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Trial registered on ANZCTR


Registration number
ACTRN12609000506291
Ethics application status
Approved
Date submitted
18/06/2009
Date registered
25/06/2009
Date last updated
2/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Midazolam Nasal Spray for the treatment of breathlessness in patients with life-limiting disease
Scientific title
Intranasal midazolam for the palliation of dyspnoea in patients with optimally treated life limiting disease
Secondary ID [1] 295381 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dyspnoea (Breathlessness) 237062 0
Condition category
Condition code
Other 237410 237410 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intra-nasal midazolam. Each participant will receive six identical spray bottles, three will contain midazolam, and three citric acid in Normal saline. The six nasal spray bottles will be numbered 1-6 and will contain either midazolam or placebo (Citric acid in Normal saline) in a random sequence. Participants will be instructed to use a total of 3 inhalations (total dose of 1.5mg active drug) no more frequently than every 4 hours. This dose is administered as 1 spray in alternating nostrils for 3 administrations.
Participants will be asked to use a study nasal spray(SNS) as their first rescue dose for dyspnoea on any day that they require a rescue dose (starting no earlier than 0600hrs), taking number 1 SNS on the first day, number 2 on the second day, number 3 on the third etc, provided no SNS has been used for 4 hours prior, or breakthrough pain medication within 6 hours. If patients do not experience dyspnoea, they are not required to use a SNS that day.
Only the first dose each day will be formally assessed, but participants can continue to use the SNS throughout the day (no more frequently than every 4 hours) if they find it useful. All SNS must be used within 14 days. Washout is at least 6 hours.
Intervention code [1] 236780 0
Treatment: Drugs
Comparator / control treatment
Citric acid 7.65mg/ml in Normal saline placebo nasal spray. Each participant will receive six identical spray bottles, three will contain midazolam, and three citric acid in Normal saline. The six nasal spray bottles will be numbered 1-6 and will contain either midazolam or placebo (Citric acid in Normal saline) in a random sequence. Participants will be instructed to use a total of 3 inhalations (total dose of 2.295mg citric acid) no more frequently than every 4 hours. This dose is administered as 1 spray in alternating nostrils for 3 administrations.
Participants will be asked to use a study nasal spray(SNS) as their first rescue dose for dyspnoea on any day that they require a rescue dose (starting no earlier than 0600hrs), taking number 1 SNS on the first day, number 2 on the second day, number 3 on the third etc, provided no SNS has been used for 4 hours prior, or breakthrough pain medication within 6 hours. If patients do not experience dyspnoea, they are not required to use a SNS that day.
Only the first dose each day will be formally assessed, but participants can continue to use the SNS throughout the day (no more frequently than every 4 hours) if they find it useful. All SNS must be used within 14 days. Washout is at least 6 hours.
Control group
Placebo

Outcomes
Primary outcome [1] 238184 0
Primary outcome is dyspnoea intensity difference (DID) between active drug and placebo, measured by recording dyspnoea score on an 11-point Numerical Rating Scale (NRS) anchored at 0 = no breathlessness to 10 = worst possible breathlessness.
Timepoint [1] 238184 0
The primary end point will be the mean of the dyspnoea intensity difference (DID) at 15 minutes after each dose, compared to baseline (DID15-DID0)
Secondary outcome [1] 242487 0
DID at 5, 30 and 60 mins, measured by recording dyspnoea score on an 11-point Numerical Rating Scale (NRS) anchored at 0 = no breathlessness to 10 = worst possible breathlessness.
Timepoint [1] 242487 0
DID at 5, 30 and 60 mins following the first dose of SNS each day
Secondary outcome [2] 242488 0
sedation (using difference in mean NRS score of placebo compared to midazolam)on 11-point NRS anchored at 0= not at all drowsy to 10= extremely drowsy
Timepoint [2] 242488 0
0, 5, 15, 30 and 60 mins following the first dose of SNS each day
Secondary outcome [3] 242489 0
anxiety scored on an 11-point NRS anchored at 0= not at all anxious to 10= extremely anxious
Timepoint [3] 242489 0
0, 5, 15, 30 and 60 mins following the first dose of SNS each day
Secondary outcome [4] 242490 0
General impression of benefit - scored in patient diary on 5-point scale where 0=no benefit to 4=excellent benefit
Timepoint [4] 242490 0
Daily when study spray used
Secondary outcome [5] 244528 0
Pain scored on an 11-point NRS where Pain right now is scored using a NRS anchored at 0= no pain to 10= worst possible pain
Timepoint [5] 244528 0
0, 5, 15, 30 and 60 mins following the first dose of SNS each day

Eligibility
Key inclusion criteria
Participants must:
be at least 18 years of age
have dyspnoea related to life-limiting disease or its treatment
have a dyspnoea score >3/10 on at least 3 occasions during the previous week
be English speaking or have an interpreter available
have an adequate performance status Australian Karnofsky Performance Scale (AKPS >30)
be able to operate a nasal spray device
be able to understand all trial requirements and complete a dyspnoea diary
have had no changes in any medication likely to affect dyspnoea (eg steroids, opioids) within 48 hours of starting the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded in the case of:
an acute respiratory event likely to resolve eg. chest infection, acute exacerbation of asthma
concurrent treatment with an unstable dose of benzodiazepines (excluding nocturnal sedation)
concurrent treatment with an unstable dose of opioids (change in baseline dose within 48 hours of study entry or during the duration of the study)
regular use (greater than 3 times/day) of breakthrough opioids for pain or dyspnoea that would interfere with assessment of benefit of the midazolam spray
a previous adverse reaction to benzodiazepines
concurrent treatment with itraconazole or ketoconazole
respiratory depression (resting respiratory rate (RR) <10 breaths/minute)
co-morbid myasthenia gravis, or acute narrow angle glaucoma
an alcohol and/or drug dependency problem
any intervention or change in therapy likely to effect dyspnoea during the study period or in the 2 weeks prior (this includes radiotherapy to the lung and/or chemotherapy or blood transfusion 72 hours prior with the potential to effect dyspnoea )
any change in oxygen prescription during the study period

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)
Patients with dyspnoea related to life-limiting disease or its treatment with an average dyspnoea score of greater than or equal to 3/10 on a dyspnoea screening scale (0 = no breathlessness, 10 = worst possible breathlessness) on at least 3 occasions during the previous week, despite optimal treatment of the underlying cause. This will include both malignant and non-malignant disease. Potentially eligible patients will be screened by research staff. Those that are eligible and provide written consent will be given six SNS numbered 1 to 6 in randomised order and written instructions on how to use the sprays. Research staff will ensure that the patient fully understands the patient information sheet and trial requirements. Computer generated pseudo-random numbers will be generated and used to allocate patients to one of 20 sequencesof the 6 SNSs. The randomization codes will be sent to the pharmacy to be dispensed. In addition, randomization codes will be printed and sealed in opaque envelopes and left in the ward in case of emergency.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All possible combinations of 3 midazolam, 3 placebo SNS will be included. Computer generated pseudo-random numbers will be generated and used to allocate patients to one of 20 sequencesof the 6 SNSs. Randomisation codes will be split equally between the 2 central coordinating centers (Arohanui Hospice and the Mater Hospital). Individual patient SNS allocation will be the responsibility of the dispensing pharmacist.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
We decided to stop recruitment after preliminary review of the data - recruitment had been slow and the results were unlikely to change by continuing recruitment
Date of first participant enrolment
Anticipated
1/08/2009
Actual
21/12/2009
Date of last participant enrolment
Anticipated
Actual
18/12/2012
Date of last data collection
Anticipated
30/12/2012
Actual
Sample size
Target
200
Accrual to date
Final
75
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1806 0
4101
Recruitment postcode(s) [2] 1807 0
4215
Recruitment postcode(s) [3] 1808 0
4169
Recruitment outside Australia
Country [1] 1844 0
New Zealand
State/province [1] 1844 0
Manawatu
Country [2] 1845 0
New Zealand
State/province [2] 1845 0
Wellington
Country [3] 1846 0
New Zealand
State/province [3] 1846 0
Auckland

Funding & Sponsors
Funding source category [1] 237178 0
Charities/Societies/Foundations
Name [1] 237178 0
Arohanui Hospice Service Trust
Country [1] 237178 0
New Zealand
Funding source category [2] 237179 0
Self funded/Unfunded
Name [2] 237179 0
Cancer Society of NZ (Central Districts & Wellington branches)
Country [2] 237179 0
Funding source category [3] 244063 0
Charities/Societies/Foundations
Name [3] 244063 0
Palmerston North Hospital Medical Research Foundation
Country [3] 244063 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Arohanui Hospice Service Trust, Clare Randall as representative
Address
1 Heretaunga St
Palmerston North 4414
Country
New Zealand
Secondary sponsor category [1] 4671 0
Hospital
Name [1] 4671 0
Mater Adult Hospital
Address [1] 4671 0
Raymond Tce
South Brisbane, Queensland
Australia 4101
Country [1] 4671 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 239270 0
Multi-Region Ethics Committee
Ethics committee address [1] 239270 0
2nd Floor, 1-3 The Terrace
P O Box 5013, Wellington 6011
Ethics committee country [1] 239270 0
New Zealand
Date submitted for ethics approval [1] 239270 0
03/07/2009
Approval date [1] 239270 0
01/10/2009
Ethics approval number [1] 239270 0
Ethics committee name [2] 239271 0
Mater Research Ethics Committee
Ethics committee address [2] 239271 0
Rm 235 Level 2
Aubigny Place
Raymond Tce
South Brisbane
QLD 4101
Ethics committee country [2] 239271 0
Australia
Date submitted for ethics approval [2] 239271 0
10/06/2009
Approval date [2] 239271 0
01/10/2009
Ethics approval number [2] 239271 0

Summary
Brief summary
Dyspnoea, defined as an uncomfortable sensation of breathing (which is often reported by patients as breathlessness), is a common symptom affecting up to 80% of cancer patients and 95% of patients with chronic obstructive pulmonary disease (COPD). Nearly half of all patients requiring palliative care report breathlessness as a problem during the last year of life. Moreover, dyspnoea is consistently high-lighted as a poor prognostic factor and harbinger of impending death. Ventilatory drive is the net result of complex automatic and subconscious, peripheral and central, neural and chemical mechanisms. Dyspnoea is the conscious perception which has taken account of the net result of those mechanisms and integrated it with other cognitive and emotive factors that are also affecting the individual. Dyspnoea is thus a subjective symptom that is debilitating to patients, impacting greatly on quality of life of both patient and carer. It is a challenging symptom to manage and is often impossible to reverse despite maximal treatment of the underlying cause. Anxiety is often reported by patients as a major component of breathlessness with breathlessness leading to anxiety and anxiety exacerbating breathlessness leading to a progressive spiral of cause and effect.
Hypothesis : Intranasal midazolam is superior to placebo for the palliation of dyspnoea in patients with optimally treated life limiting disease
Trial website
Trial related presentations / publications
A randomised, double-blind controlled trial
of intranasal midazolam for the palliation
of dyspnoea in patients with life-limiting
disease
Janet Hardy, Clare Randall, Eve
Pinkerton, Christopher Flatley, Kristen
Gibbons & Simon Allan
Supportive Care in Cancer
ISSN 0941-4355
Support Care Cancer
DOI 10.1007/s00520-016-3125-2
Public notes

Contacts
Principal investigator
Name 29771 0
Prof Janet Hardy
Address 29771 0
Mater Health Services
Dept of Palliative Care, 10th Floor
Raymond Terrace
South Brisbane
Queensland 4101
Country 29771 0
Australia
Phone 29771 0
0731632775
Fax 29771 0
Email 29771 0
[email protected]
Contact person for public queries
Name 13018 0
Clare Randall
Address 13018 0
Arohanui Hospice
1 Heretaunga St
Palmerston North 4414
Country 13018 0
New Zealand
Phone 13018 0
+64 6 3566606
Fax 13018 0
+64 6 3566631
Email 13018 0
[email protected]
Contact person for scientific queries
Name 3946 0
Clare Randall
Address 3946 0
Arohanui Hospice
1 Heretaunga St
Palmerston North 4414
Country 3946 0
New Zealand
Phone 3946 0
+64 6 3566606
Fax 3946 0
+ 64 6 3566631
Email 3946 0
[email protected]

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