients reached the cone before the signal, they will be instructed to remain until 
the signal indicated that they could proceed with the test. 
Table 4. Shuttle walk test levels
Level
Speed 
(m/s)
Time required 
for 10 m course 
(s)
Number of 
shuttles 
per level
Total time in
each level
(s)
Cumulative
distance 
walked (m)
1
0.500
20
3
60
30
2
0.667
15
4
60
70
3
0.833
12
5
60
120
4
1.000
10
6
60
180
5
1.167
8.57
7
60
250
6
1.333
7.5
8
60
330
7
1.500
6.67
9
60
420
8
1.667
6
10
60
520
9
1.833
5.45
11
60
630
10
2.000
5
12
60
750
11
2.167
4.62
13
60
880
12
2.333
4.29
14
60
1020
The explanation to the patient will be standardized (see appendix). Patients in previous 
studies found it easy to pace themselves and no difficulties were encountered in 
administering the test.
The end of the test will be determined by either (a) the patient, when he or she was too 
breathless to maintain the required speed or (b) the operator, if the patient failed to 
complete a shuttle in the time allowed (that is, was more than 0.5 m away from the cone 
when the bleep sounded).
We will be assessing the dyspnea level with modified Borg scale at baseline and then 
every minute during at the shuttle walk test as well as at the end.  We will also measure 
the heart rate, respiratory rate, blood pressure, oxygen saturation before and immediate 
after the shuttle walk test.  The total walking time and distance will also be measured. 
We will also ask the reasons for stopping or being unable to keep up with the required 
pace using a standardized statement and question: “You had to stop, what was it that 
made you stop the test?” The patients’ comments were recorded verbatim. 
C.10. Variable rest period. After the first and second shuttle walk test, patients will be
asked to sit down and rest.  How long they rest would depend on when they return to 
baseline level of dyspnea + 1 or below (e.g. if baseline dyspnea = 4, they need to return 
to a level of 5 or less to qualify for next stage) and baseline level of fatigue +1 or below.
During this rest period, patients will be assessed every 5 minutes to check their 
dyspnea and fatigue level.  If their dyspnea/fatigue level met criteria and they feel ready 


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to walk again, they will be given the study treatment and asked to wait for 10 minutes 
before they do the second walk.
C.11. Stopping rules. In the unexpected situation in which patients do not develop any 
increase from their baseline dyspnea after the first shuttle walk will not proceed to the 
next stage because of the lack of exercise-induced dyspnea.  If at any time during the 
study patients develop chest pain, severe leg cramps, staggering, diaphoresis, and/or 
dizziness, they will be asked to stop the study. If patients require more than 1 hour of 
rest and their dyspnea and fatigue level still has not returned to baseline, they will also 
be taken off study. Patient dropouts and walk test failures prior to the administration of 
drug will be replaced.
C.12. Study assessments.  See Table 5 for a detailed description of all study 
assessments.  
Table 5. Summary of Study Assessments
Assessments
Baseline
After 1st
shuttle
walk test
Rest 
Period
Before 2nd
shuttle
walk test
After 2nd
shuttle
walk test
Demographics and cancer diagnosis1
Medication history2
Karnofsky performance status, spirometry 
testing, and inspiratory pressure3
Edmonton Symptom Assessment Scale4
Dyspnea Survey5
Cancer Dyspnea Scale6
O2 saturation and respiratory rate
Dyspnea Borg/fatigue scale8
Dyspnea Numeric Rating Scale7
Walking test parameters9
Adverse effects10
Neurocognitive testing11
Global assessment, study satisfaction and 
blinding12
1 patient initials, medical record number, date of birth, sex, race, education, marital status, 
cancer diagnosis, co-morbidities, cause(s) of dyspnea, bedside spirometry and maximal 
inspiratory pressure.
2 medications that could be used to treat dyspnea, including scheduled and as needed opioids, 
bronchodilators, and steroids will be documented.
3 an 11-point assessment scale that rates patients’ functional status between 0% (death) and 
100% (completely asymptomatic) based on their ambulation, activity level, and disease 
severity 37.
4 validated questionnaire that measures 10 common symptoms in the past 4 hours (pain, 
fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and 
feeling of well being) using numeric rating scales 38.
5 characterization of patients dyspnea including the following: presence of dyspnea at rest, 
average dyspnea in last 24 hours, worse dyspnea in last 24 hours, best dyspnea in last 24 
hours, number of episodes of exacerbation per day, triggers of breakthrough dyspnea, average 
duration of each episode, current treatment for breakthrough dyspnea.
6 validated 12-item questionnaire specifically designed to assess the quality of dyspnea in 


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cancer patients during the past few days 39. Each item has a score between 1 and 5, for a 
maximum of 60. There are sub-scores for sense of effort, anxiety, and discomfort. 
7 a 0 to 10 categorical scale for rating the severity of dyspnea. It is a ratio scale with descriptive 
anchors throughout the range in which a rating of 8 signifies breathlessness twice as severe as 
4, which in turn is twice as severe as 2 40-43.  We will be measuring it every minute during the 
shuttle walk test starting from 0 minutes until the end of walk.  This will be the primary endpoint 
because it has good reliability and validity for assessing dyspnea 40,41,44 and has been used in 
multiple other studies on exertional dyspnea 45-48. The minimal clinically important difference is 
1.0 in patients with chronic obstructive pulmonary disease 49.  This scale can be administered 
quickly, and was found to be easy to use by patients 41. In a study that compared the dyspnea 
modified Borg Scale, numeric rating scale and visual analog scale, the modified Borg scale 
was preferred by participants and was recommended as the best tool to quantify dyspnea 
intensity 50. Furthermore, its use is recommended by the American Thoracic Society and 
American College of Chest Physicians for Cardiopulmonary Exercise Testing 51.
8 a 0 (no dyspnea) to 10 (worst dyspnea) categorical scale validated for rating the severity of 
dyspnea 40,42,43. The intensity and unpleasantness of dyspnea will be measured using the Borg 
scale 10 minutes prior to the shuttle walk test, every minute during the shuttle walk test 
until the end of the walk, and immediately after each shuttle walk test
9 include the total distance walked, total walking time, the distance and time of first rest due to 
dyspnea, average walking speed.
10 adverse effects related to the use of FSS, such as dizziness, drowsiness and nausea will be 
assessed using a numeric rating scale from 0-10.
11 patients will be asked to do a finger tapping test, simple math test, reverse memory of digits, 
and visual memory).  This has been used in other studies by our group.52
12 patients will be asked about their dyspnea (worse, about the same, or better) comparing 
between the level of dyspnea between the first and second shuttle walk tests 53,54.  Study 
satisfaction will be assessed with the following questions, “Was it worthwhile for you to 
participate in this research study?”, “If you had to do it over, would you participate in this 
research study again?”, “Would you recommend participating in this research study to 
others?”, “Did you quality of life get better by participating in this research study?”, and “Did 
your quality of life get worse by participating in this research study?”  Blinding will be assessed
by asking patients and study staff which group assignment they believe they received: “high 
dose”, “low dose”, or “do not know”.
C.13. Feasibility data. In addition to clinical outcomes, we will also collect feasibility
data in this study, including the following:
Rates of recruitment and retention (% of subjects able to complete the study)
Reasons for refusal and dropout
Participant satisfaction—participants will provide an opinion regarding their 
satisfaction with study overall
C.14. Patient Safety, Monitoring, and Confidentiality. 
During the study, both a research nurse and a research coordinator will be 
available to perform study assessments and provide safety monitoring.  This 
study will be conducted right outside our Supportive Care Center, where we have 
additional support from multiple clinic nurses and doctors.  The cardiopulmonary 
center is also very close. If desaturation occurs, we will put patient on 
supplemental oxygen, and determine if the patient becomes non-hypoxemic after 


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a short rest.  In the unexpected event in which the patient requires oxygen 
beyond nasal cannula or have prolonged hypoxemia at rest (>30 minutes), we will 
send the patient to ER for further assessment.  Based on our experience 
conducting similar studies on exertional dyspnea in which we routinely monitor 
their vitals, there is a minimal risk of significant saturation with exercise. A study 
physician will also be available by pager to address any concerns, distress, or 
questions, and will attend to the patient as needed. See stopping rules above for further 
details.  
Regulatory monitoring will be provided by the principal investigator and the Institutional 
Review Board (IRB). Patient confidentiality will be ensured by use of study numbers,
secure storage of clinical data, and anonymous reporting.
Research-Related Injury 
Insys will be responsible for payment of the actual and reasonable medical expenses 
incurred in diagnosing and treating any injury, illness or adverse reaction of a study 
subject that results from the administration of Fentanyl Sublingual Spray. 
C.15 Serious Adverse Event Reporting (SAE) Reporting
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 14 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event.
D. Statistical Analysis
D.1. Power Calculation. This pilot study is based on a sample of 15 evaluable subjects 
per arm, for a total of 30 patients.  We expect to enroll approximately 2-3 patients per 
month for this study.  Thus, we expect to complete the study in approximately 10-12 
months.
The primary objective of determining effect size for powering future studies is collecting 
data on the distributional properties of dyspnea scores for the two arms.  This study is 
not powered to test differential treatment effects between the two treatment groups 
measured by dyspnea modified Borg scores. Instead, with 15 patients in each group, 
we will have an 80% power to detect an effect size of 0.778 in difference of the dyspnea 
modified Borg score change after a shuttle walk test before and after the treatment (i.e., 
between the first and second shuttle walk) using a two-sided paired t-test with a 
significance level of 0.05. 
D.2. Data Analysis. Summary descriptive statistics will be provided for demographics, 
outcomes, and other collected variables such as the change of exercise induced 
dyspnea, walk distance, neurocognitive function and various physiological parameters 
at the end of each walk and the difference of these changes between two walks, and 
will include proportions, medians, means, 95% confidence intervals, and other simple 
statistics as appropriate for the measure. Each endpoint will be evaluated repeatedly 


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during the 1st and 2nd walk tests when appropriate. Repeated measures analysis may 
be employed to evaluate the change of these measures over time during each walk.  
We will also evaluate the effect of distance walked on the dyspnea in the repeated 
measures analysis, when possible.  The effect of treatment on the changes of these
measures will also be estimated in the same model when possible. Other statistical 
methods may be applied when appropriate.
E. Data Confidentiality Procedures
Health information will be protected and we will maintain the confidentiality of the data 
obtained from the patients’ charts.
Collection of identifiers: We will collect and securely store patients' identifiers 
(including name, medical record number, and demographic specifications).  Each 
patient will be assigned a study number that will be the only identifier to figure in the 
analytical file and personal data will not be disclosed in any form. The key linking these 
numbers will be retained in a securely locked file by the investigator.
Data Storage: Protection of electronic and paper records will be maintained to the best 
of our ability. All electronic records will be stored on password-protected institution 
computers behind the institution firewall.  Any paper records will be classified and stored 
in locked files inside a locked office.
Training of personnel: Only MDACC personnel trained in maintaining confidentiality, 
the principal investigator, co-investigators, collaborators, and research staff will have 
access to study records.
Data sharing: Study data will not be shared with any individuals or entities without prior 
IRB-approval. The data will be kept by the principal investigator in a locked file cabinet
or password-protected computer.
Final disposition of study records:
Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed. PHI may be maintained indefinitely, 
aggregated in the future, and used for future research studies.


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