Clinical trial NCT01832402
Conditions: Advanced Cancers
Keywords: Advanced Cancers Exercise-Induced Breakthrough Dyspnea Shortness of breath Fentanyl pectin nasal spray Placebo nasal spray Walk test Questionnaires Surveys Mental ability tests
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-06-11; Completion date: 2019-11-25
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if fentanyl nasal spray can help to control shortness of breath in patients who have been treated or are being treated for cancer.

Fentanyl is commonly used for treatment of cancer pain. It may help patients with their shortness of breath as well.

In this study, fentanyl will be compared to a placebo. A placebo is not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to receive either fentanyl or placebo. You will have an equal chance of being assigned to either group. Neither you nor the study staff will know to which group you have been assigned. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Drug/Placebo Administration:

Before you receive the study drug/placebo, you will walk back and forth in an indoor hallway for up to 6 minutes. You may feel out of breath or become exhausted. You may slow down, stop, and rest at any time you need to.

After that, you will sit down and rest (for about 30 minutes).

You will then be given the study drug/placebo by a nasal spray. You will then wait for another 20 minutes and repeat the walking test.

After that, you will sit down and rest (for about 30 minutes).

You will then be given the study drug/placebo again by a nasal spray. You will then wait for another 20 minutes and repeat the walking test for a third time.

Study Visit:

During your study visit, the study staff will collect information from your medical record about your age, sex, race, disease type, your performance status, any drugs you are taking, and possible causes of shortness of breath.

Before each walk test, you will complete the questionnaires about your symptoms.

Before and after each walk test, the study staff will record your heart rate, breathing rate, and the level of oxygen in your blood using a measuring device that will be clipped onto your finger. The study staff will also ask you 3 questions about how hard it is to catch your breath and your level of tiredness.

During each walk test, you will be asked 6 times how hard it is to catch your breath. The distance you walked and how often and for how long you stopped will be recorded.

Before and after the second and third walk tests, the study staff will ask you about any side effects from the study drug/placebo that you may be having.

During the rest period between the walk tests, you may be asked several times how hard it is to catch your breath.

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

At the end of the study visit, you will complete 1 questionnaire that asks if you think the study drug/placebo is helping you, and how satisfied you are with the study. It should take about 5 minutes to complete the questionnaire.

Length of Study:

You will be on this study for up to 3 hours. You will be taken off study if intolerable side effects occur during the study.

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

Up to 25 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Fentanyl pectin nasal (FPNS) dose equivalent to 15-25% of the morphine equivalent daily dose (MEDD). FPNS administered intranasally 20 minutes before the second 6-minute walk test. Same dose repeated at least 30 minutes after the first dose and 20 minutes prior to the third and final 6 minute walk test. Walk test administered before first dose of FPNS. Participant will rest for 30 minutes after walk test. FPNS administered, then participant will wait 20 minutes before repeating second 6 minute walk test. After second walk test, participant will rest for 30 minutes. FPNS administered for second time, then participant will wait for 20 minutes. Walk test administered again for 6 minutes. Questionnaires completed at baseline, before each walk test, and at end of final walk test. Four mental ability tests administered after each walk test to include finger tapping, simple mathematics questions, recall of numbers, and recall of objects. arm 2: Placebo nasal spray administered intranasally 20 minutes before the second 6-minute walk test. Same dose repeated at least 30 minutes after the first dose and 20 minutes prior to the third and final 6 minute walk test. Walk test administered before first dose of placebo nasal spray. Participant will rest for 30 minutes after walk test. Placebo nasal spray administered, then participant will wait 20 minutes before repeating second 6 minute walk test. After second walk test, participant will rest for 30 minutes. Placebo nasal spray administered for second time, then participant will wait for 20 minutes. Walk test administered again for 6 minutes. Questionnaires completed at baseline, before each walk test, and at end of final walk test. Four mental ability tests administered after each walk test to include finger tapping, simple mathematics questions, recall of numbers, and recall of objects.
Interventions: intervention 1: Fentanyl Pectin Nasal Spray intervention 2: Placebo Nasal Spray intervention 3: Walk Test intervention 4: Questionnaires intervention 5: Mental Ability Tests
Intervention descriptions: intervention 1: Fentanyl pectin nasal (FPNS) dose equivalent to 15-25% of the morphine equivalent daily dose (MEDD) administered intranasally 20 minutes before the second 6-minute walk test. Same dose repeated at least 30 minutes after the first dose and 20 minutes prior to the third and final 6 minute walk test. intervention 2: Placebo nasal spray administered intranasally 20 minutes before the second 6-minute walk test. Same dose repeated at least 30 minutes after the first dose and 20 minutes prior to the third and final 6 minute walk test. intervention 3: Walk test administered before first dose of drug/placebo nasal spray. Participant will rest for 30 minutes after walk test. Drug/placebo nasal spray administered, then participant will wait 20 minutes before repeating second 6 minute walk test. After second walk test, participant will rest for 30 minutes. Drug/placebo nasal spray administered for second time, then participant will wait for 20 minutes. Walk test administered again for 6 minutes. intervention 4: Questionnaires completed at baseline, before each walk test, and at end of final walk test. intervention 5: Four mental ability tests administered after each walk test to include finger tapping, simple mathematics questions, recall of numbers, and recall of objects.

Protocol documents:
Prot_SAP_000.pdf: 
 
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A Preliminary Study of Prophylactic Fentanyl Pectin Nasal Spray (FPNS) for 
Exercise-Induced Breakthrough Dyspnea 
 
 
Principal investigator: Dr. David Hui 
Supportive Care Co-investigators: Dr. Eduardo Bruera, Dr. Suresh Reddy, Dr. Anne 
Tsao 
Biostatistics Co-investigator: Mr. Gary Chisholm 
 
 
 
 
 
Table of Contents 
A. Study Objectives ...............................................................................................2 
B. Background .......................................................................................................2 
C. Experimental Approach ....................................................................................5 
D. Statistical Analysis .......................................................................................... 11 
E. Data Confidentiality Procedures...................................................................... 11 
F. References ...................................................................................................... 11 
 


 
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A. Study Objectives 
 
Primary objective 
To determine the effect of prophylactic fentanyl pectin nasal spray (FPNS) on the 
intensity of exercise-induced breakthrough dyspnea (numeric rating scale, 
adjusted for distance walked) between the first and second 6 minute walk tests. We 
aim to determine the effect size for both FPNS and placebo arm to inform a larger, 
adequately powered confirmatory randomized controlled trial. 
 
Secondary objectives 
1. To determine the effect of prophylactic FPNS on the walk distance, 
neurocognitive function, and adverse effects between the first and second 6 
minute walk tests. 
 
2. To determine the effect of prophylactic FPNS on the intensity of dyspnea, walk 
distance, neurocognitive function, and adverse effects between the first and 
third 6 minute walk tests. 
 
3. To compare prophylactic FPNS and placebo on their ability to reduce the intensity of 
exercise-induced breakthrough dyspnea, walk distance, neurocognitive 
function, and adverse effects between the first and second 6 minute walk tests, 
and also between the first and third 6 minute walk tests. 
 
B. Background 
 
B.1. Significance of Dyspnea. 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 (Ben-Aharon et al. 2008). Dyspnea is 
associated with fatigue, anxiety, decreased function and quality of life, and increased 
mortality (Hauser et al. 2006, Maltoni et al. 2005). 
 
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 (Reddy et al. 2009). 
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. This is similar to incident pain (on ambulation) which is a 
subtype of breakthrough pain. 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 


 
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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 (Reddy et al. 2009).  
 
B.2. The Current Management of Dyspnea. The current management of dyspnea 
involves treatment of any reversible causes and supportive measures to minimize the 
sensation of dyspnea, including treatments such as oxygen, opioids, bronchodilators, 
and corticosteroids (Ben-Aharon et al. 2008, Cranston et al. 2008, Jennings et al. 2002). 
A majority of the studies on cancer-related dyspnea so far have focused on patients 
with dyspnea at rest. In a crossover randomized controlled trial, Bruera et al. compared 
subcutaneous morphine and placebo in 10 patients with advanced cancer who had 
dyspnea at rest. Subcutaneous morphine was found to be superior to placebo for relief 
of dyspnea (Bruera et al. 1993). This finding was replicated by Mazzocato et al. in 
another randomized controlled trial with similar design (Mazzocato et al. 1999). 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 (Jennings et al. 
2002). 
 
Although systemic opioids are established for management of dyspnea at rest, there are 
currently no 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 (Bruera et al. 1993). 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 fentanyl (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 (Charles et al. 2008). One of the 
reasons may be due to the short duration for the primary endpoint (10 minutes). To 
date, the evidence for opioid use for breakthrough dyspnea remains limited (Table 1). 
Further research is necessary to improve the management of this distressing and 
debilitating symptom. 
 
Table 1. Studies of Opioids for Breakthrough Dyspnea 
Study 
Methodology and  
patients 
Agent and dose 
Outcome 
Bruera et al. 
Ann Intern Med 
1993 (Bruera et 
al. 1993) 
Prospective case 
series (45 cancer 
patients [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 
(Benitez-
Rosario et al. 
2005) 
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 


 
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Sitte et al. 
JPSM 2008 
(Sitte and 
Bausewein 
2008) 
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 
(Gauna et al. 
2008) 
Prospective case 
series (2 COPD 
pts, 2 cancer pts) 
10 episodes 
OTFC  
30mg/200mcg 
720mg/400mcg 
20mg/200mcg 
24mg/200mcg 
RR decreased 
Dyspnea decreased by 90-
100% in 20-60 minutes 
Charles et al. 
JPSM 2008 
(Charles et al. 
2008) 
Prospective, 
double blind 
crossover RCT (20 
cancer pts) 
Systemic 
hydromorphone 
Nebulized 
hydromorphone 
Nebulized saline 
Dyspnea decreased 
similarly in all 3 arms (1.0, 
0.9, 0.8) 
Abbreviations: RR=respiratory rate, OTFC=oral transmucosal fentanyl citrate, 
SC=subcutaneous 
 
B.3. Rapid Onset Opioids for Breakthrough Dyspnea.  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) and intranasal (Lazanda, Instanyl) formulations 
(Gordon and Schroeder 2008, Lecybyl and Hanna 2007). These fentanyl formulations 
have been successfully used to manage breakthrough pain (Christie et al. 1998, Coluzzi 
et al. 2001, Fallon et al. 2011, Farrar et al. 1998, Mercadante et al. 2007, Portenoy et al. 
1999, Portenoy et al. 2006, Portenoy et al. 2010, Slatkin et al. 2007), 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 
(Benitez-Rosario et al. 2005, Sitte and Bausewein 2008) and one prospective series 
examined the use of OTFC (Gauna et al. 2008) 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. 
 
FPNS is a particularly attractive option for breakthrough dyspnea. It was approved by 
the US Food and Drugs Administration (FDA)  in 2011 for breakthrough pain in opioid-
tolerant patients with cancer, and represents an alternative delivery system for fentanyl 
in addition to the transdermal, parenteral, and transmucosal routes. Pharmacokinetic 
studies revealed that FPNS has a bioavailability of approximately 80% (Fisher et al. 
2010, Fisher et al. 2010). The time to maximal effect (Tmax) was between 15-20 
minutes  (Fisher et al. 2010, Fisher et al. 2010).  FPNS has been found in clinical trials 
to provide greater and more rapid pain relief and reduces pain better than placebo 
(Kress et al. 2009) and transmucosal fentanyl citrate (Mercadante et al. 2009). 
 
 


 
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C. Experimental Approach 
C.1. Overall Study design. This is an 
investigator initiated study supported in 
part by Depomed, Inc.  We propose a 2-
arm, double blind, parallel randomized 
controlled trial of FPNS and placebo for 
cancer patients with breakthrough 
dyspnea (Figure 1). The main goal of this 
study is to determine the effect size for 
both FPNS and placebo arm 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 6-
minute walk test at baseline, rest until 
they return to baseline dyspnea, and then 
do a second 6-minute walk test 20 
minutes after they have been given either 
FPNS or placebo prophylactically. They 
will then rest again to return to baseline 
dyspnea, and then do another 6-minute 
walk test 20 minutes after repeating the 
same dose of either FPNS or placebo 
(with at least 30 minutes between the first 
and second dose).  This design will allow testing of both single and repeated dosing on 
dyspnea under a double blind design. 
 
Based on our experience conducting symptom control trials, this study will take between 
1.5-2 hours to complete on 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 for their time and effort. 
 
C.2. Eligibility Criteria. The eligibility criteria are shown in Table 2. 
Table 2. Study Eligibility Criteria 


 
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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 informed 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 for 
the patient 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.  Based on our experience with similar trials, we expect that a majority 
of patients will complete this study. 
C.4. Randomization. A computer generated sequence in permuted blocks will be used 
to assign patients to either FPNS or placebo and provided via a secured website, 
stratified by baseline level of dyspnea NRS at rest at the time of enrollment (i.e. 0-3, 4-
6). Biostatistics will set up a Randomization website. Investigational Pharmacy 
personnel will perform the randomization assignment. 
C.5. Blinding. Both patients and the research staff conducting the assessment will be 
blinded to the treatment assignment.  FPNS will be dispensed by Dispensing Pharmacy 
at MD Anderson.  Placebo will be identical in appearance to the FPNS. 
C.6. Research staff. An orientation will be held with research staff involved in this study 
to introduce them with the study design, and standardize the provision of each 
intervention.   
C.7. Study Interventions. The supply of study medication (both FPNS and placebo) 
will be provided by Depomed, Inc.  FPNS is FDA approved (NDA 022569/S-007) for 
treatment of breakthrough cancer pain in opioid-tolerant patients. 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.  
Inclusion Criteria 
1. Diagnosis of cancer 
2. Breakthrough dyspnea, defined in this study as dyspnea on exertion with an average intensity level 
>=3/10 on the numeric rating scale 
3. Outpatient at MD Anderson Cancer Center seen by the Supportive Care Service or Thoracic 
Medical Oncology 
4. Ambulatory and able to walk with or without walking aid  
5. On strong opioids with morphine equivalent daily dose of 80-500 mg, 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. Unwilling to provide informed consent 
10. Patients who currently have no evidence of disease 


 
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Based on clinical practice and similarly to the dose used for breakthrough pain, we will 
use an FPNS dose equivalent to 15-25% of the MEDD (Table 3).  For patients 
randomized to receive FPNS, the study medication will be provided by Dispensing 
Pharmacy and will then be administered intranasally 20 minutes before the second 6-
minute walk test.  The same dose will be repeated at least 30 minutes after the first 
dose and 20 minutes prior to the third and final 6 minute walk test. We estimated the 
FPNS dose based on the following assumptions:  
 A rescue dose of 15-25% of the MEDD is safe and adequate for relief of dyspnea 
(Bruera et al. 1993, Charles et al. 2008). 
 FPNS has approximately 80% oral bioavailability (Fisher et al. 2010, Fisher et al. 
2010).  
 With repeat dosing 30 minutes apart, the maximum concentration (Cmax) for FPNS 
is approximately 1.6x higher than the first dose. 
 
The modeled pharmacokinetic data for repeated dosing 30 minutes apart is shown in 
Figure 2.  As a precautionary measure, patients will be asked to wait for 1 hour after 
completing the last walk before leaving MD Anderson.  At the end of 1 hour, they will be 
assessed by our research staff before being released.  If excessive drowsiness or 
adverse events occur, the study physician will assess the patients.   
 
 
 
Table 3. Dose of Fentanyl Pectin Nasal Spray Based on Morphine Equivalent Daily 
Dosea 
Morphine 
equivalent daily 
dose (mg) 
Total Fentanyl 
Pectin Nasal 
Spray Dose (mcg) 
Number of  
FPNS sprays 
Number of  
Placebo sprays 


 
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80-159 
100 
1 (100 mcg in one nostril) 
1 
160-239 
200 
2 (100 mcg in each 
nostril) 
2 
240-319 
300 
3 (100 mcg in one nostril 
and 2 x 100 mcg in the 
other nostril)b 
3 
320-540 
400 
4 (2 x 100 mcg in each 
nostril) 
4 
a FPNS is available in 100 mcg. 
b For the 300 mcg dose, patients will receive 1 spray in each nostril, then another spray 
again in the one of the nostrils. 
 
Placebo will be identical in appearance to the FPNS, and given to patients 20 minutes 
before the second and the third 6-minute walk test. Both the patient and the research 
staff conducting the assessments will be blinded to the nature of the intervention. During 
this entire study, patients will be monitored closely by trained research staff, and will 
have rapid access to medical care if needed.   
 
Because this involves only 2 doses given to opioid tolerant patients, and under close 
monitoring by trained staff, we believe the dosing schedule proposed is safe.  
 
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 6-minute walk tests will be conducted based on guidelines from the American 
Thoracic Society (Laboratories 2002).  Walking aid and supplemental oxygen via nasal 
prongs are allowed as long as patients keep them the same as before enrollment and 
during the entire study.  This walking test allows patients to rest if they need to, and is 
highly acceptable to patients.  It provides important information regarding patients’ 
functional status, exercise capacity, and health-related quality of life (Guyatt et al. 1985, 
Guyatt et al. 1985).  Before and after each test, we will be assessing the (1) dyspnea 
level with numeric rating scale and Borg scale, and the (2) respiratory rate and oxygen 
saturation.  After each test, we will also be assessing (1) the distance walked at the end 
of each minute or portion of, (2) the total walking time, (3) the level of dyspnea at the 
end of each minute or portion of (NRS and Borg scale), and (4) the average walking 
speed. 
 
The 6-minute walk test has excellent short term reproducibility (Guyatt et al. 1985), 
as well as good face, construct, and predictive validity (Du Bois et al. 2011), and 
changes in this test are concordant with changes in symptoms and mortality (Olsson et 
al. 2005).  The minimal clinical significant difference is found to be 24-45 m for patients 
with idiopathic pulmonary fibrosis (Du Bois et al. 2011), and 86 m for patients with 
COPD. 
 
The first 6-minute walk test was 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. 


 
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C.10. Variable rest period. After the first and second 6 minute 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 numeric rating score + 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). During this rest 
period, patients will be assessed every 5 minutes to check their dyspnea level.  If their 
dyspnea level met criteria and they feel ready to walk again, they will be given the study 
treatment and asked to wait for 20 minutes before they walk. At least 30 minutes should 
elapse between each dose of the study medication. 
C.11. Stopping rules. Patients who do not develop any increase from their baseline 
dyspnea after the first 6-minute 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 level still 
has not returned to baseline, they will also be taken off study.  We plan to replace these 
patients and any other individuals who are not evaluable because they have not started 
the 2nd walk test. 
C.12. Study assessments.  See Table 4 for a detailed description of all study 
assessments.   
Table 4. Summary of Study Assessments 
Assessments 
Base- 
line 
Post 
1st 
6MWT 
Rest  
#1 
Pre 
2nd 
6MW 
Post 
2nd 
6MW 
Rest  
#2 
Pre 
3rd 
6MW 
Post 
3rd 
6MW 
Demographics and cancer 
diagnosis1 
 
 
 
 
 
 
 
 
Medication history2 
 
 
 
 
 
 
 
 
Karnofsky performance status3 
 
 
 
 
 
 
 
 
Edmonton Symptom Assessment 
Scale4 
 
 
 
 
 
 
 
 
Dyspnea Survey5 
 
 
 
 
 
 
 
 
Cancer Dyspnea Scale6 
 
 
 
 
 
 
 
 
O2 saturation and respiratory rate 
 
 
 
 
 
 
 
 
Dyspnea Numeric Rating Scale7 
 
 
 
 
 
 
 
 
Dyspnea Borg scale8 
 
 
 
 
 
 
 
 
Walking test parameters9 
 
 
 
 
 
 
 
 
Adverse effects10 
 
 
 
 
 
 
 
 
Neurocognitive testing11 
 
 
 
 
 
 
 
 
Global assessment12 
 
 
 
 
 
 
 
 
Blinding13 
 
 
 
 
 
 
 
 
Patient satisfaction14 
 
 
 
 
 
 
 
 
1 patient initials, medical record number, date of birth, sex, race, education, marital status, 
cancer diagnosis, co-morbidities, cause(s) of dyspnea. 
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 
(Schag et al. 1984). 
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 (Bruera et al. 1991). 


 
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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 cancer 
patients during the past few days (Tanaka et al. 2000). 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 (no dyspnea) to 10 (worst dyspnea) categorical scale validated for rating the severity of 
dyspnea (Dorman et al. 2007, Gift and Narsavage 1998, Powers and Bennett 1999).  We will be 
measuring it every minute during the 6 minute walk test at 0, 1 min, 2 min, 3 min, 4 min, 5 min 
and 6 min (or end of walk). 
8 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 (Dorman et al. 2007, Gift and Narsavage 1998, Kendrick 
et al. 2000, Powers and Bennett 1999).  We will be measuring it  0 and 6 min (or end of walk) of 
each walk. The NRS will be administered before modified Borg scale. 
 
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 FPNS, such as dizziness, drowsiness, nausea, 
stuffy/blocked nose, runny nose, itching/sneezing, nose dryness, cough, sore throat, and taste 
disturbance will be assessed using a numeric rating scale from 0-10. 
11 patients will be asked to do finger tapping 10 and 30 sec, arithmetic, reverse memory of digits, 
and visual memory).  This has been used in other studies by our group.(Bruera et al. 1992) 
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 6-minute walk tests (Guyatt et al. 
1993, Redelmeier et al. 1996). 
13 blinding will be done by asking patients which group assignment they received: “FPNS”, 
“placebo”, or “do not know”. 
14 study satisfaction is 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?”, “Did you quality of life 
get worse by participating in this research study?”   
C.13. Feasibility data. In addition to clinical outcomes, we will also collect feasibility 
data in this study Rates of recruitment and retention (% of subjects able to complete the 
study) 
 Reasons for refusal and dropout 
 Outcome measure—we will compare the sensitivity of Numeric rating scale and Borg 
scale to change, and identify key measure for future study 
 Participant satisfaction—participants will provide an opinion regarding their 
satisfaction with study overall 
C.14. Patient Safety, Monitoring, and Confidentiality. During the study, trained 
research staff will be performing study assessments and monitoring the patients 
carefully throughout the study period. A study physician will also be available by pager 
to address any concerns, distress or questions, and will attend to the patient as needed. 
Patients will be doing the test in a hallway outside the Supportive Care Center which 
typically does not have a lot of traffic, and will have immediate access to medical and 
nursing care if needed.  See stopping rules below for further details.  With the planned 


 
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doses of fentanyl in opioid-tolerant patients, we do not expect any significant side 
effects.   
 
Regulatory monitoring will be provided by the principal investigator, the Institutional 
Review Board (IRB), and the Data Safety and Monitoring Board (DSMB). Patient 
confidentiality will be ensured by use of study numbers, secure storage of clinical data, 
and anonymous reporting. 
 
D. Statistical Analysis 
D.1. Sample Size Calculation. Patients who have started the second walk test will be 
considered evaluable for this study’s primary endpoint. 10 evaluable patients in the 
fentanyl arm provides 80% power to detect an effect size as small as 1.0 when 
alpha=5% using a two-sided paired t-test to compare dyspnea between the first and 
second walk tests.  Results from this study will be used to calculate the sample size for 
an adequately powered randomized controlled trial.  
 
D.2. Data Analysis. Summary descriptive statistics will be provided for demographics, 
outcomes, and other collected variables and will include proportions, medians, means, 
95% confidence intervals, and other simple statistics as appropriate for the measure.  
Comparisons within arms will be performed using paired t-tests or signed rank tests.   
 
E. Data Confidentiality Procedures 
Health information will be protected and we will maintain the confidentiality of the data 
obtained from the patient's chart.   
 
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 guaranteed. 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 principle investigators and co-investigators, will have access to study records. 
 
Data sharing: Study data will not be shared with any individuals or entities. The data 
will be kept by the principle investigator in a locked file cabinet. 
 
Final disposition of study records: These data will be used only for this research 
study data files will be destroyed 5 years after publication of the findings. 
 
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