Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000117910
Ethics application status
Approved
Date submitted
15/01/2020
Date registered
7/02/2020
Date last updated
19/11/2020
Date data sharing statement initially provided
7/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Nasal spray ketamine/dexmedetomidine for pain relief
Scientific title
Combined dexmedetomidine/ketamine nasal spray for analgesia: a pilot feasibility and efficacy trial in healthy volunteers
Secondary ID [1] 300269 0
None
Universal Trial Number (UTN)
U1111-1246-5250
Trial acronym
KetaDex
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Analgesia 315847 0
Condition category
Condition code
Anaesthesiology 314129 314129 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Over a single 6 hour session, participants will be provided a combined dexmedetomidine + ketamine nasal solution, delivered as a titratable dose. Ketadex® is a 125mg/mL Ketamine and 250mcg/mL dexmedetomidine nasal solution that is administered in a proprietary nasal delivery device to administer up to 8 sprays of 12.5mg ketamine and 25mcg dexmedetomidine per 0.1ml spray. Each mL contains 144.175mg of ketamine hydrochloride equivalent to 125mg of ketamine, 295 mcg of dexmedetomidine hydrochloride equivalent to 250 mcg (0.25mg) of dexmedetomidine, 1.05mg of sodium citrate dihydrate and 0.15 mg of edetate disodium dihydrate in water.

The dosing conditions are as follows:
1. Low dose: 25µg dexmedetomidine + 12.5mg ketamine (1 intranasal spray) OR
2. Medium dose: 100µg dexmedetomidine + 50mg ketamine (4 intranasal sprays performed by 1 X 0.1ml in each nostril initially followed by 1 X 0.1ml in each nostril one minute later) OR
3. High dose: 200µg dexmedetomidine + 100mg ketamine [8 intranasal sprays, performed by 1 X 0.1ml in each nostril, followed by 1 X 0.1ml in each nostril one minute later (4 intranasal sprays). Repeated one minute later with 1 X 0.1ml in each nostril, followed by 1 X 0.1ml in each nostril one minute later (4 intranasal sprays)].
Intervention code [1] 316544 0
Treatment: Drugs
Comparator / control treatment
Three doses (high, medium, low) are being compared.
Control group
Dose comparison

Outcomes
Primary outcome [1] 322517 0
Sedation [Richmond Agitation-Sedation Scale (RASS) score (mean)]
Timepoint [1] 322517 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [1] 378783 0
Subjective drug effects [Cambridge Neuropsychological Test Automated Battery (CANTAB)(CANTAB)]
Timepoint [1] 378783 0
Baseline, 3 hours and 6-hours post treatment
Secondary outcome [2] 378784 0
Driving performance, measured as difference in standard deviation of the lateral position (SDLP) over time, as assessed by a computerised driving simulator
Timepoint [2] 378784 0
Baseline and 6 hours post treatment
Secondary outcome [3] 378785 0
Difference in standard deviation of speed (SDS) as measured by the driving simulator across time
Timepoint [3] 378785 0
At baseline and 6-hours post treatment
Secondary outcome [4] 378786 0
Difference in lapses (change in mean lateral position of the car greater than 100cm, lasting for at least 8 seconds) across time, measured using the driving simulator
Timepoint [4] 378786 0
At baseline and at 6-hours post-treatment
Secondary outcome [5] 378787 0
Difference in concentration of ketamine in the blood between groups
Timepoint [5] 378787 0
Immediately prior to administration of the treatment (baseline) and thereafter at 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 360mins post-dose
Secondary outcome [6] 378788 0
Non-invasive Blood pressure, as assessed using bench-top sphygmomanometer
Timepoint [6] 378788 0
Baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours)
Secondary outcome [7] 378789 0
Heart rate, assessed using pulse oximetry
Timepoint [7] 378789 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [8] 378790 0
Respiratory rate, assessed using bench-top sphygmomanometer
Timepoint [8] 378790 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [9] 378791 0
02 saturation using pulse oximetry
Timepoint [9] 378791 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [10] 378792 0
Cardiovascular side effects (Heart rate <55/minute), as assessed using pulse oximetry
Timepoint [10] 378792 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [11] 378793 0
Cardiovascular events (Systolic BP <85mmHg), as assessed using bench-top sphygmomanometer
Timepoint [11] 378793 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [12] 378794 0
Respiratory side effects (O2 saturation <90%), as assessed using pulse oximetry
Timepoint [12] 378794 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [13] 378795 0
Respiratory rate <8/minute, assessed using pulse oximetry
Timepoint [13] 378795 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours).
Secondary outcome [14] 378796 0
Gastrointestinal (GIT) side effect (Nausea), assessed using binary (y/n) questioning
Timepoint [14] 378796 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours), at 12-hours post discharge
Secondary outcome [15] 378797 0
Gastrointestinal (GIT) side effect (Vomiting), assessed using binary (y/n) questioning
Timepoint [15] 378797 0
At baseline, every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 10 assessments over 6 hours), at 24-hours post discharge
Secondary outcome [16] 378798 0
Gastrointestinal (GIT) side effect (Bowel movements/constipation), assessed using binary (y/n) questioning
Timepoint [16] 378798 0
on follow up at 24 hours post
Secondary outcome [17] 378799 0
Local side effects of intranasally administered solution (burning), assessed using binary (y/n) questioning
Timepoint [17] 378799 0
Every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24-hours post discharge
Secondary outcome [18] 378800 0
Local side effects of intranasally administered solution (stinging), assessed using binary (y/n) questioning
Timepoint [18] 378800 0
Every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24-hours post discharge
Secondary outcome [19] 378801 0
Local effects of intranasally administered solution (taste), assessed using binary (y/n) questioning
Timepoint [19] 378801 0
Every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24-hours post discharge
Secondary outcome [20] 378802 0
local effects of intranasally administered solution (eye watering), assessed using binary (y/n) questioning
Timepoint [20] 378802 0
Every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24-hours post discharge
Secondary outcome [21] 378803 0
Local effects of intranasally administered solution (dry eye), assessed using binary (y/n) questioning
Timepoint [21] 378803 0
Every 30 minutes for the first three hours post-dosing, and every hour thereafter (total 9 assessments over 6 hours), at 24-hours post discharge.
Secondary outcome [22] 378804 0
Cessation of study drugs due to intolerance or aforementioned side effects
Timepoint [22] 378804 0
Monitored continuously throughout
Secondary outcome [23] 379247 0
Individual subjective drug effects on alertness (0= alert, 100= drowsy)
Timepoint [23] 379247 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [24] 379249 0
Self-reported clear-headedness (0 = clear headed, 100=muzzy)
Timepoint [24] 379249 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [25] 379250 0
Self reported coordination (0=well-coordinated, 100=clumsy)
Timepoint [25] 379250 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [26] 379251 0
Self-reported mental ability (0=quick witted, 100=mentally slow)
Timepoint [26] 379251 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [27] 379252 0
Self-reported attention (0=attentive, 100=dreamy)
Timepoint [27] 379252 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [28] 379253 0
Self-reported proficiency (0=proficient, 100=incompetent).
Timepoint [28] 379253 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [29] 379254 0
Reaction Time (Processing and Psychomotor Speed)
Timepoint [29] 379254 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [30] 379255 0
Rapid Visual Information Processing (Sustained Attention)
Timepoint [30] 379255 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [31] 379256 0
Paired Associates Learning (PAL) score
Timepoint [31] 379256 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [32] 379257 0
Spatial Working Memory (Working Memory & strategy)
Timepoint [32] 379257 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [33] 379258 0
Attention (Attention Switching)
Timepoint [33] 379258 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB
Secondary outcome [34] 379259 0
Verbal Recognition Memory (VRM)
Timepoint [34] 379259 0
At baseline, 3 hours and 6 hours post-treatment. As assessed using the CABTAB

Eligibility
Key inclusion criteria
- Male/female, 21 to 45 years.
- Weight 50-130kg
- Full drivers licence
- Free from neurological conditions, depression or psychiatric disorders.
- No history of drug abuse or dependence
- No known allergy to study drugs
- Not currently taking medications that could affect the outcome of the study.
Minimum age
21 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Patients unable to provide written informed consent
- Body mass index (BMI) over 40 kg/m2 or weight over 130kg
- Patient is pregnant or lactating
- Chronic pain medication
- History of psychosis
- History of neurological conditions or previous or current history of psychiatric, renal,
cardiac, endocrine, gastrointestinal, or bleeding disorders.
- Documented complex regional pain syndrome
- Current participation in any other trials involving investigational or marketed products
within 30 days prior to the screening visit.
- Patient has been previously enrolled in the NasDex trial
- Individuals with any history of nasal disorders, nasal surgeries, sinus surgeries or sinus
disease

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)
Allocation will be concealed by sealed opaque envelopes, which are to be kept in a locked filing cabinet in the Principal Investigator's once and will only be opened in the case of an emergency. In addition, the full randomisation list will be kept in a password protected document in a restricted access confidential folder on a secure server. Only the person who is responsible for generating the randomisation list (a disinterested third party) will have the password to access this document.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation of the treatment group (low, medium or high dose) will be determined by random allocation by a disinterested third party. All consenting participants will be assigned a participant number. The randomisation order that has been placed next to the participants’ number will be the allocated treatment order for that individual using publicly available randomisation software (Research Randomiser Software Version 4.0).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All statistical tests will be performed two tailed at the 5% significance level and performed using IBM SPSS statistical package.

All data will initially be assessed for normality. Group comparisons will be performed using chi-square tests for equal proportion, student t-tests for normally distributed data and Wilcoxon rank sum tests otherwise, with result reported as proportions (n), means (standard deviations) and medians (interquartile range) respectively. Multivariate analysis will be the predominant statistical analysis method to identify potential associations between each treatment.

Demographic data will be presented with summary statistics (number of participants, mean, standard deviation, median and range). CANTAB, Driving data and RASS scores will be reported as mean ± SEM.

Intragroup changes in CANTAB data and RASS scores will be analysed using separate Linear Fixed Effects Models. Appropriate covariance structure will be interpreted as to best fit the data. Time will be entered into the model as the repeated measures factor and target variables will be included as the outcome variable. Where a main effect is observed, post-hoc paired t-tests with Bonferroni correction for multiple comparisons will be conducted to assess changes over time. Structured regression will be used to determine efficacy for each treatment.

Correlations between CANTAB, Driving VAS scores, performance outcomes on CANTAB tasks, Driving outcomes and RASS scores across time points as function of treatment will be conducted using Pearson product moment coefficient r.

All statistical analyses for performance outcomes will be conducted with the use of SPSS 24.0 (SPSS Inc., USA), and tests are two-tailed with a conventional level of significance of p< 0.05.

Whole blood (and metabolite) concentration (ketamine, norketamine and dexmedetomidine) will be used for PK/PD modelling by nonlinear fixed effect modelling (NONMEM® program).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/03/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15621 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 29023 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 304692 0
Hospital
Name [1] 304692 0
Monash Medical Centre
Country [1] 304692 0
Australia
Primary sponsor type
Hospital
Name
Monash Medical Centre
Address
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country
Australia
Secondary sponsor category [1] 305004 0
None
Name [1] 305004 0
Address [1] 305004 0
Country [1] 305004 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305112 0
Monash Health Human Research Ethics
Ethics committee address [1] 305112 0
Ethics committee country [1] 305112 0
Australia
Date submitted for ethics approval [1] 305112 0
20/01/2020
Approval date [1] 305112 0
18/06/2020
Ethics approval number [1] 305112 0

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

Contacts
Principal investigator
Name 99306 0
Prof Yahya Shehabi
Address 99306 0
Director of Research,
Critical Care and Peri-Operative Medicine
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country 99306 0
Australia
Phone 99306 0
+61 3 9594 2730
Fax 99306 0
Email 99306 0
[email protected]
Contact person for public queries
Name 99307 0
Amie Hayley
Address 99307 0
Mail H20
Swinburne University of Technology,
Faculty of Health, Arts and Design
School of Health Sciences
Centre for Human Psychopharmacology
PO Box 218 Hawthorn, Victoria, 3122 Australia
Country 99307 0
Australia
Phone 99307 0
+61 3 9214 5585
Fax 99307 0
Email 99307 0
[email protected]
Contact person for scientific queries
Name 99308 0
Amie Hayley
Address 99308 0
Mail H20
Swinburne University of Technology,
Faculty of Health, Arts and Design
School of Health Sciences
Centre for Human Psychopharmacology
PO Box 218 Hawthorn, Victoria, 3122 Australia
Country 99308 0
Australia
Phone 99308 0
+61 3 9214 5585
Fax 99308 0
Email 99308 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It is expected that the results of this trial will be disseminated via peer-reviewed publications and at academic conferences. For these purposes the data will be collated and analysed as group data. If required by the publishing journal, de-identified raw data will be uploaded to an appropriate repository.

Otherwise, as the Intellectual Property of this study are owned by the sponsor and may be used for the purposes of commercialisation of the study product, the trial data will not be made available.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.