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Trial registered on ANZCTR


Registration number
ACTRN12617001399381
Ethics application status
Approved
Date submitted
14/09/2017
Date registered
4/10/2017
Date last updated
17/07/2019
Date data sharing statement initially provided
17/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Intra-nasal fentanyl for breathlessness
Scientific title
Intranasal Fentanyl versus Placebo for treatment of episodic breathlessness in hospice patients with advanced non-malignant terminal diseases, a randomized double blind crossover feasibility study
Secondary ID [1] 290965 0
nil known
Universal Trial Number (UTN)
U1111-1195-5691
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breathlessness in palliative care patients who have terminal illness from a non-malignant disease 301707 0
Condition category
Condition code
Respiratory 301406 301406 0 0
Other respiratory disorders / diseases
Cardiovascular 301407 301407 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants are to be randomized into 2 treatment groups with sequences composed of 2 sets of 3 administrations (number 1-3 and 4-6), with each set comprising of fentanyl 5 microgram/puff, and placebo- an inactive drug. Patients in group 1 receive fentanyl in bottles 1-3 and placebo in bottles 4-6. Patients in group 2 receive placebo in bottles 1-3 and fentanyl in bottles 4-6. Patients are instructed to treat 6 episodes of acute shortness of breath using the order the spray bottles are ordered and they are to record their response at set interval. If symptom persists after 15 minutes, they are to take their usual rescue medication. Results are then analyzed to determine efficacy and any adverse effects of the treatment. Intra-nasal fentanyl, 5mcg/puff, 2 puffs are administered into each nostril = total dose of 20mcg for each breathlessness episode. This can be repeated upto hourly. The number of episodes to be treated is six episodes per patient. This is based on pharmacokinetic study that shows therapeutic concentration is achieved within 2 minutes and elimination half -lives are found to be 29.8 and 31.2 minutes for solution pH of 6 and 8 respectively. (Lim, Sunderland et al 2003). Based on the above mentioned half-lives, the wash out period between fentanyl and placebo is 60 minutes.
Adherence is based on what is reported by patients using study questionnaires that record study drug use. The questionnaires are collected and checked with patients at the final study visit.
it is expected six breathlessness episodes are very readily achievable over 24 hours to 7 day period in hospice patients who have high symptom burden.
Lim S, Paech MJ, Sunderland B, Roberts MJ, Banks SL, Matthew R. Pharmacokinetics of Nasal Fentanyl. Journal of Pharmacy Practice and Research. 2003;33(1):59-63
Intervention code [1] 296915 0
Treatment: Drugs
Comparator / control treatment
placebo - normal saline intra-nasal spray
Control group
Placebo

Outcomes
Primary outcome [1] 300799 0
change in Visual analogue dyspnea scale at 15 minutes after administration of the studied drug
Timepoint [1] 300799 0
At 15 minutes after drug administration
Secondary outcome [1] 330887 0
The secondary outcome is for each subject, the proportion of episodes requiring rescue medications after 15 minutes of drug administration. An expected total of 6 episodes are treated with either placebo or fentanyl as per protocol.
Timepoint [1] 330887 0
at 15 minutes after drug administration
Secondary outcome [2] 339079 0
Adverse events are recorded by patients on "episodes' questionnaires" and by investigator during initial and final visits on specified final visit questionnaires and initial visit recording sheets. Each adverse event is also to be recorded by investigator on subjects' adverse event log. These events are tallied as part of data analysis. All questionnaires are designed specifically for this study.
Previous studies using much higher dosage of intra-nasal fentanyl (50-200mcg per dose) showed the following possible side effects: Nausea, Constipation, vertigo, respiratory depression, nasal symptoms (stinging, itchy), changes in mental status. Of note, there was no respiratory depression observed below a dosage of 100mcg. Enrolled subjects (after giving consent) are assessed for respiratory depression at initial visits by site PIs. Remaining side effects are listed in "episode questionnaires" which patients are required to fill out for each episode of breathlessness after administration of study drug and the final visit questionnaire.
Christrup LL, Foster D, Popper LD, Troen T, Upton R. Pharmacokinetics, Efficacy, and Tolerability of Fentnayl Following Intranasal Versus Intravenous Administration in Adults Undergoing Third-Molar Extraction: A Randomized, Double Blind, Double-Dummy, Two-Way, Crossover Study. Clinical Therapeutics. 2008;30(3):469-81
Kress H, Oronska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and Tolerability of Intranasal Fentanyl Spray 50 to 200 mcg for Breakthrough Pain in Patients with Cancer: A Phase III, Multinational, Randomized, Double-Blind, Placebo-Controlled, Crossover Trial with a 10- Month, Open-Label Extension Treatment Period. Clinical Therapeutics. 2009;31(6):1177-91
Timepoint [2] 339079 0
Reporting of adverse event begins at randomisation until subjects' final visits, 2 weeks after randomisation.

Eligibility
Key inclusion criteria
The study population is composed of enrolled hospice patients with the following eligibility criteria:
Age, 18 and above
Primary diagnosis of non-malignant disease
Symptom of episodic dyspnoea on a daily basis at least once per day in the previous week
already on rescue opioid for episodic dypsnea
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Diagnosis of malignancy
Non English speaking
Unable to give informed consent
confirmed or suspected pregnancy
history of current history of depression

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
numbered containers are prepared by on-site pharmacist who has no contact with participants or involved in data collection.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
patients are randomised into either arm using an online random number generator
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Since this is a feasibility study, one could estimate the sample size for this study by taking a percentage of sample size for a phase 3 study designed in a similar way but with an intention to answer the research question definitively. (Abernathy, Currow et al 2003) This can be done by using effect size of another study that examined a related medication – oral morphine on a similar population for the relief of refractory dyspnoea. The effect size is calculated to be 0.408, mean VAS-D (SD): morphine 40.3 (23), placebo 49.9 (24). Using a of 0.05 and ß of 0.2, and paired sample t-test, the sample size (total number of episodes) in each arm is calculated to be 50. As each patient receives both placebo and treatment, the total number of patients required is 50. As each participant is expected to treat 6 episodes of breathlessness, the number of participants = (50x2) ÷6 = 17 patients.
Based on the same study mentioned above, an estimated drop-out rate of 20% is to be factored into the final sample size calculation = 17*1.2 = 20.4 patients. i.e. a sample size of 20 patients for this study.
Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, Double Blind, Placebo Controlled Crossover Trial Of Sustained Release Morphine For The Management Of Refractory Dyspnoea. BMJ: British Medical Journal. 2003;327(7414):523-6.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8593 0
New Zealand
State/province [1] 8593 0
Wellington
Country [2] 8827 0
New Zealand
State/province [2] 8827 0
Palmerston North

Funding & Sponsors
Funding source category [1] 295380 0
Hospital
Name [1] 295380 0
Te Omanga Hospice
Address [1] 295380 0
136 Woburn Road, Lower Hutt, Wellington 5010
Country [1] 295380 0
New Zealand
Primary sponsor type
Individual
Name
Medical Director, Dr Ian Gwynne Robson
Address
Te Omanga Hospice
136 Woburn Road, Lower Hutt, Wellington 5010
Country
New Zealand
Secondary sponsor category [1] 295089 0
None
Name [1] 295089 0
Address [1] 295089 0
Country [1] 295089 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297424 0
Health and Disability Ethics Committee
Ethics committee address [1] 297424 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 297424 0
New Zealand
Date submitted for ethics approval [1] 297424 0
12/10/2017
Approval date [1] 297424 0
09/03/2018
Ethics approval number [1] 297424 0

Summary
Brief summary
This study aims to examine the effect of fentanyl applied intra-nasally for the management of shortness of breath in patients with advanced non- malignant disease when their symptoms have become less responsive to treatment of the underlying disease. Intranasal fentanyl is already widely used for the treatment of pain in clinical practice and therefore their side effects are well known. The dosage used in this study is much lower than what is normally used for pain, therefore the risk of adverse events is expected to be lower than expected. Eligible patients enrolled in the hospice programme are invited to participate.
Trial website
Trial related presentations / publications
Study proposal was presented at the 8th Annual Research Forum in Sydney (2 March 2017), Palliative Care Clinical Studies Collaborative,
Public notes

Contacts
Principal investigator
Name 71854 0
Dr Salina Iupati
Address 71854 0
c/o Te Omanga Hospice,
136 Woburn Road
Lower Hutt 5010
Country 71854 0
New Zealand
Phone 71854 0
+6445697921
Fax 71854 0
Email 71854 0
salina.iupati@teomanga.org.nz
Contact person for public queries
Name 71855 0
Dr Salina Iupati
Address 71855 0
c/o Te Omanga Hospice,
136 Woburn Road
Lower Hutt 5010
Country 71855 0
New Zealand
Phone 71855 0
+6445697921
Fax 71855 0
Email 71855 0
salina.iupati@teomanga.org.nz
Contact person for scientific queries
Name 71856 0
Dr Salina Iupati
Address 71856 0
c/o Te Omanga Hospice,
136 Woburn Road
Lower Hutt 5010
Country 71856 0
New Zealand
Phone 71856 0
+6445697921
Fax 71856 0
Email 71856 0
salina.iupati@teomanga.org.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results