Clinical trial NCT01856114
Conditions: Advanced Cancers
Keywords: Advanced Cancers Cancer with evidence of active disease Exercise induced breakthrough dyspnea Shortness of breath Fentanyl Buccal Tablets FBT Placebo Walk tests Questionnaires Surveys
Sponsor: M.D. Anderson Cancer Center
Start date: 2014-05-27; Completion date: 2019-12-04
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if fentanyl can change perception of shortness of breath in cancer patients. Researchers also want to learn if the study drug can help to improve your physical function. In this study, fentanyl will be compared to a placebo.

Fentanyl is commonly used for treatment of cancer pain.

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 either receive fentanyl or placebo. You will have an equal chance of being assigned to either group. Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Visit:

During your study visit, the study staff will collect information from your medical record about your age, sex, race, disease type, how well you are able to perform the normal activities of daily living, any drugs you are taking, and possible causes of shortness of breath.

You will complete 2 questionnaires. One (1) of them will have questions about any breathing symptoms you may be having, and the other asks about any other symptoms you may be having. It should take about 10 minutes to complete these questionnaires.

The study staff will then record your vital signs (heart rate, breathing rate, and the level of air breathed out using a measuring device that will be clipped onto your finger). You will also be asked how hard it is to catch your breath and to rate your level of tiredness.

You will then walk back and forth in an indoor corridor for up to 6 minutes. This is called a walk test. You may slow down, stop, and rest at any time you need to.

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

You will then be given a study drug/placebo tablet to put it in between your upper gum and cheek. You will then wait for another 30 minutes, be asked about any side effects you may be having, and repeat the walking 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.

During each walk test, you will be asked 6 times how hard it is to catch your breath. How often you stopped and for how long will be recorded. 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 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 fill out 1 questionnaire that asks if you think the study drug/placebo is helping you, how satisfied you are with the study, and which treatment you think you received. It should take about 5 minutes to complete the questionnaire.

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:

Thirty (30) 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 20 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: After a six minute walk test, participant will sit down and rest for up to 1 hour. They will then be given a Fentanyl tablet to put in between upper gum and cheek. Study physician 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, an FBT dose equivalent to 20-50% of the MEDD used. After 30 minutes, participant asked about any side effects they may be having, and repeat the walking test. During each walk test, participant asked 6 times how hard it is to catch their breath. The total distance walked will also be recorded. Completion of two questionnaires at beginning of study visit. It should take about 10 minutes to complete. At the end of study visit, completion of last questionnaire. It should take about 5 minutes to complete the questionnaire. arm 2: After a six minute walk test, participant will sit down and rest for up to 1 hour. They will then be given a Placebo tablet to put in between upper gum and cheek. After 30 minutes, participant asked about any side effects they may be having, and repeat the walking test. During each walk test, participant asked 6 times how hard it is to catch their breath. The total distance walked will also be recorded. Completion of two questionnaires at beginning of study visit. It should take about 10 minutes to complete. At the end of study visit, completion of last questionnaire. It should take about 5 minutes to complete the questionnaire.
Interventions: intervention 1: Fentanyl Buccal Tablet intervention 2: Placebo Buccal Tablet intervention 3: Questionnaires
Intervention descriptions: intervention 1: Fentanyl buccal tablet given to put in between upper gum and cheek one hour after a six minute walk test. intervention 2: Placebo buccal tablet given to put in between upper gum and cheek one hour after a six minute walk test. intervention 3: Completion of two questionnaires at beginning of study visit. It should take about 10 minutes to complete. At the end of study visit, completion of last questionnaire. It should take about 5 minutes to complete the questionnaire.

Protocol documents:
Prot_SAP_000.pdf: 
 
2013-0043 
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Page 1 of 15 
 
 
 
 
 
A Preliminary Study of Prophylactic Fentanyl Buccal Tablet (FBT) for Exercise-
Induced Breakthrough Dyspnea 
 
 
 
Principal investigator: Dr. David Hui 
Supportive Care Co-investigator: Dr. Eduardo Bruera 
Thoracic Oncology Co-investigator: Dr. Anne Tsao 
Pulmonary Medicine Co-investigator: Dr. Dave Balachandran 
Biostatistics Co-investigator: Diane Liu 
 
 
 
 
 
Table of Contents 
A. Study Objectives ...............................................................................................2 
B. Background .......................................................................................................2 
C. Experimental Approach ....................................................................................4 
D. Statistical Analysis .......................................................................................... 11 
E. Data Confidentiality Procedures...................................................................... 12 
F. References ...................................................................................................... 13 
 


 
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A. Study Objectives 
 
Primary objective: 
To determine the variances of the change in intensity of exercise-induced 
breakthrough dyspnea (numeric rating scale) of prophylactic fentanyl buccal tablet 
(FBT) and placebo between the first and second 6 minute walk tests.  The variance will 
allow us to properly power a future definitive study. 
 
Secondary objective: 
1. To compare the final dyspnea scores at the end of the two walk tests, after 
adjusting for distance walked. A similar comparison will be performed for placebo.  
We hypothesize that FBT is superior to no FBT in reducing dyspnea at the end of 
a 6 minute walk test.   
 
2. To compare the intensity of exercise-induced breakthrough dyspnea, walk 
distance, neurocognitive function, and physiologic parameters (respiratory rate, 
O2 saturation) of patients administered prophylactic FBT given 30 minutes before 
a 6 minute walk test to that of patients given placebo 30 minutes before a 6 
minute walk test.  We hypothesize that FBT is superior to placebo in reducing 
dyspnea and improving walk distance and physiologic parameters. 
 
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. 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 (Reddy et al. 2009).  
 


 
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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 (SC) 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), 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 
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. 
Prospective case 
OTFC  
RR decreased 


 
2013-0043 
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JPM 2008 
(Gauna et al. 
2008) 
series (2 COPD 
pts, 2 cancer pts) 
10 episodes 
30mg/200mcg 
720mg/400mcg 
20mg/200mcg 
24mg/200mcg 
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 reporting on the use of transmucosal and intranasal fentanyl 
(Benitez-Rosario et al. 2005, Sitte and Bausewein 2008) and one prospective series 
examining 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. 
 
FBT is a particularly attractive option for breakthrough dyspnea.  It was approved by the 
US Food and Drugs Administration in 2006 for “breakthrough pain in opioid-tolerant 
patients with cancer”, and represents an alternative delivery system for fentanyl that 
also utilizes a transmucosal route like OTFC.  Pharmacokinetic studies directly 
comparing FBT and OTFC have demonstrated that fentanyl enters the systemic 
circulation faster and to a greater extent with the effervescent system. It has an absolute 
bioavailability of 65% (Lecybyl and Hanna 2007).  The time to maximal effect (Tmax) was 
between 0.58-0.75 hour (Darwish et al. 2006, Lecybyl and Hanna 2007). FBT has been 
found in clinical trials to provide greater and more rapid pain relief, and reduces pain 
better than placebo (Portenoy et al. 2006, Slatkin et al. 2007). In a prospective series, 
Weinstein et al. reported on the long term safety of 197 patients who received FBT 
during maintenance phase (median of 122 days). Nausea (32%), vomiting (24%), 
fatigue (18%), constipation (15%), and headaches (15%) were the most common side 
effects (Weinstein et al. 2009).  
 
C. Experimental Approach 


 
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C.1. Overall Study design. This is an investigator-initiated study supported by Teva 
Pharmaceutical Industries.  We propose a 2-arm, double blind, parallel randomized 
controlled trial of FBT and placebo for cancer 
patients with breakthrough dyspnea (Figure 1).  
The main goal of this study is to determine the 
effect size for both FBT 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 another 6-
minute walk test after they have been given 
either FBT or placebo prophylactically. 
 
Based on our experience conducting symptom 
control trials, this study will take each patient 
approximately 1 hour 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 for their time and effort. 
 
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. Randomization and Trial Conduct. Patient randomization will be 
conducted through the Clinical Trial Conduct 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 in CTC is as follows:  Edit 
the patient to be replaced modifying MRN and the stratification factor.  Then add a 
history of the changes made to the Notes section. Randomization will be 1:1 between 
Table 2. Study Eligibility Criteria 
Inclusion Criteria 
1. 
Diagnosis of cancer with evidence of active disease 
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, Thoracic Medical Oncology or 
Cardiopulmonary Center 
4. 
Ambulatory and able to walk with or without walking aid  
5. 
On strong opioids with morphine equivalent daily dose of 60-130 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 
9. 
Must speak and understand English. 
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. Bilirubin >5x Upper limit of normal if documented in the last month and not lowered to <5x normal prior to study 
enrollment* 
11. Diagnosis of acute pulmonary embolism within past 2 weeks 
12. Diagnosis of pulmonary hypertension 
13. Unwilling to provide informed consent 


 
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the placebo and treatment arms, and stratified by baseline level of dyspnea NRS 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.  FBT will be dispensed by Dispensing 
Pharmacy at MD Anderson.  Identically appearing placebo is not available from the 
manufacturer.  Thus, placebo will be produced by a compounding pharmacy, and will be 
similar in appearance to FBT. Both the patient and the research staff conducting the 
assessments will be blinded to the nature of the intervention.  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 supply of study medication (both FBT and placebo) will 
be provided by Teva Pharmaceutical Industries Ltd.  FBT was FDA approved (NDA 
021947) in 2006 for “the management of breakthrough pain in patients with 
cancer who are already receiving and who are tolerant to 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 FBT dose equivalent to 
20-50% of the MEDD (Table 3).  For patients randomized to receive FBT, the study 
medication will be provided by Dispensing Pharmacy and will then be administered 30 
minutes before the second 6-minute walk test.  We estimated the FBT dose based on 
the following assumptions:  
 A single rescue dose of 25-50% of the MEDD is safe and effective for relief of 
dyspnea (Bruera et al. 1993, Charles et al. 2008, Mercadante et al. 2012). 
 Fentanyl buccal tablet has approximately 65% oral bioavailability (Darwish et al. 
2007). 
 
Table 3. Dose of Fentanyl Buccal Tablet Based on Morphine Equivalent Daily 
Dose 
Morphine 
equivalent daily 
dose (mg) 
FBT dose (mcg)a 
Number of FBT 
tablets 
Number of 
placebo tablets 
60-65 
100 
1 x 100 mcg 
1 
66-130 
200 
2 x 100 mcg 
 
2 
Abbreviations: FBT, fentanyl buccal tablet 
a FBT is available in 100 mcg and 200 mcg strengths.   
 
Instructions for taking study medication: Once the tablet is removed from the envelope, 
the patient should immediately place the entire tablet in the buccal cavity (above a rear 
molar, between the upper cheek and gum). Patients should not split the tablet. The FBT 


 
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tablet should not be sucked, chewed, or swallowed, as this will result in lower plasma 
concentrations than when taken as directed. The FBT tablet should be left between the 
cheek and gum until it has disintegrated, which usually takes approximately 14-25 
minutes. After 30 minutes, if remnants from the tablet remain, they may be swallowed 
with a glass of water. 
 
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 a one-time dose given to opioid tolerant patients, and under 
close monitoring by trained staff, we believe the dosing schedule proposed is safe. As a 
precautionary measure, patients will be asked to wait for 4 hours after the last walk 
before driving or operating heavy machinery. 
 
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).  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 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 and fatigue 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. 
 
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 


 
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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 30 minutes before they do the second walk.   
 
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.  Patient dropouts and 
walk test failures prior to the administration of drug or placebo will be replaced. 
 
C.12. Study assessments.  See Table 4 for a detailed description of all study 
assessments.   
 
Table 4. Summary of Study Assessments 
Assessments 
Baseline After 1st 6 
min walk 
test 
Rest  
Period 
Before 2nd 
6 min walk 
test 
After 2nd 6 
min walk 
test 
Demographics and cancer diagnosis1 
 
 
 
 
 
Medication history2 
 
 
 
 
 
Karnofsky performance status, spirometry 
testing1 
 
 
 
 
 
Edmonton Symptom Assessment Scale4 
 
 
 
 
 
Dyspnea Survey5 
 
 
 
 
 
Cancer Dyspnea Scale6 
 
 
 
 
 
O2 saturation, blood pressure, heart rate 
and respiratory rate 
 
 
 
 
 
Dyspnea Numeric Rating Scale7 
 
 
 
 
 
Dyspnea Borg scale/Fatigue Borg scale8 
 
 
 
 
 
Walking test parameters9 
 
 
 
 
 
Adverse effects10 
 
 
 
 
 
Neurocognitive testing11 
 
 
 
 
 
Global assessment, study satisfaction and 
blinding12 
 
 
 
 
 
1 patient initials, medical record number, date of birth, sex, race/ethnicity, education, marital 
status, cancer diagnosis, co-morbidities, cause(s) of dyspnea, C-A-G-E, Karnofsky 
Performance Status, height/weight and spirometry. 
2 medications that could be used to treat dyspnea, including scheduled and as needed opioids, 
bronchodilators, steroids, and supplemental oxygen 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 24 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). It also includes two 
additional questions about financial and spiritual distress. 
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 


 
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duration of each episode, current treatment for breakthrough dyspnea. It also includes two 
additional questions about financial and spiritual distress. 
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 and fatigue. 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).   
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 FBT, such as dizziness, drowsiness, nausea, and 
itching 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).  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?”, “Did you quality of life get worse by participating in this research 
study?”  Blinding will be assess by asking patients and study staff which group assignment 
they believe they received: “FBT”, “placebo”, 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 
 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. If a patient desaturated at the end of the walk 
(<90%), we will put her on oxygen and consider a referral to cardiopulmonary center.  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 


 
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rules above for further details.  With the planned 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. Power Calculation. The sample size of 20 patients is determined by sponsor 
funding for this research.  To account for replacements, we will ask for the maximum 
sample size to be 25. 
 
The primary objective of determining effect size for powering future studies is simply a 
matter of collecting data on the distributional properties of dyspnea scores for the two 
arms.  We do not expect the variances of the differences within placebo and treatment 
to be equal based on preliminary results of a recent similar study.  Therefore for proper 
sample size calculations a placebo arm is necessary.  We base our estimates on our 
other similar study, in which we observed a standard deviation for the difference within 
treatment arm of approximately 2.0 and a standard deviation for the difference within 
placebo arm of approximately 3.0.  10 patients will provide a 95% CI for the standard 
deviation of the difference within placebo of (2.1, 5.5).  10 patients will provide a 95% CI 
for the standard deviation of the difference within treatment of (1.4, 3.7).  [NCSS PASS 
2005 – Helps and Aids – Standard Deviation Estimator]  
 
For the secondary objectives, 10 evaluable patients in the FBT 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.   
 
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.   
 
Patients who started but failed to complete the 2nd walk test will not be replaced; 
instead they will be included in the analysis and treated as fully evaluable patients.  If 
we are able to collect a final dyspnea score from such patients then we will use that 
score along with the distance walked to failure as their values for analysis.  Should we 
be unable to collect the final dyspnea score, we will assign that patient a dyspnea value 
equal to the maximal score on the dyspnea assessment along with a distance walked to 
the point of failure.  Patient dropouts and walk test failures prior to starting the second 
walk test will be replaced. 
 
Comparisons within arms (1st secondary objective) will be performed using multiple 
linear regression based on the difference of the final dyspnea scores of the first and 
second walk tests.  We will include baseline dyspnea and distance walked as 


 
2013-0043 
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Page 12 of 15 
covariates.  Size and significance of the difference in dyspnea will be determined by 
examination of the intercept. 
 
Comparisons between arms (2nd secondary objective) will be performed to determine if 
treatment is different from placebo for exercise induced dyspnea, walk distance, 
neurocognitive function and various physiological parameters.  Each endpoint will be 
evaluated at the end of the 2nd walk test.  Analysis method will be linear regression of 
placebo vs fentanyl adjusted for the baseline value of the endpoint being evaluated. 
 
It is understood that 10 or 20 patients is too few for a proper analysis of linear 
regression with more than one factor. All hypothesis tests for this study are purely 
exploratory. The type I error rate will be 5% for each comparison. 
 
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 principal investigator, co-investigators, 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 
and password protected computer behind the institution firewall. 
 
Final disposition of study records: PHI may be maintained indefinitely, aggregated in 
the future, and used for future research studies. 
 
 


 
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