Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000305729
Ethics application status
Approved
Date submitted
18/03/2013
Date registered
19/03/2013
Date last updated
17/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of methoxyflurane on cardiac function in healthy male and female adults
Scientific title
A Phase I, Double-Blind, Double-Dummy, Randomised, Placebo- and Positive-Controlled, 3-Way Crossover, Thorough QT/QTc Study to Evaluate the Effect of a Supratherapeutic Single Dose of Methoxyflurane (Penthrox®) on Cardiac Repolarisation in Healthy Male and Female Subjects
Secondary ID [1] 282077 0
Nil
Universal Trial Number (UTN)
U1111-1140-2440
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Effects on Cardiac QT/QTc Interval of an intervention that is used for pain relief. 288568 0
Condition category
Condition code
Anaesthesiology 288903 288903 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single-centre, double-blind, double–dummy, randomised, placebo- and positive-controlled, 3 way crossover, thorough QT/QTc (TQT) study in healthy male and female subjects.

The effects of methoxyflurane at a supratherapeutic dose will be compared with matching placebo. A dose of 400 mg moxifloxacin will be included as a positive control for the effect on cardiac repolarisation.

Each active treatment (methoxyflurane and moxifloxacin) will have a placebo. There will be three treatment groups, defined as follows:
A. single oral dose of moxifloxacin placebo + single inhaled dose of methoxyflurane (supratherapeutic dose)
B. single oral dose of moxifloxacin (400 mg) + single inhaled dose of methoxyflurane placebo
C. single oral dose of moxifloxacin placebo + single inhaled dose of methoxyflurane placebo.
There is a washout period of 1 week (7days) between treatment periods.
Twelve (12) mL of methoxyflurane is added to the inhaler. The single dose of methoxyflurane (and methoxyflurane placebo) consists of 12 consecutive breaths, with finger on diluter hole.
Once the participants have been administered a treatment, they will be observed for 24 hours.
Intervention code [1] 286675 0
Treatment: Drugs
Comparator / control treatment
The study has two controls: placebo and active control. The effects of methoxyflurane at a supratherapeutic dose will be compared with matching placebo. A dose of 400 mg moxifloxacin will be included as a positive control for the effect on cardiac repolarisation. See above for information, dosing frequency and duration of treatment of placebo and active controls.
The moxifloxacin placebo is microcrystalline cellulose. The methoxyflurane placebo is water.
Control group
Placebo

Outcomes
Primary outcome [1] 289032 0
Change from pre-dose baseline in the QT interval corrected according to the Fridericia formula (QTcF).

QT assessment will be obtained using a 12-lead continuous ECG device (12L Holter; 1000Hz sampling rate)
Timepoint [1] 289032 0
-30 min, -15 min, 0 h, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 23.5 h post-dose
Secondary outcome [1] 301607 0
A study-specific QT correction of the exponential family (i.e. general form QTcSS=QT/RR to the power of beta, where beta is determined from the baseline and placebo data).

QT assessment will be obtained using a 12-lead continuous ECG device (12L Holter; 1000Hz sampling rate).
Timepoint [1] 301607 0
-30 min, -15 min, 0 h, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 23.5 h post-dose
Secondary outcome [2] 301844 0
Heart rate will be assessed using a 12-lead continuous ECG device (12L Holter; 1000Hz sampling rate).
Timepoint [2] 301844 0
-30 min, -15 min, 0 h, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 23.5 h post-dose
Secondary outcome [3] 301845 0
RR, PR, QRS, QT using a 12-lead continuous ECG device (12L Holter; 1000Hz sampling rate)
Timepoint [3] 301845 0
-30 min, -15 min, 0 h, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 23.5 h post-dose

Eligibility
Key inclusion criteria
Healthy male and female subjects, aged 18 to 45 years inclusive, body mass index (BMI) >=18 and <=29 kg/m2, weight >=50 kg, with satisfactory medical history and current conditions, as defined.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Known cardiovascular disorders
- ECG abnormalities that may reflect underlying heart disease and which may interfere with the accurate assessment of the QT interval
- Known clinically significant arrhythmias or rhythm disturbances
- A history of, or risk factors for Torsades de Pointes
- A supine heart rate at screening outside 45-90 bpm
- Consumption of any medication especially those with a known QT prolongation effect, within 30 days before the first dose of study drug, except occasional paracetamol use (up to 1 g/day).
- Existence of any condition that could possibly interfere with drug absorption
- Significant renal insufficiency, as indicated by an estimated creatinine clearance using the Cockcroft-Gault formula of <75 mL/min (males or females), at screening
- Personal or family history of hypersensitivity to fluorinated anaesthetics

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)
Eligible subjects will be randomised on Day 1 (Study Period 1) and allocated the next randomisation number at the site. The randomisation number will define the order each subject receives the treatments during the study (e.g., ABC, BCA, etc.). The randomisation code and sealed individual code-break envelopes will be prepared by a nominated individual(s) in the biometrics department.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be assigned in the order in which they are enrolled into the study and receive the next available randomization sequence number allocated to the study site. The randomization sequence is computer generated.
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 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
8/04/2013
Actual
18/04/2013
Date of last participant enrolment
Anticipated
Actual
22/04/2013
Date of last data collection
Anticipated
Actual
22/05/2013
Sample size
Target
39
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 286908 0
Commercial sector/Industry
Name [1] 286908 0
Medical Developments International
Country [1] 286908 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Medical Developments International
Address
4 Caribbean Drive, Scoresby, VIC 3179 Australia
Country
Australia
Secondary sponsor category [1] 285695 0
None
Name [1] 285695 0
Address [1] 285695 0
Country [1] 285695 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288967 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 288967 0
The Alfred Hospital
55 Commercial Road
Melbourne
Victoria 3004
Ethics committee country [1] 288967 0
Australia
Date submitted for ethics approval [1] 288967 0
06/03/2013
Approval date [1] 288967 0
04/04/2013
Ethics approval number [1] 288967 0

Summary
Brief summary
Penthrox® (methoxyflurane) is an analgesic/device combination product, which is currently registered and marketed in Australia. Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anaesthetics. It is inhaled as a vapour at low (sub-anaesthetic) concentrations to provide analgesia in stable, conscious patients. hERG studies have indicated a potential for QT prolongation, a known property of this pharmacological class. However, clinical history has provided no indication that methoxyflurane may cause ventricular tachyarrhythmia or Torsades de Pointes (TdP) under conditions of use in analgesia. This study is specifically design to assess drug effects on the QT interval.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38326 0
Dr Jason Lickliter
Address 38326 0
Nucleus Network Ltd
5th Floor, Burnet Tower
89 Commercial Road
Melbourne
Victoria 3004
Country 38326 0
Australia
Phone 38326 0
+61 3 9076 8906
Fax 38326 0
Email 38326 0
[email protected]
Contact person for public queries
Name 38327 0
Ms Sue Mason
Address 38327 0
Nucleus Network Ltd
5th Floor, Burnet Tower
89 Commercial Road
Melbourne
Victoria 3004
Country 38327 0
Australia
Phone 38327 0
+61 3 9076 9017
Fax 38327 0
+61 3 9076 8911
Email 38327 0
[email protected]
Contact person for scientific queries
Name 38328 0
Ms Sue Mason
Address 38328 0
Nucleus Network Ltd
5th Floor, Burnet Tower
89 Commercial Road
Melbourne
Victoria 3004
Country 38328 0
Australia
Phone 38328 0
+61 3 9076 9017
Fax 38328 0
+61 3 9076 8911
Email 38328 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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