A Randomized Controlled Trial of Dexamethasone for Dyspnea in Cancer Patients
Phase: PHASE2
Conditions: Dyspnea, Malignant Neoplasm
Sponsor: M.D. Anderson Cancer Center

 
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A Randomized Controlled Trial of Dexamethasone for Dyspnea in Cancer Pa-
tients   
 
Principal investigator: Dr. David Hui 
Co-investigators: Dr. Eduardo Bruera, Dr. Sandra Hanneman, Dr. Anne Tsao, Dr. Rony Dev 
Biostatistics Collaborators: Sanjay Shete, PhD; Dr. Kristofer Jennings, PhD; Diana Urbauer, MS 
 
Table of Contents 
A. Objectives 
2 
B. Background 
2 
C. Rationale 
4 
D. Experimental Approach 
6 
E. Statistical Analysis 
14 
F. Data Confidentiality Procedures  
15 
G. References 
16 
 
 
 
 

 
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This study proposal was submitted the National Institutes of Health and re-
ceived a score of 12 (i.e. top 2 percentile).  National Cancer Institute is con-
sidering it for funding.  
A. Objectives 
Primary Objective: Compare the intensity of dyspnea (numeric rating scale [NRS]) in the dexa-
methasone arm with that in the placebo arm at week 1.  
Our working hypothesis is that dexamethasone will improve dyspnea compared with placebo in 
patients with cancer. 
 
Secondary Objective #1: Compare the effects of dexamethasone with those of placebo in terms 
of personalized dyspnea response (based on a personalized dyspnea goal), unpleasantness of 
dyspnea, other symptoms, health-related quality of life, respiratory physiologic function, and 
adverse effects at week 1 and week 2, as well as the intensity of dyspnea at week 2.  
Our working hypothesis is that short-term, high-dose dexamethasone will improve personalized 
dyspnea response, unpleasantness of dyspnea, symptom burden, health-related quality of life, 
and respiratory physiologic function, with limited adverse effects. 
 
Secondary Objective #2: Identify predictive markers of dyspnea response to dexamethasone.  
Our working hypothesis is that baseline inflammatory response (interleukin [IL]-1β, IL-6, IL-8, IL-
10, IL-6:IL-10 ratio, and tumor necrosis factor-α [TNF-α] levels) and certain patient characteris-
tics (e.g., high baseline dyspnea and restrictive lung disease pattern) are associated with in-
creased treatment response. 
 
Secondary Objective #3: Determine the association between adverse event (AE) development 
(i.e. G3+ AEs, hospitalizations, specific adverse events) and the dose/duration of dexame-
thasone. Our working hypothesis is that longer duration and higher dose is associated with 
greater AEs. 
 
Secondary Objective #4: Examine the similarities and differences between CTCAE and PRO-
CTCAE reporting.  We will identify where  CTCAE and PRO-CTCAE overlap and how they differ 
from each other. 
 
B. Background 
B.1. Dyspnea. Dyspnea is defined by the American Thoracic Society as “a subjective experience 
of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity… 
dyspnea sensations also vary in their unpleasantness and in their emotional and behavioral 
significance” (Parshall et al. 2012). Dyspnea occurs in approximately 10-70% of cancer patients 
and is one of the most feared symptoms (Solano et al. 2006). It is particularly common in 
patients with advanced cancer and those with intrathoracic malignancies (Hui et al. 2015a, 
Tishelman et al. 2007). Dyspnea that “persists at rest or with minimal activity and is distressful 
despite optimal therapy of advanced lung or heart disease” is considered to be refractory 

 
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(Mahler et al. 2010). Several large studies reported that 30-50% of patients with cancer suffer 
from refractory dyspnea in the last few months of life, and the symptom increases in both 
frequency and intensity as death approaches (Currow et al. 2010, Dudgeon et al. 2001, Seow et 
al. 2011). More recently, a prospective study revealed that up to 70% of patients with advanced 
cancer reported dyspnea in the last week of life despite intensive palliation in an acute 
palliative care unit (Hui et al. 2015a). Importantly, dyspnea is associated with decreased daily 
function, quality of life, and survival (Cuervo Pinna et al. 2009, Maltoni et al. 2005, Reddy et al. 
2009). Because of its high prevalence and impact on quality of life, dyspnea presents a major 
public health concern for patients living with cancer. Multiple professional organizations, 
including the Institute of Medicine and National Hospice and Palliative Nurses Association, 
identified dyspnea as a priority for research (Board 2001, Buck et al. 2015). 
B.2. 
Pathophysiology. 
Over 
the 
years, 
understanding 
of 
the 
pathophysiologic 
pathways 
contributing 
to 
dyspnea 
has 
improved (Figure 1), which may allow 
development of better therapies for this 
devastating symptom (Mahler 2011, Manning 
and Schwartzstein 1995). The sensory cortex 
receives 
afferent 
input 
from 
various 
peripheral and central stimuli, generating the 
sensation of breathlessness (Mahler 2011, 
Parshall et al. 2012). Parenchymal metastasis, 
lymphangitic 
carcinomatosis, 
airway 
obstruction, pleural effusion, pneumonia, 
pulmonary embolism, and atelectasis may 
cause dyspnea in the context of progressive 
cancer—all of which are associated with an 
inflammatory response. 
B.3. Role of inflammation in dyspnea. 
Cytokines drive the inflammatory response, 
and dysregulation of cytokines is seen with chronic inflammation and cancer (Marrugal et al. 
2016). COPD, as a disease model for dyspnea, is characterized by a substantial inflammatory 
component, including elevated serum IL-6 and TNF-α (Falk et al. 2008). In patients with asthma, 
increased levels of IL-1β and IL-6 predicted increased perception of dyspnea (Carpio et al. 
2016). In patients with restrictive lung disease, serum IL-1β and TNF-α levels were correlated 
with the severity of lung injury (Bauer et al. 2000). De Brito et al. (De Brito et al. 2016) recently 
found elevated serum IL-6 in patients with pneumonia; IL-6 levels were correlated with dyspnea 
(r = 0.61, P = 0.012) in patients with severe pneumonia, as was the ratio between systemic 
levels of IL-6 and IL-10 (i.e., IL-6:IL-10), an anti-inflammatory cytokine that serves as a 
biomarker for the severity of pneumonia—a decreased ratio indicated response to treatment. 
Few studies have examined the relationship between inflammatory biomarkers and dyspnea in 
cancer patients. In one study that included 1466 patients with advanced cancer, levels of C-
reactive protein (CRP), a marker of acute inflammation, >10 mg/L were associated with 
increased levels of dyspnea (35 mg/L compared with 27 mg/L for CRP < 10 mg/L; P < 0.001) 

 
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(Laird et al. 2013). Collectively, the literature indicates that selective inflammatory biomarkers 
(i.e., IL-1β, IL-6, IL-8, IL-10, and TNF-α) play a role in the pathogenesis of dyspnea, indicating 
that further research is needed in the oncology setting. 
B.4. Treatment options for dyspnea. Because of the paucity of research on dyspnea, there are 
currently no US Food and Drug Administration (FDA)-approved therapies for dyspnea. 
Contemporary management of dyspnea involves treatment of any reversible causes and 
supportive measures to minimize the sensation of dyspnea. Medications such as opioids, 
bronchodilators, and benzodiazepines offer moderate benefits (Barnes et al. 2016, Ben-Aharon 
et al. 2008, Cranston et al. 2008, Jennings et al. 2002). Given the important role of 
inflammation in cancer-related dyspnea, corticosteroids show promise as a therapeutic option, 
although few studies have examined this option (Table 1).  
C. Rationale 
C.1. Role of corticosteroids in dyspnea. Steroids have been shown to modulate the 
inflammatory response and improve dyspnea in patients with obstructive lung disorders 
(Calverley et al. 2003, Lapperre et al. 2009). In systematic reviews, systemic corticosteroids 
have been shown to reduce respiratory symptoms, improve FEV1, and shorten hospitalization 
in acute exacerbations of COPD (Falk et al. 2008, Walters et al. 2009, Wood-Baker et al. 2007). 
Inhaled steroids have also been demonstrated to improve various clinical outcomes in patients 
with COPD, including reducing the number of physician visits and decreasing airway 
hyperreactivity (Calverley et al. 2007, Lung Health Study Research 2000, Yang et al. 2007). 
These findings from non-cancer populations may or may not apply to patients with cancer. On 
the one hand, restrictive lung diseases are predominant in the oncology setting instead of 
obstructive lung disorders, secondary to inflammation, infiltration, fibrosis, effusion, or 
respiratory muscle weakness. On the other hand, cancer is known to induce host inflammatory 
response and often produces cytokines with both systemic and peripheral effects (Wang et al. 
2010), raising the possibility that corticosteroids may also be effective for the management of 
dyspnea among patients with cancer.  
C.2. Limited research on the effect of corticosteroids on cancer-related dyspnea. A handful of 
studies show that systemic corticosteroids may be effective for the management of dyspnea in 
patients with cancer. However, all studies to date were hypothesis-generating, including four 
small retrospective case reports/series, two randomized controlled trials in which dyspnea was 
only an exploratory outcome, and one randomized trial that was only a feasibility study and not 
adequately powered. This lack of confirmatory data has contributed to substantial variations in 
how corticosteroids are prescribed in practice (Denton and Shaw 2014a, Gannon and 
Mcnamara 2002, Matsuo et al. 2012). Some clinicians see value in a therapeutic trial of 
corticosteroids on the basis of anecdotal evidence, particularly given that few other options 
currently exist. Others are less certain about the benefits of corticosteroids and hesitate to 
prescribe them out of concerns about adverse effects (Denton and Shaw 2014b, Hougardy et al. 
2000). Those who prescribe corticosteroids for dyspnea struggle to decide which corticosteroids 
to use and what would be the optimal dose, schedule, duration, and tapering scheme. 
Understandably, multiple systematic reviews of dyspnea concluded that high-quality 
randomized controlled trials are needed to examine the efficacy of corticosteroids (Simon et al. 
2012, Viola et al. 2008). 

 
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C.3. Dexamethasone for cancer-related dyspnea (Hui et al. 2016a). We recently completed a 
double-blind, randomized, controlled trial to examine the effect of dexamethasone on dyspnea. 
Cancer patients with dyspnea were randomized to receive either dexamethasone (8 mg twice 
daily for 4 days, then 4 mg twice daily for 3 days) or placebo for 7 days, followed by an open-
label phase for 7 days. We documented the within-arm changes in dyspnea (according to the 
dyspnea NRS), spirometry measures, quality of life, and toxic effects. Forty-one patients were 
randomized and 35 (85%) completed the blinded phase. As shown in Table 2, dexamethasone 
was associated with a significant reduction in dyspnea by day 4 (average change in dyspnea NRS 
score -1.9, 95% confidence interval [CI] -3.3 to -0.5, P = 0.01) and by day 7 (average change in 
dyspnea NRS score -1.8, 95% CI -3.2 to -0.3, P = 0.02). In contrast, placebo was associated with 
an average change in dyspnea NRS score of -0.7 (95% CI -2.1 to 0.6, P = 0.38) by day 4 and -1.3 
(95% CI -2.4 to -0.2, P = 0.03) by day 7. This preliminary study was not powered to detect the 
between-arm difference. Dexamethasone was well tolerated with no significant toxicities. This 
pilot study provided important preliminary data for the current proposed trial. First, it showed 
that a double-blind, randomized, controlled trial of dexamethasone was feasible, with a low 
attrition rate. We expect to be able to enroll patients and successfully complete the proposed 
trial because the eligibility criteria are similar. Second, the study showed that dexamethasone 
was associated with a rapid within-arm improvement in dyspnea and may potentially represent 
an improvement over the placebo arm. Third, the moderate effect size for a single-modality 
intervention is encouraging given that there are currently no FDA-approved therapies for 
dyspnea. Confirmation of the benefit of dexamethasone in the proposed study will pave the 
way for future studies examining combination therapies that may result in a greater effect size. 
Finally, dexamethasone, at a dose of 8 mg twice daily for 4 days, was well tolerated with no 
significant adverse effects; thus, it is reasonable to consider extending this same dose for a total 
of 7 days.  Based on the findings from this preliminary study, we propose a larger confirmatory 
trial to definitively assess the efficacy of dexamethasone for dyspnea, with the potential to 
greatly improve patients’ symptom burden, function, and quality of life. 
 
Table 1. Change in dyspnea in the dexamethasone and placebo arms (statistically significant 
values in boldface type) 
Variable 
Dexamethasone 
Placebo 
Mean difference 
between arms (95% 
CI) 
N 
Mean (SD) 
Mean change from 
baseline (95% CI) 
N 
Mean (SD) 
Mean change from 
baseline (95% CI) 
ESAS dyspnea (average over the past 24 hours) 
 
 
 
 
Baseline 
19 
5.0 (2.1) 
- 
19 
4.7 (1.5) 
- 
- 
Day 4 
15 
3.3 (1.8) 
-1.9 (-3.3 to -0.5),  
P = 0.01 
15 
3.7 (2) 
-0.7 (-2.1 to 0.6),  
P = 0.38 
-1.2 (-3 to 0.6) 
Day 7 
16 
3.6 (2.6) 
-1.8 (-3.2 to -0.3),  
P = 0.02 
14 
3.3 (2.1) 
-1.3 (-2.4 to -0.2),  
P = 0.03 
-0.5 (-2.2 to 1.2) 
EORTC Quality of Life Questionnaire-C30 Dyspnea (over the past week) 
 
Baseline 
19 
57.9 (29.1) 
- 
19 
49.1 (20.4) 
- 
- 
Day 4 
15 
46.7 (16.9) 
-15.6 (-29.3 to -1.8),  
P = 0.04 
15 
46.7 (24.6) 
0 (-14 to 14),  
P > 0.99 
-15.6 (-33.5 to 2.3) 
Day 7 
16 
47.9 (17.1) 
-10.4 (-21.1 to 0.3),  
P = 0.08 
13 
43.6 (16) 
-5.1 (-19 to 8.8),  
P = 0.69 
-5.3 (-21.2 to 10.6) 
 
 
 

 
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D. Experimental Approach 
D.1. Overall Study design. This is a parallel, two-
arm, 
double-blind, 
randomized, 
placebo-
controlled trial of dexamethasone for cancer pa-
tients with dyspnea (Figure 2). We plan to enroll 
201 patients (134 in the dexamethasone group 
and 67 in the placebo group, Section D.1.11.1), 
with a target enrollment rate of five to six pa-
tients per month. The eligibility criteria are 
shown in Table 2. After providing written in-
formed consent, enrolled patients will complete 
baseline questionnaires to assess the severity of 
their dyspnea. Study drug may be mailed to par-
ticipants. At MD Anderson, sometimes patients 
do not have time to pick up study medication af-
ter enrollment and do not start the study until a 
few days later. For HHS/LBJ, patients will get 
their medication via MD Anderson pharmacy so their medications will also need to be mailed to 
them. On the basis of our experience, we believe that the proposed study is feasible and will 
not add an undue burden for patients. The rationale for the proposed study design is as follows.  
 
D.1.1. Dexamethasone. Dexamethasone was chosen over other corticosteroids because it is 
a synthetic, long-acting, potent corticosteroid with minimal mineralocorticoid activity. It is 
commonly used in the oncology setting for management of fatigue, pain, anorexia, and nausea 
and vomiting (Chow et al. 2015, Hesketh et al. 2016, Yennurajalingam et al. 2013). Moreover, 
dexamethasone demonstrated promising activity in our preliminary trial (Hui et al. 2016a) (Sec-
tion D.1.1.3). 
 
D.1.2. Oral route. The oral route was selected instead of the inhaled route because 
dexamethasone is expected to exert its effect both peripherally and centrally. Absorption of 
inhaled corticosteroid may be less reliable. The oral route is also more convenient than the 
intravenous route in the ambulatory setting. Furthermore, our preliminary data (Section 
D.1.1.3) suggest that oral dexamethasone was associated with dyspnea improvement. 
 
D.1.3. Dosing. In our preliminary study, dexamethasone was given at a dose of 8 mg orally 
twice daily for 4 days, followed by 4 mg twice daily for 3 days, and the peak effect was reached 
within 4 days. We observed no significant adverse effects in the dexamethasone group at this 
dose compared with placebo. Thus, we would like to extend the use of dexamethasone at a 
dose of 8 mg twice daily to 7 days to evaluate its longer-term effects. This dose is justified 
because high-dose prednisone (i.e., 100 mg daily, which is equivalent to 16 mg of 
dexamethasone) is often given in the oncology setting as part of cancer treatment. 
 
D.1.4. Tapering. The tapering schedule is designed according to routine clinical practice, 
which reduces the dexamethasone dose to half (4 mg twice daily, then 2 mg twice daily) before 
stopping to minimize cortisol deficiency due to hypothalamic-pituitary-adrenal axis 
suppression. Given that the total duration of treatment with dexamethasone is 2-4 weeks, we 
do not expect substantial adverse effects. 

 
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D.1.5. Study duration and endpoint. The duration to the primary endpoint will be 7 ± 2 
days of high-dose dexamethasone/placebo. This was carefully chosen over longer time frames 
because (1) dyspnea is highly distressing and rapid symptomatic relief is essential; and (2) 
prolonged use of high-dose dexamethasone may result in greater side effects. We will assess 
the longer-term use of dexamethasone at lower doses for up to 4 weeks as part of our 
secondary analysis.  
 
D.1.6. Open label phase. This will offer all patients the opportunity for a trial of the active 
agent, which may enhance the rate of recruitment. It will also allow us to taper the 
corticosteroid dose slowly and to explore longer-term use of corticosteroids beyond 2 weeks. 
 
D.1.7. Placebo control. The use of placebo control is justified because definitive evidence to 
suggest that dexamethasone is superior to placebo remains lacking (i.e., clinical equipoise). 
Patients in either study arm will have access to other contemporary treatments if already 
scheduled (e.g., opioids, bronchodilators). Because the primary outcome measure is a patient-
reported outcome, placebo control is essential. Indeed, our previous research studies have 
consistently shown that a placebo offers clinically significant benefits with minimal harm 
(Bruera et al. 1993, Bruera et al. 2007). 
 
D.1.8. Randomization in 2:1 ratio. The 2:1 ratio was elected to maximize the number of 
patients available for response predictor analysis (Aim 2) and to help to improve our chances of 
recruitment. On the basis of our preliminary data favoring dexamethasone, we believe this ratio 
is justified. 
 
D.1.9. Selection of putative predictive markers.  
 
 
D.1.9.1 Inflammatory biomarkers. Dexamethasone is hypothesized to modulate the 
inflammatory response to help treat dyspnea. We have selected IL-1β, IL-6, IL-8, IL-10, and TNF-
α for their specific relevance to dyspnea on the basis of our literature review.  
 
 
D.1.9.2. Pulmonary function. A large proportion of patients with cancer have restrictive 
lung disease (Hui et al. 2016a). In the fibrotic interstitial lung disease setting, there is evidence 
to support the use of corticosteroids for dyspnea (Bajwah et al. 2013). Thus, restrictive lung 
disease may be a predictive marker. Cachexia, a common syndrome in patients with advanced 
cancer, is associated with decreased respiratory muscle function (Coats 2002, Remels et al. 
2013, Roberts et al. 2013), which in turn may be associated with dyspnea (Chiu et al. 2004, 
Travers et al. 2008). Indeed, short-term corticosteroids have been reported to have a positive 
impact on muscle strength in patients with various inflammatory disorders (Manzur et al. 2008, 
Sunderkotter et al. 2016). Mechanistically, a positive association between dyspnea response to 
dexamethasone and pulmonary function (i.e., baseline or change) would suggest that the 
therapeutic effect of corticosteroids on dyspnea is mediated peripherally, and a lack of 
association may imply more a central effect. 
 
 
D.1.9.3. Baseline dyspnea function. Studies from our group and others consistently 
demonstrated that a high baseline symptom score is associated with a greater likelihood of 
response to both active intervention and placebo (De La Cruz et al. 2010, Hui et al. 2015b). 
Thus, the randomization scheme will stratify by this variable. We will also adjust for this 
variable in our statistical analysis. 
 
D.2. Eligibility criteria (Table 2). We designed these criteria to maximize the study’s 
generalizability. We will be stratifying by baseline dyspnea intensity and study site. We also 

 
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considered stratifying by other factors such as pulmonary function and inflammatory markers, 
but no other factors have been consistently found to be predictive markers at this time in 
cancer patients.  
 
Table 2. Study eligibility criteria  
Inclusion criteria 
1. Diagnosis of cancer 
2. Dyspnea with an average intensity ≥4 on the dyspnea NRS (range 0-10) over the past week 
3. Seen at an outpatient clinic at MD Anderson Cancer Center or LBJ Hospital General Oncology Clinic 
4. Able to communicate in English or Spanish 
5. Karnofsky performance status ≥30% 
6. Age 18 years or older 
Exclusion criteria 
1. Delirium (i.e., score >13 on the Memorial Delirium Assessment Scale; range 1-30) 
2. Oxygen saturation <90% despite supplemental oxygen >6 L/minute 
3. Previous allergic reactions to dexamethasone 
4. Diagnosis of diabetes mellitus uncontrolled with oral hypoglycemic agents or insulin 
5. Postsurgical open wound that has not healed at the time of enrollment 
6. Any infection requiring antibiotics at the time of study enrollment 
7. Major surgery within the past 2 weeks 
8. Megestrol use at the time of study enrollment 
9. Neutropenia (absolute neutrophil count <1.0 × 109/L) at the time of study enrollment (bloodwork is 
not required if patient did not have chemotherapy within past 2 weeks) 
10. Currently receiving or expected to start cytotoxic chemotherapy or immunotherapy within 1 week 
of study enrollment and additional dexamethasone cannot be used concurrently as per attending 
oncologist 
11. Severe anemia (hemoglobin <8 g/L) not corrected prior to study enrollment (bloodwork is not 
required if patient did not have chemotherapy within past 2 weeks) 
12. COPD exacerbation at the time of study enrollment 
13. Heart failure exacerbation at the time of study enrollment 
14. Expected to undergo therapeutic thoracentesis in the next 2 weeks 
15. High anxiety score (≥15/21) on the Hospital Anxiety and Depression Scale (HADS)  
16. Chronic systemic corticosteroid use (>14 days) at the time of study enrollment  
17. Any expected corticosteroid use during study enrollment at higher doses than will be used in this 
study 
 
D.3. Recruitment. The research staff will screen patients in the outpatient setting to identify 
potential candidates. For patients who are eligible on the basis of chart review, our research 
staff will approach them either in-person, or through remote methods for permission to con-
duct further screening for eligibility. Remote methods will consist of phone or vetted video-
conferencing platforms  (WebEx, Skype, FaceTime, or Zoom) to call potential participants to ex-
plain the study and gauge interest. If the participant wishes to participate, MyChart or e-mail 
will be used to send the consent form and research staff will obtain consent through this meth-
od. 
 

 
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A 2-step consent process will be used.  A verbal script is provided in the Appendix.  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. 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. 
 
The outpatient supportive care clinic alone has more than 7000 patient visits per year, with 
approximately 50 new consultations per week. Patients at the thoracic medical oncology and 
radiation oncology clinics will also be enrolled. To augment recruitment and study 
generalizability, we will also enroll patients from the General Medical Oncology Clinic at The 
Harris Health System (LBJ), a county hospital in Houston. In 2015, the program had 
approximately 500 new consultations and 9500 total patient visits. Our team has successfully 
recruited from this clinic for other supportive care trials (Yennurajalingam et al. 2013).  
 
To improve retention, we also plan to offer participants $50 gift cards for completion of day 
7 and day 14 in-person or phone assessments, for a total of up to $100, to compensate them 
for their time and the costs associated with transportation. The research staff will also provide 
$15 valet parking vouchers to MD Anderson patients upon completion of in-person 
assessments at Baseline, day 7, and day 14 for a total of up to $45. LBJ patients will receive $6 
parking vouchers for Day 7 and Day 14. A $6 Target gift card will be provided to LBJ patients at 
Baseline.  
 
D.4. Randomization and stratification. After patient enrollment, randomization will be con-
ducted by a pharmacist using permuted blocks and an institutional Clinical Trial Conduct (CTC) 
website. To minimize the possibility that imbalance in baseline dyspnea levels will affect meas-
urement of the primary outcome, we will stratify patients by baseline dyspnea NRS score at en-
rollment (4-6 and 7-10) and study site (MDA vs. LBJ). Only the pharmacists preparing the study 
medications will have access to the treatment assignment. We will maintain allocation con-
cealment. 
 
D.5. Study interventions. Dexamethasone is a commonly used medication in cancer patients.  It 
is approved by the US Food and Drug Administration for treatment of multiple indications, 
including allergic disorder (including asthma), cerebral edema associated with primary or 
metastatic brain tumor, craniotomy, or head injury, collagen disease, disorder of ear, disorder 
of endocrine system, disorder of eye, disorder of gastrointestinal tract, disorder of 
hematopoietic structure, disorder of respiratory system (treatment of berylliosis, fulminating or 
disseminated 
pulmonary 
tuberculosis 
(when 
used 
concurrently 
with 
appropriate 
antituberbulosis therapy), idiopathic eosinophilic pneumonias and symptomatic sarcoidosis, 
Loeffler's syndrome not manageable by other means and aspiration pneumonitis), disorder of 
skin, 
exacerbation 
of 
multiple 
sclerosis, 
hypercalcemia 
of 
malignancy, 
idiopathic 
thrombocytopenic purpura, inflammatory disorder of musculoskeletal system, macular retinal 
edema, mycosis fungoides, neoplastic disease, palliative management of leukemias and 
lymphomas, nephrotic syndrome, Idiopathic or due to lupus erythematosus without uremia, 
non-infectious posterior uveitis, trichinosis with neurologic or myocardial involvement, 
tuberculosis of meninges with subarachnoid block or impending block when used concurrently 

 
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with antituberculosis therapy.  However, it has not been specifically approved for management 
of dyspnea. 
 
Our study proposes to use oral dexamethasone for the management of dyspnea.  Based on 
our preliminary data, the intervention arm will receive dexamethasone at a dose of 8 mg given 
orally twice daily for 7 days, then 4 mg given orally twice daily for 7 days. We do not plan to 
seek FDA approval for the new indication of dyspnea. 
 
The control arm will receive placebo capsules prepared by a compounding pharmacy (e.g. 
Greenpark Pharmacy) identical in appearance to dexamethasone 4 mg capsules, and will be in-
structed to take two capsules twice a day for 7 days, followed by one capsule twice a day for 7 
days. 
 
In the open label phase, patients assigned to either arm will be asked to take dexame-
thasone 4 mg orally twice a day for 7 days, then 2 mg orally twice a day for 7 days.  Both dexa-
methasone and placebo capsules used throughout this study will be dispensed by Investiga-
tional Pharmacy at MD Anderson. Dexamethasone/placebo capsules and open-label tablets will 
be provided free of charge to patients during the study period.  
 
We will keep track of adherence by pill count. Patients will receive daily phone calls or other 
remote contact for reminders and assessments.  They can take it as soon as possible if they for-
get a dose. 
 
D.6. Blinding. Both patients and the research staff conducting the assessment will be blinded to 
the treatment assignment.  Placebo capsules identical to dexamethasone 4mg capsules in ap-
pearance and taste will be manufactured by a compounding pharmacy, and both will be dis-
pensed by Investigation Pharmacy at MD Anderson.  At the end of the blinded phase, we will 
assess blinding by asking patients which study arm they believe they have been randomized to.  
 
To minimize bias during statistical analyses, we will also blind the biostatisticians to the group 
assignment (groups A/B instead of dexamethasone/placebo) until they have completed the 
analyses pre-specified in the statistical analysis section after completion of study enrollment.   
 
D.7. Study assessments. See Table 3 for a detailed description of study assessments. Study 
assessments will be conducted either in-person, by phone, or other remote methods as 
previously detailed (vetted platforms consisting of WebEx, Skype, FaceTime, or Zoom) during 
the course of the study. 
D.7.1. Baseline characteristics. We will collect the following information to characterize the 
study population: date of birth, sex, race, education, marital status, cancer diagnosis, 
comorbidities, cause(s) of dyspnea, medications (e.g., scheduled and as-needed opioids, 
bronchodilators), and Karnofsky Performance Status (Schag et al. 1984). 
D.7.2. Dyspnea NRS. The dyspnea NRS score will be the primary study outcome measure. 
The dyspnea NRS is an 11-point categorical scale validated for rating the average intensity of 
dyspnea over the past 24 hours, ranging from 0 (no dyspnea) to 10 (worst dyspnea) (Dorman et 
al. 2007, Gift and Narsavage 1998, Powers and Bennett 1999). It has been extensively validated 
and translated into multiple languages, including Spanish (Carvajal et al. 2011, Chang et al. 
2000, Moro et al. 2006, Nekolaichuk et al. 2008, Paiva et al. 2015, Rees et al. 1998, Richardson 
and Jones 2009, Vignaroli et al. 2006, Watanabe et al. 2012, Zeng et al. 2011). Dyspnea NRS 

 
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score was chosen as the primary outcome measure instead of the modified Borg scale score 
because the dyspnea NRS was more responsive to change in our preliminary study (Hui et al. 
2016a). Specifically, the dyspnea NRS has good discriminatory performance, with area under 
the receiver-operating characteristic curve of 0.71 for improvement and 0.79 for deterioration 
(Hui et al. 2015b). The MCID was 1 point for improvement and 1 point for deterioration (Hui et 
al. 2015b). In addition to intensity, we will assess the affective component (unpleasantness 
associated with dyspnea) using the same scale as one of the secondary measures.  
 
D.7.3. Personalized dyspnea goal and personalized dyspnea response. The personalized 
dyspnea goal is determined by asking the patient, “At what level of shortness of breath 
intensity would you feel comfortable?” Personalized dyspnea response is defined as dyspnea 
NRS score ≤ personalized dyspnea goal. Thus, personalized dyspnea response provides a simple 
yet individualized therapeutic “target” and allows for intra-patient determination of a symptom 
response that is both practical and meaningful (Section D.2.1.1). However, because 
personalized dyspnea goal has never been tested in randomized, controlled trials, we will 
consider personalized dyspnea response only as a secondary outcome. 
 
D.7.4. Unpleasantness associated with dyspnea. We will ensure that each patient 
understands the differences between intensity and unpleasantness of breathlessness by 
providing clear instructions as follows: “Intensity refers to the pure level or magnitude of the 
sensation. It is like a physical measure: for example, ‘how much do you weigh in pounds?’ 
Intensity does not contain any pleasantness or unpleasantness, like or dislike, or measure of 
how terrifying the experience is to you. Unpleasantness describes how much you like or dislike 
something or feel terrified by it. High unpleasantness indicates that your breathing feels very 
bad or terrifying regardless of whether the intensity is high or low.” 
 
D.8. Medication use during study and cointerventions. During the 2-week blinded phase, pa-
tients may continue their usual treatments for dyspnea, including opioids, supplemental oxy-
gen, and bronchodilators. These treatments will be documented and adjusted for in the analy-
sis. Our eligibility criteria are designed to specifically exclude patients who have reversible 
causes of acute dyspnea, such as pleural effusions, COPD exacerbations, or pneumonia. 
 
D.9. Research staff training. 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 interven-
tion.  We will also conduct principal investigator research meetings 2-4x/month. 
 
D.10. Patient Safety, Monitoring, and Confidentiality. Prior to study initiation, all research staff 
participating in this study will receive an orientation to the devices and forms in this study to 
ensure consistent assessments.  During the study, trained research staff will be performing 
study assessments and monitoring the patient carefully throughout the study period. In addi-
tion to daily phone calls, or contact through other remote methods, patients will be given the 
contact information of the research staff in case they develop any significant adverse effects, 
and will be treated as they arise as per clinical practice.  The study may be discontinued at the 
discretion of the treating physician or study principal investigator.  Regulatory monitoring will 
be provided by the principal investigator, the Institutional Review Board, and the Data Safety 

 
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and Monitoring Board. Patient confidentiality will be ensured by use of patient initials, secure 
storage of clinical data, and anonymous reporting. 
 

 
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Table 3. Study assessments 
Assessment 
Baseline 
(in person) 
Days 0-6 
(phone or 
remote 
contact) 
Day 7±2 
(in per-
son11) 
Days 8-
13 
(phone 
or re-
mote 
contact) 
Day 
14±2 
(in per-
son11) 
Day 28±2, 
Day 42±2 
(phone or 
remote 
contact) 
Screening (Appendix A, B) 
 
 
 
 
 
 
Demographics (Appendix C) 
 
 
 
 
 
 
Dyspnea NRS score (primary outcome: intensity; secondary: 
unpleasantness; assessment requires <1min)1 (Appendix D) 
 
 
 
 
 
 
Personalized dyspnea goals (<1min)2  (Appendix I) 
 
 
 
 
 
 
Biomarkers (blood draw, 15min)3  (Appendix J) 
 
 
 
 
 
 
Physiologic measures (i.e., spirometry, vital signs, maximal 
inspiratory pressure [MIP]; 20min)4 (Appendix J) 
 
 
 
 
 
 
Edmonton Symptom Assessment System (<3min)5 (Appendix E) 
 
 
 
 
 
 
HADS (<5min)6  (Appendix H) 
 
 
 
 
 
 
EORTC Quality of Life Questionnaire (QLQ)-C30 (<10min)7 (Appendix 
F) 
 
 
 
 
 
 
Adverse effects (10min)8 (Appendix K) 
 
 
 
 
 
 
Global assessment (<1min)9 (Appendix G) 
 
 
 
 
 
 
Pill count and check of blinding (<1min)10 (Appendix L) 
 
 
 
 
 
 
1The dyspnea NRS is a categorical scale ranging from 0 (no dyspnea) to 10 (worst dyspnea), validated for rating the average intensity of dyspnea 
over the past 24 hours (Dorman et al. 2007, Gift and Narsavage 1998, Powers and Bennett 1999). It is part of the ESAS (Bruera et al. 1989). The 
MCID is 1 point (Hui et al. 2015b). We will ask patients to rate the unpleasantness of dyspnea over the past 24 hours as well using the same 
NRS (i.e., ranging from 0 to 10).  
2We will assess personalized dyspnea goals for dyspnea intensity by asking “At what level of intensity would you feel comfortable, on a scale of 
0 to 10 where 0 = no shortness of breath and 10 = worst possible?” (Hui et al. 2016b). As an exploratory measure, we will also assess the 
personalized dyspnea goal for unpleasantness related to dyspnea: “At what level of unpleasantness would you feel comfortable, on a scale of 0 
to 10 where 0 = no unpleasantness related to shortness of breath and 10 = worst possible?” Personalized dyspnea response is defined as 
dyspnea NRS ≤ personalized dyspnea goal. To assess the stability of personalized dyspnea goals, we will ask participants to provide this on day 
14 ± 2 as well. 
3A blood sample (~10 mL) will be obtained using sterile venipuncture techniques between 1200 and 1600 to control for potential diurnal 
variation at designated data points. Samples obtained in EDTA-containing Vacutainers will be transported on ice in a secure cooler to the 
bioscience laboratory at the University of Texas. Samples will be centrifuged for 15 minutes at 3000 rotations per minute within 24 hours and 
plasma will be aliquoted into cryovials for storage at -80°C until batch processing. Following standardized protocols of specific enzyme-linked 
immunosorbent assays for each biomarker (R&D Systems, Minneapolis, MN), inflammatory biomarkers (IL-1β, IL-6, IL-8, IL-10, and TNF-α) will 
be assessed in duplicate by the same trained person. Intra- and interassay coefficients of variation will be calculated to check precision. This 
type of bioassay has been routinely performed in this laboratory with high precision.  
4The MicroLoop Spirometer (Micro Direct Inc, Lewiston, ME) will be used at baseline, day 7, and day 14. It is approved by the American 
Thoracic Society and the US FDA. Various spirometry parameters will be obtained, such as forced expiratory volume (FEV1), forced vital 
capacity (FVC), FEV1/FVC, peak inspiratory flow, and peak expiratory flow. Respiratory rate and oxygen saturation will be assessed in person. 
We will also assess MIP using the NS 120-TRR NIF Monitor (Instrumentation Industries Inc., Bethel Park, PA) according to the American Thoracic 
Society Guideline (Ats/Ers 2002). At least three consecutive inhalation scores will be recorded, with a 1-minute pause between each effort. We 
will use the average of the top three measures that varied by <20% for analysis. 
5The ESAS is a 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). 
6The HADS consists of 14 items with 4-point numeric rating scales, including seven items on depression (HADS-D) and seven items on anxiety 
(HADS-A) (Zigmond and Snaith 1983). HADS has been validated for depression and anxiety in various settings. The average Cronbach alpha for 
HADS-A was 0.83, and 0.82 for HADS-D. Using a cutoff of 8 or greater for either subscale, the sensitivity and specificity were both 
approximately 80% for both HADS-A and HADS-D (Bjelland et al. 2002). 
7The EORTC QLQ-C30 is a well-validated quality-of-life assessment for patients with cancer, consisting of 30 questions that encompass three 
symptom scales (pain, fatigue, and nausea/vomiting) and six questions about single symptoms, as well as five functional scales (physical, 
cognitive, role, emotional, and social) and one scale assessing global health status/quality of life. Each scale consists of two to five items, and all 
items have four response categories (not at all, a little, quite a bit, and very much), except for two items assessing overall health status/quality 
of life, which use a 7-point scale. 
8In addition to clinician assessment of adverse effects according to CTCAE v4.03, adverse effects related to the use of dexamethasone, such as 
heartburn (F, S), nausea (F, S), pain in the abdomen (F, S, I), vomiting (F, S), arm/leg swelling (F, S, I), fatigue (F, I), decreased appetite (S, I), 
anxiety (F, SI, I), feelings that nothing could cheer you up (F, S, I), insomnia (S, I), sad or unhappy feelings (F,S, I), hiccups (F, S), hives (P), itchy 
skin (S), and rash (P) will be rated by patients using the PRO-CTCAE, which has recently been translated and validated in Spanish (Arnold et al. 
2016, Basch et al. 2014, Bennett et al. 2016, Dueck et al. 2015). F = frequency, S = severity, I = interference with usual or daily activities, P = 
presence. 
9Patients will be asked about their dyspnea (worse, about the same, or better) to compare the level of dyspnea before and after the study 
(Guyatt et al. 1993, Redelmeier et al. 1996). 
10We will assess adherence by pill count on day 7 and day 14. We will also examine the success of blinding by asking patients to guess which 
treatment was given (“dexamethasone,” “placebo,” or “do not know”). 
11 If patient available, otherwise, a phone call or other remote method will be conducted to administer the questionnaires.  

 
2017-0591 
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E. Statistical Analysis 
E.1. Sample size calculation. We will use 2:1 randomization as outlined in Section D.1.2.8. With 
a two-sided 5% alpha, normally distributed data, equal variance between treatment groups, 
and a within-group standard deviation of 2.0 (based on our preliminary data; Section D.1.1.3), 
we will need a total of 174 (116 + 58) patients to have 80% power to detect a mean difference 
of 1.0 between treatment groups. Assuming 15% attrition, we will need to enroll 134 patients in 
the dexamethasone arm and 67 in the placebo arm (201 total).  
E.2. Data analysis 
 
E.2.1. Primary objective. The primary endpoint will be dyspnea NRS score at day 7. Primary 
analysis will be a linear model comparing mean day 7 scores between treatment groups while 
adjusting for baseline levels. We will graph the data and perform residual analyses to verify 
assumptions of the model and take appropriate actions if the assumptions appear to be 
validated (e.g., transforming the data).  
 
We will analyze the data with modified intention-to-treat analysis, by including all patients 
who were randomized started the study treatment, regardless of whether they complete the 
study.  We will perform multiple imputation to handle missing data for the primary outcome.  
We will also conduct sensitivity analyses with worst case scenario (assume no change if no 
primary outcome data) and last value carry forward approaches.   
 
E.2.2. Secondary objective #1. We will compare treatment groups at day 7 and day 14 for 
the values of the outcomes listed above. For the numeric outcomes (FEV1, FVC, MIP, oxygen 
saturation, ESAS, HADS, EORTC QLQ-C30, PRO-CTCAE frequency/severity/interference), we will 
perform linear model analyses as indicated in Aim 1. For personalized dyspnea response, we 
will use logistic regression analysis. For clinician-rated CTCAE adverse effects, we will tabulate 
by grade, type, attribution, and treatment group and compare the incidence of grade 3 or 
higher treatment-related toxic effects between treatment groups using logistic regression. For 
the daily dyspnea NRS values, we will use linear mixed-effects models to compare changes in 
scores over time between treatment groups (for the first 7 days and for the first 14 days). For 
the numeric endpoints, we will have 80% power to detect an effect size (mean difference 
divided by within-group standard deviation) of 0.5. For personalized dyspnea response, we will 
have >80% power to detect a 25% difference (e.g., 10% vs. 35%).To avoid issues with multiple 
testing, results will be considered hypothesis-generating rather than hypothesis-testing. 
 
E.2.3. Secondary objective #2. The primary endpoint will be the baseline to day 7 difference 
in dyspnea NRS (>1.0 is considered clinically significant). We will use logistic regression analysis 
to identify independent predictors of this outcome, including baseline dyspnea NRS, restrictive 
or obstructive lung disease pattern, MIP, sex, and baseline inflammatory cytokine levels (IL-1β, 
IL-6, IL-8, IL-10, and TNF-α). We will plot the data and use residual analyses to verify 
assumptions of the model and take appropriate actions if they appear to be validated (e.g., 
transforming the data). We will use the variance inflation factor to identify collinearity. With 
116 dexamethasone-treated patients, we would have at least 80% power to detect an odds 
ratio of 2.5 (for a one-unit change in a normally distributed marker) if the response probability 
is at least 30% (assuming 5% alpha and a correlation between the marker and the other factors 
in the model of 0.30). As an exploratory analysis, we will perform a similar analysis to that 
described for the primary endpoint to determine whether patients achieved their personal goal 
in dyspnea improvement. We will perform a similar exploratory linear regression analysis using 

 
2017-0591 
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Page 15 of 21 
the difference between the day 7 and baseline dyspnea NRS scores as the endpoint. Additional 
exploratory correlative analyses will be conducted for changes in inflammatory markers 
between day 7 and baseline. 
 
E.2.4. Secondary objective #3.  We will calculate summary statistics for duration of 
dexamethasone dosing and cumulative dexamethasone dose.  Two-sample t-tests or Wilcoxon 
rank sums tests will be used to examine whether binary events, such as adverse events, are 
associated with higher doses or duration of dexamethasone.  If number of hospital admissions 
follows a Poisson distribution or zero-inflated Poisson distribution, we will use the appropriate 
model to examine the association of number of hospitalizations with cumulative dose and 
duration.  All patients, regardless whether they received placebo, will be used to examine dose 
and duration initially.  In these analyses, dose and duration for patients who received placebo 
will be set to zero.  In a second set of analyses, only those patients who received 
dexamethasone will be included in the analyses.  All testing will be 2-sided with 5% alpha.  We 
will consider limiting the false detection rate to 10%. 
 
E.2.5. Secondary objective #4.  We will tabulate agreement between CTCAE adverse events 
and adverse events collected from the PRO-CTCAE form.  We will also conduct chi-squared 
testing or Fisher’s exact tests to determine whether treatment assignment or any other 
potential factors affects agreement.  All testing will be 2-sided with 5% alpha.  We will consider 
limiting the false detection rate to 10%. 
 
E.2.6  Open label phase: We will conduct descriptive analyses to summarize the findings in 
the open-label phase in each arm.  Exploratory analyses, as appropriate, will also be conducted 
to examine the between-group difference for various outcomes for hypothesis-generating 
purposes only. 
 
E.2.7. Interim analysis: We will conduct two interim analyses (when roughly 33% and 67% 
of patients have been enrolled). We will look at both superiority (efficacy) and futility using 
O’Brien-Fleming boundaries. For futility, the p-value boundaries are 0.980, 0.359, and 0.046. 
For superiority, the Z-value boundaries are +/- 3.710, +/- 2.511, +/- 1.993.  Calculations were 
done in East 6. 
 
F. Data Confidentiality Procedures  
Health information will be protected and we will maintain the confidentiality of the data ob-
tained from the patient's chart to the best of our ability.   
 
Collection of identifiers: We will collect and securely store patients' identifiers (including 
name, medical record number, and date of birth).  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 dis-
closed 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, and research staff will have access to study records. 

 
2017-0591 
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Page 16 of 21 
 
Data sharing: Study data will not be shared with any individuals or entities without an IRB-
approved protocol.  
 
Final disposition of study records: PHI may be maintained indefinitely, aggregated in the fu-
ture, and used for future IRB-approved research studies.  
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