The Use of Intranasal Fentanyl for the Treatment of Incident Dyspnea in Congestive Heart Failure: A Prospective Trial
The Use of Intranasal Fentanyl for the Treatment of Incident Dyspnea in Congestive Heart Failure: A Prospective Trial
Study Objective The primary object of this study is to investigate the safety and
 effectiveness of fentanyl on the management of incident dyspnea.

 Study Design The study design will be a cross over study with a minimum of a one hour wash
 out period.
Clinical question and hypothesis In patients with congestive heart failure who experience
 episodic activity-induced dyspnea (incident dyspnea), will the administration of intranasal
 fentanyl pre-activity result in subjective improvement in dyspnea and objective improvement
 in functional capacity? Will there be side effects from this treatment?

 We expect that pre-activity treatment with intranasal fentanyl will result in both subjective
 improvements in dyspnea ratings as well as an increased measurement of functional capacity.
 We also suspect that this treatment will not increase the patient's experienced side effects.

 Study Objective The primary object of this study is to investigate the safety and
 effectiveness of fentanyl on the management of incident dyspnea.

 Study Design The study design will be a cross over study with a minimum of a one hour wash
 out period.

 Participation in this study will be for 2 hours over 1-2 days.

 Primary Endpoints

 • Walking distance from the 6MWT

 Secondary Endpoints

 -  Subjective rating of dyspnea and side effects

 -  Heart rate, respiratory rate, oxygen saturation and participants' general appearance.

 Sample Size We hope to study 20 patients. Given the paucity of data so far, it is not
 possible to statistically calculate the appropriate power for this study and 20 patients is
 an approximation based on clinical experience.

 There is not enough data available currently for our statistician to find a power calculation
 that eliminates type 1 and 2 error. Based on anecdotal evidence and experience with this
 medication in the clinical setting, we have estimated that the number needed to determine a
 clinically relevant difference is likely around 20.

 Patient Population We will study the application of fentanyl in patients ages 18 or older, of
 either gender, with either a diagnosis of NYHA Class 3 or 4 heart failure.

 Inclusion Criteria

 -  Patients must be experiencing activity-induced incident dyspnea without reversible
 causes. They would have controlled background dyspnea without opioids.

 -  Patients must be physically able to safely ambulate in order to complete the 6MWT (may
 have mobility devices and may use supplement oxygen prescribed pre-study).

 Exclusion Criteria

 -  Patients who are unable to perform the 6MWT for any reason or have contraindications to
 performing the 6MWT

 -  Patients that have anatomical pathologies that would make intranasal administration
 impossible

 -  Patients with known allergies/sensitivities to fentanyl/sufentanil

 Withdrawal Criteria Participants may voluntarily withdraw from the study at any time they
 feel uncomfortable with the protocol. They will also be withdrawn if they experience chest
 pain, palpitations, syncope, presyncope, or worsening dyspnea. Objectively, they will be
 withdrawn if blood pressure drops below 90/50, heart rate drops below 60 or rises above 100,
 if oxygen saturation drops below 90%, or if respiratory rate drops below 8 or rises above 20.
 If any of: oxygen saturation, blood pressure, or respiratory rate drop below the cut off
 point and do not recover within 5 min of rest, the antidote, Naloxone will be administered
 with a subcutaneous injection. The trial may be stopped early if the treatment arm
 statistically demonstrates superiority or increased harm.

 Treatment of Subjects All patients will do the walk test with and without and fentanyl. They
 will be instructed to continue any current medications that have been previously prescribed
 and to not make any changes to their medications. Should they be on any medications for
 dyspnea such as diuretics, bronchodilators, inhaled steroids, continuous oxygen, opioids
 etc., they are to be continued.

 Before the first walk test, the patient will be asked to rate their baseline dyspnea,
 somnolence, anxiety, pain and nausea using the ESAS VAS scale. The research team will record
 baseline heart rate, respiratory rate, oxygen saturation and describe the patient's general
 appearance. The patient will complete the 6MWT under appropriate supervision from our
 research team.

 The research team will re-measure the study patient's heart rate, respiratory rate, oxygen
 saturation and describe their general appearance for comparison to baseline. Any other
 adverse effects or symptoms will be recorded. These measures will be repeated at 10 minutes
 and 20 minutes post-6MWT to document any resolution of symptoms post activity. Following the
 6MWT, treatment for dyspnea will be provided if required. The patient will also rerate their
 dyspnea, somnolence, anxiety, pain and nausea using the ESAS VAS scale for an objective
 measure.

 After a minimum of 1 hour (wash out period), they will proceed to the second phase of the
 test.

 For the second phase, the patient will once again be asked to rate their baseline dyspnea,
 somnolence, anxiety pain and nausea using the ESAS VAS scale. This is to ensure consistency
 among their baseline measures. The research team will record their objective measures as
 stated above. The patients will then be given the fentanyl treatment and the 6MWT will be
 repeated.

 Patients would be administered a spray of 50mcg of fentanyl intranasally as suggested as the
 first titration step outlined in the Incident Pain and Dyspnea protocol, developed by the
 Winnipeg Regional Health Authority Palliative Care Program
 (http://palliative.info/IncidentPain.htm).

 Following the 6MWT, the patient will again be asked to rate their baseline dyspnea,
 somnolence, anxiety and nausea using the ESAS VAS scale. The research team will complete and
 record objective measurements. As in phase 1 these measures will be repeated at 10 minutes
 and 20 minutes post-6MWT to document any resolution of symptoms post activity.

 Assessment of Efficacy By collecting data at the time points described above, we will be able
 to compare the averaged baseline symptoms with exertion induced symptoms. Most importantly,
 the data will allow us to compare the difference in subjective symptoms between
 pre-exertional treatment with intranasal fentanyl with symptoms without pre-exertional
 treatment. Using the 6MWT, we would be able to objectively assess any change in the study
 patient's walking distance, which would represent a change in their functional capacity.

 Assessment of Safety Patients will be monitored with a subjective symptom assessment scale
 (ESAS) and also with vital sign monitoring. If adverse events occur, the patients will be
 monitored by the research nurse with vitals signs taken every 5 minutes until the patient
 settles. If the patient does not settle within 5 minutes, as evidenced by an improvement in
 vital signs and/or subjective report, the research nurse will determine whether naloxone
 should be administered. If naloxone is not indicated, or the patient does not improve with
 the administration of naloxone, the research nurse will report the patient's condition to the
 patients primary nurse in charge of his/her care on the ward. The research nurse will further
 assist the primary nurse in providing standard medical care to the participant as necessary.
 If naloxone is administered, the research nurse will inform the primary ward nurse and will
 continue to monitor the patient with vital signs every 5 min for an hour. After an hour has
 elapsed, it is anticipated the study medication will have cleared from the participants body,
 and any unresolved adverse effects will be managed according to standard medical practice by
 the ward doctors and nurses. All adverse events will be documented. All serious adverse
 events (representing a significant health hazard to the participant) will be reviewed by the
 medical monitor and reported to the sponsor and the University of Manitoba Research Ethics
 Board and Health Canada accordingly.

 Statistical Analysis Comparison of subjective rank data (non-parametric) between phase 1 and
 phase 2 will be analyzed using the Wilcoxin rank sum test. Comparison of objective numerical
 data (parametric) between phase 1 and 2 will be analyzed using paired t-tests. The 6MWT
 interpretation will include both absolute differences and percentage differences.
Inclusion Criteria:

 -  Patients must be experiencing activity-induced incident dyspnea without reversible
 causes. They would have controlled background dyspnea without opioids.

 -  Patients must be physically able to safely ambulate in order to complete the 6MWT (may
 have mobility devices and may use supplement oxygen prescribed pre-study).

 Exclusion Criteria:

 -  Patients who are unable to perform the 6MWT for any reason or have contraindications
 to performing the 6MWT

 -  Patients that have anatomical pathologies that would make intranasal administration
 impossible

 -  Patients with known allergies/sensitivities to fentanyl/sufentanil