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Trial registered on ANZCTR


Registration number
ACTRN12615001168549
Ethics application status
Approved
Date submitted
8/10/2015
Date registered
2/11/2015
Date last updated
10/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A First In Human study to compare 2 formulations of dexmedetomidine
Scientific title
An Open-label, Randomized, Two-period, Cross-over Study to Assess the Bioavailability, Safety, and Tolerability of the Dexmedetomidine Transdermal System (DMTS) versus Intravenous Dexmedetomidine in Healthy Subjects
Secondary ID [1] 287511 0
nil
Universal Trial Number (UTN)
U1111-1174-7375
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain Management 296270 0
Condition category
Condition code
Anaesthesiology 296544 296544 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dexmedetomidine Transdermal System (DMTS):
The DMTS is a patch that contains 7.32 mg of dexemedetomidine. Based on the non-clinical data, the expected delivered dose is 1.44 mg at an average rate of 20 mcg/h over three days.


The patch will be checked for integrity at 6, 12, 24, 48 hours after application, and immediately prior to patch removal.

There will be a minimum washout period of 2 days.


Intervention code [1] 292901 0
Treatment: Drugs
Comparator / control treatment
The control treatment is a 24 hour infusion of Precedex (dexmedetomidine hydrocholoride).

It will be administered as a single continuous IV infusion at a rate of 10 mcg/hr for 24 hours. A total of 240 mcg will of dexmedetomidine hydrochloride will be given.

Time of infusion of start/stop and infusion rate will be documented in clinic notes to monitor dose delivered.

Control group
Active

Outcomes
Primary outcome [1] 296165 0
The primary outcome is the bioavailability profile of dexmedetomidine following a single 3-day application of the DMTS compared with a 24-hour IV infusion of Precedex by determining the blood level of dexmedetomidine.
Timepoint [1] 296165 0
While on patch treatment, blood levels will be evaluated at:
pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, and 60 hours after application; before patch removal, 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after patch removal.
Primary outcome [2] 296445 0
The primary outcome is the pharmacokinetic profile of dexmedetomidine following a single 3-day application of the DMTS compared with a 24-hour IV infusion of Precedex by determining pharmacokinetic parameters (Tmax, Cmax, AUC, and half-life) with blood samples
Timepoint [2] 296445 0
When on IV Precedex treatment, blood levels will be evaluated at:
predose, 5, 10, 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after the start of infusion; 5, 10, 15, 30, 45 minutes, 1, 2, 3, 4, 6, and 8 hours after the end of the infusion.
Secondary outcome [1] 317678 0
To assess the safety and tolerability of the DMTS, including assessment of skin irritation, clinical laboratory tests, physical exams, vital signs, ECGs, cardiac telemetry, and concomitant medications, and adverse events.

Precedex is approved for us in the intensive care or operating room setting. The use of Precedex by continuous infusion is limited to 24 hours. Known side effects of Precedex include:
Bradycardia (slower than average heart beat)
Sinus arrest
Decreased secretion of tears to lubricate eyes
Decreased blood pressure and/or heart rate
Withdrawal symptoms

As the DMTS patch is using the same active ingredient, just administered in a different way, it can be assumed that both products will have similar side effect profiles.
Timepoint [1] 317678 0
Vital signs: daily
Clinical laboratory tests: pre-dose, day 6; end of study*
Physical exams: pre-dose; end of study*
ECG: Pre-dose, end of study*
Cardiac telemetry: Day 1-2 if on IV treatment; Day 1-4 if on DMTS treatment
Skin irritation: During patch treatment, 1 hour and 24 hour after patch removal
Concomitant medications: daily
Adverse events: daily
*End of Study for participants on the patch will be study day 12 and for participants on IV infusion, it will be study day 10. End of Study may also refer to any early discontinuation.
Secondary outcome [2] 317679 0
Adhesion of the DMTS by assessing the percentage of the patch area adheres

This will be visually assessed by the study staff.
Timepoint [2] 317679 0
During patch treatment, 6, 12, 24, 48 h after application and immediately prior to its removal
Secondary outcome [3] 317680 0
Sedation effect of dexmedetomidine as assessed by the original Wilson sedation scale.
Timepoint [3] 317680 0
During patch treatment: 1, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30, 30, 32, 36, 48, 50, 52, 54, 56, 60, 72, 96, and 120 hours after patch application.

During IV treatment: 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours after the start of the infusion.


Eligibility
Key inclusion criteria
1. Healthy male or female subjects 18 to 45 years of age, inclusive.
2. Subjects must be non-smokers, as defined by cessation of smoking and use of all other tobacco and nicotine products (including chewing tobacco, snuff, e-cigarettes, nicotine patches, etc.) for at least 1 year prior to screening.
3. Body mass index (BMI) within the range of 18 to 29 kg/m2, inclusive, and a weight of at least 50 kg.
4. Free of any dermatologic conditions (eg, psoriasis, eczema), excessive hair, skin allergies, or sensitivities that may compromise the subject’s ability to wear the investigational product at any of the application sites for the specified duration of treatment.
5. Female subjects of childbearing potential must be practicing abstinence or using and willing to continue using a medically acceptable form of contraception for at least
1 month prior to screening (at least 3 months for oral contraceptives) and for at least 30 days after the last study drug administration.
6. Female subjects must have a negative serum pregnancy test at screening and prior to dosing.
7. Must be able to speak, read, and understand English sufficiently to understand the nature of the study, to provide written informed consent, and to allow completion of all study assessments.
8. Must understand and provide written informed consent, prior to the initiation of any protocol-specific procedures.
9. Must be willing and able to abide by all study requirements and restrictions.
Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. A history or presence of drug or alcohol dependence (excluding caffeine), including subjects who have ever been in a drug rehabilitation program based on medical history of the past 10 years.
2. Clinically significant abnormalities as judged by the investigator or designee and determined by physical examination (PE), medical history, 12-lead electrocardiogram
(ECG), vital signs, laboratory values, including serum kidney and liver function tests.
3. Presence of postural hypotension (determined through examination by the investigator or designee), or recent history of severe dizziness or fainting due to postural hypotension on standing.
4. Subjects with a history of seizures, asthma, or obstructive pulmonary disease.
5. Presence or history of any of the following disorders that are deemed clinically significant by the investigator or designee: a psychiatric disorder (including suicidal ideation and behavior), organic brain disorder, or seizure disorder.
6. Presence or history of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including ulcers or gastrointestinal bleeding), endocrine, immunologic, dermatologic, neurologic, oncologic, psychiatric disease, or any other condition, which, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results.
7. Abnormality (eg, scar, tattoo) or unhealthy skin (eg, burns, wounds) at the application site, according to examination by the investigator at screening, admission to the clinic, or prior treatment period of the study.
8. An existing chronic skin disease or history of skin disease at the application site within the 30 days prior to screening.
9. Use of any drugs containing estrogens within 30 days prior to the first study drug administration and throughout the study.

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)
This is an open-label study whereby the study staff (including the study doctor), pharmacist, study monitor, and participant will be aware of the assigned treatment. The randomisation list maintained and used by the study staff for treatment allocation. Treatment allocation is not concealed.

Once the participant is deemed eligible for study entry by a study doctor, the participant will be allocated the next treatment available on the randomisation list by study staff. Once allocated, the study doctor will confirm study entry by signing off on the treatment order.

Each eligible participant will be randomized in a 1:1 ratio, as per the randomisation list, to one of the two treatment sequences:

Sequence A: Precedex treatment first then a DMTS treatment
Sequence B: DMTS treatment first then Precedex treatment







Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Two-period
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
The PK parameters will be summarized for both dosage forms using descriptive statistics (arithmetic and geometric means, standard deviation, median, range, and coefficient of variation).

All participants who receive study treatment will be included in the summaries and listings of safety data.

This is a pilot study and the first study of DMTS. The sample size was determined based on our past clinical experience in developing transdermal products.

Recruitment
Recruitment status
Completed
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 in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 4372 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 10595 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 292085 0
Commercial sector/Industry
Name [1] 292085 0
Teikoku Pharma USA, Inc.
Address [1] 292085 0
1718 Ringwood Avenue
San Jose, CA 95131
Country [1] 292085 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
L4, 88 Jephson Street
Toowong, QLD 4066
Country
Australia
Secondary sponsor category [1] 290763 0
Commercial sector/Industry
Name [1] 290763 0
Teikoku Pharma USA, Inc.
Address [1] 290763 0
1718 Ringwood Avenue
San Jose, CA 95131
Country [1] 290763 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293569 0
Bellberry
Ethics committee address [1] 293569 0
129 Glen Osmond Road
Eastwood, SA 5063
Ethics committee country [1] 293569 0
Australia
Date submitted for ethics approval [1] 293569 0
09/09/2015
Approval date [1] 293569 0
19/10/2015
Ethics approval number [1] 293569 0
2015-09-630

Summary
Brief summary
This is a first in human study for the DMTS.

This study is evaluating a different formulation of dexmedetomidine by determining the bioavailability and pharmacokinetics of dexmedetomidine following a single 3-day application of the DMTS compared with a 24 hour IV infusion of Precedex and assessing the safety and tolerability.

This is an open-label, randomized, two-period, cross-over study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60490 0
Dr Janakan Krishnarajah
Address 60490 0
Linear Clinical Research
L1, B Block
QEII Medical Centre
Hospital Avenue
Nedlands, WA 6009
Country 60490 0
Australia
Phone 60490 0
+61 8 6382 5118
Fax 60490 0
Email 60490 0
jkrishnarajah@linear.org.au
Contact person for public queries
Name 60491 0
Mr James Song
Address 60491 0
Teikoku Pharma USA, Inc.
1718 Ringwood Ave
San Jose, CA 95131
Country 60491 0
United States of America
Phone 60491 0
+1 408 501 1821
Fax 60491 0
Email 60491 0
jsong@teikokuusa.com
Contact person for scientific queries
Name 60492 0
Mr James Song
Address 60492 0
Teikoku Pharma USA, Inc.
1718 Ringwood Ave
San Jose, CA 95131
Country 60492 0
United States of America
Phone 60492 0
+1 408 501 1821
Fax 60492 0
Email 60492 0
jsong@teikokuusa.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary