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Trial registered on ANZCTR


Registration number
ACTRN12616000472471
Ethics application status
Approved
Date submitted
21/03/2016
Date registered
11/04/2016
Date last updated
11/04/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A healthy volunteer study to determine the maximum tolerable dose of the dexmedetomidine transdermal system and how much is available in the body.
Scientific title
A Single Ascending Dose and Bioavailability Study of Dexmedetomidine Transdermal System in Healthy Subjects
Secondary ID [1] 288766 0
None
Universal Trial Number (UTN)
U1111-1180-8380
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute pain management in perioperative setting. 298017 0
Condition category
Condition code
Anaesthesiology 298175 298175 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study consists of 2 parts:
Part 1: open label single ascending dose study
Part 2: randomized cross-over study comparing the Dexmedetomidine Transdermal System (DMTS) to an IV dose of dexmedetomidine

Dexmedetomidine Transdermal System (DMTS) is a 3 cm squared patch. Each 3 cm squared patch contains 0.73 mg of dexmedetomidine and formulated to deliver an average rate of 2 mcg/h over 3 days. Each patch will be worn for 3 consecutive days without any patch changes. The patch will be applied to a non-hairy portion of the subject's upper arm.

Patch adhesion will be assessed visually by the study staff at 6, 12, 24, and 48 hours after application and immediately prior to removal.

Part 1 is a single ascending dose study to determine a maximum tolerable dose (MTD) . The study will increase dose by 3 cm squared patch. The starting dose is 6 cm squared, followed by 9 cm squared, 12 cm squared, 15 cm squared, 18 cm squared, 21 cm squared, and 24 cm squared. Dose escalation decision will be made by a separate safety monitoring committee. The committee will review safety data from the previous dose group and decided whether a dose escalation is permitted.

Part 2 consists of 3 days of DMTS treatment followed by 3 days of washout, and IV dexmedetomidine followed by 3 days of washout.
Intervention code [1] 294206 0
Treatment: Drugs
Comparator / control treatment
The control group only relates to the bioavailability (Part 2) portion of this study.

The control treatment is a 10-minute IV infusion of dexmedetomodine hydrochloride at a dose of 1mcg/kg.
Control group
Active

Outcomes
Primary outcome [1] 297684 0
A primary outcome of this study is the assessment of the maximum tolerated dose (MTD) of DMTS following a single 3-day application.

The MTD will be determined by testing increasing doses on different cohorts of subjects until the highest dose with acceptable side effects is found.

At the end of each cohort, a safety monitoring committee will review the following data: skin irritation, clinical lab results (haematology, chemistry, and urinalysis), vital signs, adverse events, cardiac telemetry, sedation scores and concomitant medications.


Timepoint [1] 297684 0
Maximum tolerated dose will be assessed on Day 1 (dosing)- Day 7.
Primary outcome [2] 297685 0
A primary outcome of this study is the bioavailability of dexmedetomidine from the DMTS at the maximum tolerated dose against Precedex IV infusion. This outcome is determined by assessing the blood level of dexmedetomidine and calculating the dexmedetomidine clearance for the Precedex treatment. .
Timepoint [2] 297685 0
While on patch, 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, 12, 24, 32, and 40 hours after patch removal.

While on IV Precedex treatment, blood levels will be evaluated at pre-dose, 5, 10, 15, 20, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 6, 7, 8 and 12 hours after the start of infusion.
Secondary outcome [1] 321830 0
To assess the pharmacokinetic profile of DMTS following a single 3-day application of the DMTS compared with a 10-minute Precedex IV infusion. The pharmacokinetic profile is assessed by determining pharmacokinetic parameters (Tmax, Cmax, AUC, and half-life) via blood samples.
Timepoint [1] 321830 0
While on patch, 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, 12, 24, 32, and 40 hours after patch removal.
Secondary outcome [2] 321831 0
To assess the sedation effect of dexmedetomidine as per the original Wilson sedation scale.
Timepoint [2] 321831 0
While on patch, sedation will be assessed 1, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30, 32, 36, 48, 50, 52, 54, 56, and 60 hours after patch application; before patch removal, 8, 16, 24, 32, 40, and 48 hours after patch removal.

While on IV treatment, sedation will be assessed just before the end of the infusion, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after infusion start.
Secondary outcome [3] 321832 0
To assess the adhesion of the DMTS by assessing the percentage of area the patch adheres to. This will be visually inspected by the study staff.
Timepoint [3] 321832 0
Patch adhesion will be assessed at 6, 12, 24, and 48 hours after application and immediately prior to removal.
Secondary outcome [4] 321833 0
To assess the systemic safety and tolerability of the DMTS as determined by vital signs, physical exams, clinical laboratory tests, ECG findings, cardiac telemetry events, concomitant medications and adverse events.
Timepoint [4] 321833 0
Assessments will occur:
Vital Signs: daily
Physical exams: predose and end of study
Clinical laboratory tests: predose, Day 4 or Day 7, end of study
ECG: predose, end of study
Cardiac telemetry: Continuous reading starting from 12 hours before study drug administration to 12 hours after completion.
Concomitant medications: daily
Adverse events: daily
Secondary outcome [5] 321834 0
The dermal tolerability of the DMTS through assessment of skin irritation.
Timepoint [5] 321834 0
Skin irritation will be assessed at 1 and 24 hour after patch removal.

Eligibility
Key inclusion criteria
1. Healthy male or female subjects 18 to 45 years of age, inclusive.
2. Subjects must be non-smokersfor at least 1 year prior to screening.
3. 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. Female subjects of non-childbearing potential must be amenorrheic for at least 2 years or had a hysterectomy, a bilateral tubal ligation and/or a bilateral oophorectomy. Male subjects who are not surgically sterile and have female partners of childbearing potential must ensure that they and their partners use the methods of contraception outlined above.
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
Sex
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.
10. Use of any prescription drug within 14 days of the first study drug administration and throughout the study.
11. Use of any prescription or non-prescription product containing any sympathomimetic amine (eg, pseudoephedrine, phenylephrine, and others commonly found in cold preparations) within 14 days prior to the first study drug administration and throughout the study.
12. Use of any prescription medications or natural health products (except vitamin or mineral supplements, or acceptable forms of birth control) within 14 days prior to the first study drug administration and throughout the study, unless in the opinion of the investigator or designee, the product will not interfere with the study procedures or data integrity, or compromise the safety of the subject.
13. Use of a non-prescription drug within 7 days prior to the first study drug administration; subjects who have taken over-the-counter medications, other than those described above, may still be entered into the study, if in the opinion of the investigator or designee, the medication received will not interfere with the study procedures or data integrity, or compromise the safety of the subject.
14. Positive test result for drugs of abuse at screening or prior to study drug dosing.
15. Positive alcohol test at screening or prior to study drug dosing.
16. Female subjects who are currently pregnant or lactating or who are planning to become pregnant within 30 days of last study drug administration.
17. History of allergy or hypersensitivity to dexmedetomidine or dexmedetomidine hydrochloride.
18. Positive for hepatitis B, hepatitis C, or the human immunodeficiency virus (HIV).
19. Donation of blood or loss of blood (> 100 mL) within 30 days prior to the first study drug administration.
20. Subject has a personal responsibility or already confirmed appointment(s) or court date(s) that would in any way prevent him/her from meeting the time commitments and visits required by the study.
21. Treatment with any investigational drug, device, or biologic within 30 days prior to the first study drug administration.
22. A subject who, in the opinion of the investigator or designee, is considered unsuitable for study entry and/or is unlikely to comply with the study protocol for any reason.

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 subject will be aware of the assigned treatment. The randomisation list for the bioavailability portion of the study will be maintained and used by the study staff for treatment allocation. Treatment allocation is not concealed.

If the subject is deemed eligible for the MTD portion of the study, the subject will be allocated the next dose. A subject will be considered eligible to participate in this study if all inclusion criteria are met and no exclusion criteria are met.

The study inclusion and exclusion criteria are the same for Part 1 and Part 2 of the study. Only 1 part of the study is offered at any given time. For example, a subject will only be enrolled into Part 2 when Part 1 is complete.

If the subject is deemed eligible for the bioavailability portion of the study, the subject will be randomized to one of the two treatment sequences. Each eligible subject in the bioavailability portion of the study will be randomized in a 1:1 ratio, as per the randomisation list, to one of two treatment sequences:

Sequence A: Precedex IV infusion first then DMTS treatment
Sequence B: DMTS treatment first then Precedex treatment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In the MTD portion of the study, single ascending doses will be evaluated sequentially and subject will be assigned to the dose cohort being evaluated at the time of their enrolment.

In the bioavailability portion of the study, a simple randomisation using a randomisation table created by the computer software will be used. Subjects will be randomised in a 1:1 ratio. No stratification factors in this randomisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This study consists of 2 parts:
Part 1 is a open-label, single ascending dose study involving a single group.
Part 2 is a randomised two-period cross-over study
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
The statistical analyses will be performed using SAS and a specialized software may be used to derive pK parameters as appropriate.

The sample size was based on prior experience, no formal power calculation was performed.

Dexmedetomidine is known to cause bradycardia. This study is designed to find out the dose below which bradycardia does not occur.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
12/04/2016
Actual
Date of last participant enrolment
Anticipated
2/06/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
42
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 5448 0
Linear Clinical Research - Nedlands

Funding & Sponsors
Funding source category [1] 293131 0
Commercial sector/Industry
Name [1] 293131 0
Teikoku Pharma USA Inc
Country [1] 293131 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
88 Jephson Street
Toowong, QLD 4066
Country
Australia
Secondary sponsor category [1] 291927 0
Commercial sector/Industry
Name [1] 291927 0
Teikoku Pharma USA Inc
Address [1] 291927 0
1718 Ringwood Avenue
San Jose, CA 95131
Country [1] 291927 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294630 0
Bellberry
Ethics committee address [1] 294630 0
129 Glen Osmond Road
Eastwood, SA 5063
Ethics committee country [1] 294630 0
Australia
Date submitted for ethics approval [1] 294630 0
24/02/2016
Approval date [1] 294630 0
22/03/2016
Ethics approval number [1] 294630 0
2016-02-132

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

This open-label study consists of 2 parts:
Part 1 is a single ascending dose study to determine the maximum tolerated dose of DMTS.
Part 2 is bioavailability study

The primary objective of this study is to determine the maximum tolerable dose (MTD) of the DMTS following a single 3 -day application (Part 1) and how much dexmedetomdine from the DMTS at the MTD is available in the body after a 3-day treatment (Part 2).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64398 0
Dr Sam Salman
Address 64398 0
Linear Clinical Research
AL1, B Block
QEII Medical Centre
Hospital Avenue
Nedlands, WA 6009
Country 64398 0
Australia
Phone 64398 0
+61 8 6382 5118
Fax 64398 0
Email 64398 0
[email protected]
Contact person for public queries
Name 64399 0
Mr James Song
Address 64399 0
Teikoku Pharma USA Inc
1718 Ringwood Avenue
San Jose, CA 95131
Country 64399 0
United States of America
Phone 64399 0
+1 408 501 1821
Fax 64399 0
Email 64399 0
[email protected]
Contact person for scientific queries
Name 64400 0
Mr James Song
Address 64400 0
Teikoku Pharma USA Inc
1718 Ringwood Avenue
San Jose, CA 95131
Country 64400 0
United States of America
Phone 64400 0
+1 408 501 1821
Fax 64400 0
Email 64400 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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