Fentanyl Buccal Tablet or Morphine for Exertional Dyspnea in Cancer Patients

Study Overview
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Brief Summary
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This phase II trial studies fentanyl buccal tablet or morphine to see how well it works compared to a placebo in controlling shortness of breath during or after physical activity in cancer patients. Fentanyl sublingual tablet and morphine are opioids normally used to control pain that may also help to prevent or control shortness of breath during or after physical activity in cancer patients.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the effect of prophylactic fentanyl buccal tablet (FBT), morphine sulfate, and placebo on the increase in the intensity of exertional dyspnea (0-10 point modified Borg scale) measured before versus at the end of a shuttle walk test (SWT). SECONDARY OBJECTIVES: I. To compare the effects of prophylactic FBT, morphine sulfate, and placebo on SWT distance and dyspnea unpleasantness, average daily dyspnea (intensity and unpleasantness, oxygen cost diagram), personalized daily activity (ability to complete activity), personalized dyspnea response, symptom burden (Edmonton Symptom Assessment System [ESAS]), quality of life (EuroQol-5 Dimension-5 Level [EQ-5D-5L]), and dyspnea severity and functional impairment based on the Patient Reported Outcomes Measurement Information System (PROMIS) dyspnea instruments. II. To explore the effects of prophylactic FBT, morphine sulfate, and placebo on neurocognitive function, addictive potential (Drug Effects Questionnaire), adverse effects (Common Terminology Criteria for Adverse Events [CTCAE], Patient-Reported Outcomes version of CTCAE [PRO-CTCAE]), and pattern of opioid use. OUTLINE: Patients are randomized to 1 of 3 groups. GROUP I: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive FBT sublingually daily on days 6-19. GROUP II: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive morphine orally (PO) daily on days 6-19. GROUP III: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive placebo (sublingually or PO) daily on days 6-19.

Official Title
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Efficacy and Safety of Rapid-Onset Opioids for Exertional Dyspnea in Cancer Patients

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: Fentanyl Citrate Buccal Tablet
* Drug: Morphine
* Other: Physical Performance Testing
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of cancer with evidence of active disease Dyspnea on exertion with an average intensity level ≥4/10 on a modified Borg scale Outpatient at participating centers Ambulatory and able to walk, with or without walking aid On strong opioids with morphine equivalent daily dose (MEDD) of 60-400 mg for ≥1 wk (i.e. at least 4 out of 7 days), with stable (i.e. ±30%) regular dose over the last 3 d Karnofsky performance status ≥40% Age ≥18 yrs Able to complete study assessments Able to speak English or Spanish Reside within 65 miles of participating centers or expected to visit MD Anderson in person at least once a month Exclusion Criteria: Dyspnea at rest ≥7/10 on modified Borg scale at enrollment Supplemental oxygen requirement >6 L/min Delirium (i.e. Memorial Delirium Assessment Scale ≥13) History of unstable angina or myocardial infarction 1 mo prior to enrollment Hemodynamic instability requiring hospitalization History of substance use disorder or abnormal urinary drug screen within the past year, or at risk of opioid abuse as determined by Screener and Opioid Assessment for Patients with Pain (SOAPP14) ≥7 History of or known allergy to fentanyl or morphine sulfate Using scheduled benzodiazepines at the time of enrollment and cannot stop during the study Severe anemia (Hb <7 g/L) if documented in the last month and not corrected prior to study enrollment* Bilirubin ≥5x upper limit of normal if documented in the last month and not lowered to <5x normal prior to enrollment* Diagnosis of acute pulmonary embolism within past 2 wks Diagnosis of pulmonary hypertension Diagnosis of malignant pleural effusion with therapeutic thoracentesis expected in the next 2 wks Currently pregnant or breastfeeding Unwilling to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (shuttle walk test, FBT)<br>Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive FBT sublingually daily on days 6-19. | Drug: Fentanyl Citrate Buccal Tablet<br>* Given transmucosally<br>* Other names: Fentora;Other: Physical Performance Testing<br>* Complete shuttle walk test<br>* Other names: Physical Function Testing;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Group II (shuttle walk test, morphine)<br>Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive morphine PO daily on days 6-19. | Drug: Morphine<br>* Given PO<br>Other: Physical Performance Testing<br>* Complete shuttle walk test<br>* Other names: Physical Function Testing;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Active Comparator: Group III (shuttle walk test, placebo)<br>Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive placebo (sublingually or PO) daily on days 6-19. | Other: Physical Performance Testing<br>* Complete shuttle walk test<br>* Other names: Physical Function Testing;Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in modified Borg scale dyspnea intensity before and after the Shuttle Walk Test (SWT) | Will first determine whether the three treatment groups are different; if so, will test the three pairwise comparisons with intention-to-treat analyses. Repeated-measures analysis of variance (ANOVA) will be implemented using linear mixed effects models with the difference in intervention period SWT modified Borg scale dyspnea intensity before and after SWT as the response variable and the treatment group and observation period SWT measures as predictor variables. | Days 5, 8, 12, 15, and 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SWT distance | Will be analyzed using linear mixed effects models similar to the primary analysis. | Days 5, 8, 12, 15, and 19 | 
| Dyspnea unpleasantness | Will be analyzed using linear mixed effects models similar to the primary analysis. | Days 5, 8, 12, 15, and 19 | 
| Daily dyspnea intensity and unpleasantness | Will be analyzed using linear mixed effects models similar to the primary analysis. | Days 1-19 | 
| Personalized daily activity | Will be analyzed using linear mixed effects models similar to the primary analysis. | Days 1-4, 6-7, 9-11, 13-14, and 16-18 | 
| Oxygen cost diagram | Will be analyzed using linear mixed effects models similar to the primary analysis. | Days 1-19 | 
| Symptom burden Questionnaires | Will be measured by the Edmonton Symptom Assessment System and analyzed using linear mixed effects models similar to the primary analysis. | Days 1-19 | 
| Quality of life Questionnaires | Will be measured by the EuroQol-5 Dimension-5 Level Questionnaire and analyzed using linear mixed effects models similar to the primary analysis. | Days 1-19 | 
| Neurocognitive function | Will perform paired t-test or ANOVA if the data are normally distributed and the Wilcoxon rank-sum test or Kruskal-Wallis if the data are non-normal. | Up to day 19 | 
| Addictive potential | Will be measured by the Drug Effects Questionnaire. Will perform paired t-test or ANOVA if the data are normally distributed and the Wilcoxon rank-sum test or Kruskal-Wallis if the data are non-normal. | Up to day 19 | 
| Frequency, severity, and interference of adverse effects | Will be measured by the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). Will perform paired t-test or ANOVA if the data are normally distributed and the Wilcoxon rank-sum test or Kruskal-Wallis if the data are non-normal. | Up to day 19 | 
| Total opioid dose | Will perform paired t-test or ANOVA if the data are normally distributed and the Wilcoxon rank-sum test or Kruskal-Wallis if the data are non-normal. | Up to day 19 | 
| Number of rescue doses per day | Will perform paired t-test or ANOVA if the data are normally distributed and the Wilcoxon rank-sum test or Kruskal-Wallis if the data are non-normal. | Up to day 19 | 
| Dyspnea severity and functional impairment | Will be measured using the Patient Reported Outcomes Measurement Information System (PROMIS) dyspnea instruments. | Day 1, 5, 12, 19 |