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Trial registered on ANZCTR


Registration number
ACTRN12614000543684
Ethics application status
Approved
Date submitted
8/05/2014
Date registered
21/05/2014
Date last updated
21/05/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
The analgesic efficacy, tolerability, safety and pharmacokinetics of a sublingual wafer formulation of ketamine in burns patients undergoing painful dressing changes
Scientific title
The analgesic efficacy, tolerability, safety and pharmacokinetics of a sublingual wafer formulation of ketamine in burns patients undergoing painful dressing changes
Secondary ID [1] 284563 0
NIL KNOWN
Universal Trial Number (UTN)
U1111-1156-5606
Trial acronym
KET002
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Burns 291834 0
Condition category
Condition code
Anaesthesiology 292198 292198 0 0
Pain management
Injuries and Accidents 292289 292289 0 0
Burns

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each patient will be dosed on two occasions, dressing change one and two, with a single dose of two 25mg racemic ketamine wafers or a single dose of two placebo wafers sublingually. The two treatment occasions will be separated by a minimum wash out period of 24 hours. The sequence of the two treatments will be randomly assigned.
Intervention code [1] 289335 0
Treatment: Drugs
Comparator / control treatment
Two sublingual placebo wafers
Control group
Placebo

Outcomes
Primary outcome [1] 292069 0
Primary outcome is Numerical rating scale (NSR) for pain intensity.
Timepoint [1] 292069 0
Timepoint: Baseline, and then at five minute intervals from commencement of dressing change until 20 minutes.
Secondary outcome [1] 308129 0
Burn specific pain anxiety scale (BSPAS)
Timepoint [1] 308129 0
Timepoint: Measurements carried out immediately prior to start of dressing change, 20 minutes after start of dressing change and 2 hours after dosing.
Secondary outcome [2] 308130 0
To assess time to rescue analgesia
Timepoint [2] 308130 0
Timepoint: from commencement of dressing change until rescue analgesia is required or 20 minutes have lapsed.
Secondary outcome [3] 308131 0
To assess incidence of use of rescue medication in participants
Timepoint [3] 308131 0
Timepoint: Before 20 minutes have elapsed from start of dressing change.
Secondary outcome [4] 308132 0
To assess safety using vital signs including systolic and diastolic blood pressure, pulse rate and pulse oximetry, body temperature and respiratory rate.
Timepoint [4] 308132 0
Timepoint: Prior to commencement of dressing change and at completion of dressing change.
Secondary outcome [5] 308133 0
To assess safety using pulse oximetry
Timepoint [5] 308133 0
Timepoint: measured continuously from dosing until completion of the dressing change.
Secondary outcome [6] 308134 0
To assess adverse events for safety. Examples include: an unfavourable and uintended sign such as an abnormal laboratory finding, symptom or disease temporally associated with the use of the iinvestigational product.
Timepoint [6] 308134 0
Timepoint: AE probing performed prior to start of dressing change, 20 minutes after start of dressing change and 2 hours after dosing. Also, spontaneous AE reporting by participant at any time.
Secondary outcome [7] 308135 0
To evaluate the pharmacokinetics of ketamine using blood samples
Timepoint [7] 308135 0
Schedule A: PK samples will be taken at 10, 20 and 40 minutes, and at 2 and 4.5 hours folloowing dosing.
Schedule B: PK samples will be taken at 0.5, 1, 1.5. 3 and 6 hours following dosing.
Secondary outcome [8] 308136 0
To assess safety using laboratory investigations (biochemistry, haematology and urinalysis).
Timepoint [8] 308136 0
Timepoint: Baseline and 24 hours after dosing.
Secondary outcome [9] 308142 0
To evaluate participant's assessment of treatment on a 5-point Likert Scale (poor, fair, good, very good and excellent).
Timepoint [9] 308142 0
Timepoint: Following completion of the dressing change on each treatment occassion.
Secondary outcome [10] 308145 0
To determine participant's treatment preference
Timepoint [10] 308145 0
Timepoint: Following completion of the second dressing change at the 24 hour timepoint.

Eligibility
Key inclusion criteria
1) Adult burn patients aged 18-65 years requiring at least two anticipated dressing changes of likely duration at least 20 minutes and anticipated to be sufficiently painful that procedural analgesia is clinically indicated.

2) Good general health without clinically significant renal, hepatic, cardiac or respiratory disease, as determined by the Investigator.

3) Agree to and be capable of understanding and signing an Informed Consent Form.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Cirrhosis or other evidence of clinically significant disorder in hepatic function, as determined by the Investigator.

2) Renal impairment as evidenced by estimated creatinine clearance (CrCL), from the Cockcroft-Gault method, of less than 30 mL/min.

3) Any condition in which a significant elevation of blood pressure would be hazardous, e.g. severe cardiovascular disease, heart failure, severe or poorly controlled hypertension, recent myocardial infarction, current stroke or cerebral trauma, intracerebral mass or haemorrhage.

4) History of hypersensitivity to ketamine or any of the excipients.

5) Suspected increased cerebrospinal fluid pressure.

6) Glaucoma.

7) Current (within the last six months) major affective disorder, as assessed by the Investigator.

8) Uncontrolled hyperthyroidism.

9) Acute intermittent porphyria.

10) Pregnant or breastfeeding women.

11) Participation in another clinical trial of an investigational agent within 30 days of entry into the present trial.

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)
All participants are to provide written informed consent before any trial related procedure. Participants will be assigned a unique screening number consisting of two parts, a centre number (assigned by the sponsor) and a Participant number. The investigator will assign participant numbers sequentially. Once assigned, participant identification numbers will not be reused and will remain with the participant throughout the trial.
Participants must meet all inclusion and exclusion criteria to be randomized to trial treatment.

The method of allocation of concealment used will be sealed opaque envelopes in order for treatment to remain blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated in a 1:1:1:1 ratio to one of the following four treatment sequences:

1.Ketamine for treatment one and ketamine for treatment two.
2.Placebo for treatment one and placebo for treatment two.
3.Ketamine for treatment one and placebo for treatment two.
4.Placebo for treatment one and ketamine for treatment two.

Within each treatment sequence (1, 2, 3 or 4) participants are further randomised in a 1:1 fashion to the order of the PK sampling schedule, A for dressing one and B for dressing two, or vice versa. The treatment is blinded, the PK sampling schedule is not blinded.

Computerised sequence generation will be used to create the random order for the allocation of subjects into different groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Factorial
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Standard descriptive statistics (n, mean, median, minimum, maximum and SD) will be used to summarise all continuous variables by treatment, treatment sequence and time point. Categorical measures will be summarised by frequency and percentage, for each treatment, treatment sequence and time point.
The NRS scores for pain will be analysed using a mixed model for repeated measures (MMRM) analysis with factors for treatment, treatment sequence, dressing change, baseline NRS and a random term for participant. Aspects of the cross-over trial, namely carryover effects will be explored.
An appropriate variance-covariance matrix will be employed.
Additional analyses of the primary outcome will be undertaken including:
1) Inclusion of a time dependent covariate for use of rescue analgesia in the MMRM
2) A Per Protocol (PP) analysis including only values recorded prior to administration of rescue medication
3) Analysis using an MMRM of the time-averaged AUC.

Time to rescue will be analysed by an appropriate multivariate failure time model and presented graphically with Kaplan/Meier plots by treatment and by treatment sequence.
Incidence of rescue medication use will be summarised and analysed with a generalized linear mixed model. Factors used for the primary analysis of the primary outcome (NRS score) will be included in the model. The logit link will be employed.
Anxiety assessments will be analysed using an MMRM as described for the primary outcome (NRS).
The participant’s assessment of treatment will be summarised by treatment and treatment sequence using frequency and percentage of participants selecting each value on the Likert scale.
The frequency and percentage of participants preferring each treatment, or with no preference, will be summarised and exact 95% confidence limits presented.
Mixed effects modelling will be used to obtain estimates of PK parameters, related variability and to explore potential PKPD relationships.

This is an early phase trial with limited information on the expected effect size or, more importantly, on the variability. A sample size of 40 participants (10 for each treatment sequence) is a large enough sample size to provide a reasonably precise estimate of the difference between ketamine and placebo and to provide a reasonable estimate of variability and carry-over effects as assessed with the Balaam design.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/10/2013
Actual
16/04/2014
Date of last participant enrolment
Anticipated
30/09/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 2439 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 8060 0
6847 - Perth

Funding & Sponsors
Funding source category [1] 289194 0
Commercial sector/Industry
Name [1] 289194 0
Mr Eddy Lee
Country [1] 289194 0
Singapore
Primary sponsor type
Commercial sector/Industry
Name
Ix Biopharma Pty Ltd
Address
c/o MKG & Partners, 24 Augusta Street
Willetton, WA 6155
Country
Australia
Secondary sponsor category [1] 287867 0
None
Name [1] 287867 0
Address [1] 287867 0
Country [1] 287867 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290969 0
Royal Perth Hospital Ethics Committee
Ethics committee address [1] 290969 0
Ethics committee country [1] 290969 0
Australia
Date submitted for ethics approval [1] 290969 0
05/11/2012
Approval date [1] 290969 0
09/05/2013
Ethics approval number [1] 290969 0
EC 2012/175

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48190 0
Prof Stephen Schug
Address 48190 0
Pharmacology, Pharmacy and Anaesthesiology Unit
School of Medicine and Pharmacology
The University of Western Australia Anaesthesia
Level 2, MRD Building G Block
Royal Perth Hospital
GPO Box X2213
Perth, WA 6847
Country 48190 0
Australia
Phone 48190 0
+ 61 8 9224 0201
Fax 48190 0
+ 61 8 9224 0279
Email 48190 0
[email protected]
Contact person for public queries
Name 48191 0
Stephen Schug
Address 48191 0
Pharmacology, Pharmacy and Anaesthesiology Unit
School of Medicine and Pharmacology
The University of Western Australia Anaesthesia
Level 2, MRD Building G Block
Royal Perth Hospital
GPO Box X2213
Perth, WA 6847
Country 48191 0
Australia
Phone 48191 0
+ 61 8 9224 0201
Fax 48191 0
+ 61 8 9224 0279
Email 48191 0
[email protected]
Contact person for scientific queries
Name 48192 0
Paul Rolan
Address 48192 0
Director, Drug Development
Discip0line of Pharmacology
Faculty of Health Sciences
5th Level, medical School North
University of Adelaide, SA 5005
Country 48192 0
Australia
Phone 48192 0
+ 61 (0) 40 567 0420
Fax 48192 0
+61 (0) 8 8224 0695
Email 48192 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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