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Trial registered on ANZCTR


Registration number
ACTRN12619000476134
Ethics application status
Approved
Date submitted
7/02/2019
Date registered
22/03/2019
Date last updated
28/01/2020
Date data sharing statement initially provided
22/03/2019
Date results information initially provided
28/01/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
An Ascending Dose Study of the Dexmedetomidine Transdermal
System in Healthy Subjects
Scientific title
An Ascending Dose Study of the Dexmedetomidine Transdermal System (DMTS) in Healthy Subjects to determine the maximum tolerated dose (MTD) of the DMTS
Secondary ID [1] 296590 0
Nil known
Universal Trial Number (UTN)
U1111-1225-8478
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Pain Management in postoperative setting 310401 0
Condition category
Condition code
Anaesthesiology 309117 309117 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The DMTS is being developed for the transdermal delivery of dexmedetomidine via a 2 cm square patch which is applied directly to the subject's upper arm.

The patch will be worn for 4-days days followed by a 48-hour washout period. The patch can be removed earlier if it cannot be tolerated by the subject. At the conclusion of the 48-hour period, the subject will be discharged from the clinic and the study. Each subject can only be enrolled in the study once.

The study consists of up to 8 cohorts, which will be evaluated sequentially.

Cohort 1: 0.49 mg (1 DMTS)
Cohort 2: 0.73 mg (1.5 DMTS)
Cohort 3: 0.98 mg (2 DMTS)
Cohort 4: 1.22 mg (2.5 DMTS)
Cohort 5: 1.47 mg (3 DMTS)
Cohort 6: 1.71 mg (3.5 DMTS)
Cohort 7: 1.96 mg (4 DMTS)
Cohort 8: 1.96 mg (4 DMTS staggered administration)

The 4 DMTS in cohort 8 will be administered in a staggered fashion, where by the total dose will be split across 2 doses, given 12 hours apart. The safety monitoring committee will decide how the dose will be staggered

The patch will be visually inspected daily by the study staff for adherence.

Intervention code [1] 312900 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308097 0
Determine the maximum tolerated dose (MTD) of the DMTS in the absence of a prescribed hydration regimen. The MTD is the dose below the non-tolerated dose.

Tolerability is based on when 2 or more subjects experience any of the following (or when 1 subject experiences 2 or more): the presence of clinically significant low blood pressure or clinically significant slow heart rate or a Wilson sedation score of 5.

Blood pressure will be measured via blood pressure monitor. And sedation will be assessed as per the original Wilson sedation scale.

The DMTS is still under investigation so the full safety profile is yet not established. However, the more frequent adverse events experienced so far include sedation, drowsiness, slow hear rate, low blood pressure, dry mouth, application site redness application site rash, headache, light-headedness, and nausea.
Timepoint [1] 308097 0
Tolerability will be assessed through out the study by a member of the study staff.

Sedation will be assessed 1, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30, 32, 36, 48, 50, 52, 54, 56, 60, 72, and 84 hours after DMTS application; before DMTS removal (ie, 96 hours after DMTS application), 8, 16, 24, 32, and 40 hours after DMTS removal.

Blood pressure will be measured prior to DMTS application, then every 2 hours after patch application up to 24 hours. Then it will be measured every 12 hours up to 84 hours after DTMS application; before DMTS removal (ie, 96 hours after DMTS application) followed by a measurement every 8 hours, up to 40 hours after DMTS removal.
Secondary outcome [1] 353935 0
The pharmacokinetic profile of the DMTS as assessed by determining the pharmacokinetic parameters (Tmax, Cmax, AUC, and half-life) via blood samples
Timepoint [1] 353935 0
Sampling Time points: Predose and 2,4,6,8,10,12,14,16,18, 20, 22, 24,36,48,60,72 and 84 hours after application
Before DMTS removal (i.e. 96 hours after DMTS application), and 0.5, 1,2,3,4,6,9,12,24,32,40,48 hours after DMTS removal
Secondary outcome [2] 353936 0
The sedation effect of dexmedetomidine as per the original Wilson sedation scale.
Timepoint [2] 353936 0
Sedation levels evaluated at: 1, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30, 32, 36, 48, 50, 52, 54, 56, 60, 72, and 84 hours after DMTS application
Before DMTS removal (ie, 96 hours after DMTS application), 8, 16, 24, 32, and 40 hours after DMTS removal
Secondary outcome [3] 353937 0
Adhesion of the DMTS as assessed by the percentage of area the patch adheres to. This will be done via visual inspect by study staff.
Timepoint [3] 353937 0
DMTS adhesion will be assessed visually at 6, 12, 24, 36, 48, 60, 72, and 84 hours after DMTS application and immediately prior to DMTS removal
Secondary outcome [4] 353938 0
The systemic safety of the DMTS by assessing adverse events, clinical laboratory tests (chemistry, hematology, adrenal testing, urinalysis), vital signs (heart rate, blood pressure, body temperature), ECGs, skin irritation, and physical exam (general appearance, neurological status, height, and weight).

Skin irritation assessments will be visually assessed by the study staff and will be evaluated based on the presence and severity of redness, swelling, and lesions.
Timepoint [4] 353938 0
Any adverse events that occur from the time informed consent is signed through to the end of study visit. will be reviewed and assessed by the study staff.

Clinical laboratory tests will be drawn at the screening visit, clinic check-in , and at end of study (3 days after patch removal).

Vital signs (heart rate , blood pressure, respiratory rate, and oxygen saturation) will be measured at the screening visit, prior to DMTS application, then every 2 hours after patch application up to 24 hours. Then it will be measured every 12 hours up to 84 hours after DTMS application; before DMTS removal (ie, 96 hours after DMTS application) followed by a measurement every 8 hours, up to 40 hours after DMTS removal.

Skin irritation assessments will be performed at 1 hour and 24 hour after DMTS removal.

ECG recordings will be taken at screening visit, clinic check-in, and end of study (3 days after DMTS removal).

Physical exams will be conducted at screening visit, clinic check-in, and end of study (3 days after DMTS removal).
Secondary outcome [5] 353939 0
The dermal tolerability of the DMTS will be visually assessed by the study staff through the evaluation of of skin irritation (presence and severity of redness, swelling, and lesions),
Timepoint [5] 353939 0
Assessments of skin irritation will be performed at 1 hour and 24 hours after
DMTS removal.

Eligibility
Key inclusion criteria
1. Healthy male or female subjects, 18 to 60 years of age, inclusive.
2. Subjects must be non-smokers, as defined by cessation of smoking and consumption of no more
than 2 tobacco/nicotine-containing products (including chewing tobacco, snuff, e-cigarettes, nicotine patches, etc.) within 6 months prior to screening.
3. Have a body weight greater than 50 kg, and body mass index of 18.0 to 38.0, inclusive.
4. Free of any dermatologic conditions (for example, psoriasis, eczema), excessive hair, skin allergies, or sensitivities that may compromise the subject’s ability to wear the investigational product at the application sites for the specified duration of treatment.
5. Female subjects are eligible only if all the following apply:
a. Not pregnant, not lactating, and not planning to become pregnant during the study or for
1 menstrual cycle thereafter
b. Surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner who is surgically sterile; or have a monogamous same gender sex partner; or is using 2 highly effective forms of contraception, such as an insertable, injectable, transdermal, combination oral contraceptive, and male condom. Contraception should be used for 1 month prior to the study, during the study, and for 1 month following the study.
6. Male subjects with female sex partners of childbearing potential must be surgically sterile or commit to the use of a reliable method of birth control during the study and for 1 month following the study.
7. 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. Voluntarily provide written informed consent, prior to the initiation of any protocol-specific procedures.
9. Willing and able to abide by all study requirements and restrictions.
Minimum age
18 Years
Maximum age
60 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 and nicotine), 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 , medical history, 12-lead electrocardiogram, vital signs, laboratory values, including serum kidney and liver function tests.
3. Supine heart rate less than 60 or greater than 100 bpm, systolic blood pressure (BP) less than 90 or greater than 140 mmHg, or diastolic BP less than 60 or greater than 90 mmHg, when measured after being supine for at least 5 minutes
4. Presence and or significant history of postural hypotension (determined through examination by the investigator or designee), or history of severe dizziness or fainting on standing.
5. Subjects with a history of seizures, asthma (except for childhood asthma which has been
asymptomatic for greater than or equal to 10 years), or obstructive pulmonary disease.
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/disorder (including suicidal ideation and behavior, organic brain disorder, or seizure disorder), 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 (for example, scar, tattoo) or unhealthy skin (for example, 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 prescription drug (except acceptable forms of birth control) within 14 days prior to study drug administration and throughout the study.
10. Use of any prescription or non-prescription product containing any sympathomimetic amine (for example, pseudoephedrine, phenylephrine, and others commonly found in cold preparations) within 14 days prior to study drug administration and throughout the study.
11. Use of any natural health products (except vitamin or mineral supplements) within 14 days prior to 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.
12. Use of a non-prescription drug within 7 days prior to 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.
13. Positive test result for drugs of abuse at screening or prior to study drug dosing (testing can be repeated at the discretion of the investigator).
14. Positive alcohol test at screening or prior to study drug dosing.
15. Female subjects who are currently pregnant or lactating or who are planning to become pregnant within 30 days of last study drug administration.
16. History of allergy or hypersensitivity to dexmedetomidine or dexmedetomidine hydrochloride.
17. Positive for hepatitis B, hepatitis C, or the human immunodeficiency virus (HIV).
18. Donation of blood or loss of blood (greater than 100 mL) within 30 days prior to study drug administration.
19. 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.
20. Treatment with any investigational drug, device, or biologic within 30 days prior to study drug administration.
21. 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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not Applicable.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not Applicable.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Dose escalation study. After the 4-day patch application, there is a 2-day wash-out period.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis


Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
4/02/2019
Date of last participant enrolment
Anticipated
29/04/2019
Actual
24/06/2019
Date of last data collection
Anticipated
5/05/2019
Actual
30/06/2019
Sample size
Target
80
Accrual to date
Final
82
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 12772 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 25213 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 301168 0
Commercial sector/Industry
Name [1] 301168 0
Teikoku Pharma USA, Inc.
Country [1] 301168 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
381 MacArthur Avenue, Hamilton QLD
Country
Australia
Secondary sponsor category [1] 300791 0
Commercial sector/Industry
Name [1] 300791 0
Teikoku Pharma USA, Inc
Address [1] 300791 0
1718 Ringwood AveSan Jose, CA 95131
Country [1] 300791 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301912 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 301912 0
129 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [1] 301912 0
Australia
Date submitted for ethics approval [1] 301912 0
28/09/2018
Approval date [1] 301912 0
09/10/2018
Ethics approval number [1] 301912 0

Summary
Brief summary
This is a Phase 1, open-label, non-randomized single-ascending dose study of DMTS in healthy subjects to study the maximum tolerated dose (MTD) as primary objective.
The study consists of up to 8 cohorts, which will be evaluated sequentially. Subjects in each cohort will receive a 4-day application of DMTS followed by a 48-hour washout period. Subjects in Cohort 1 will receive 1 DMTS (0.49 mg dexmedetomidine). If this dose is well tolerated, the dose will be increased in each subsequent cohort up to a maximum of 4 DMTS (1.96 mg dexmedetomidine). Dose escalation will occur only after review by a safety monitoring committee of safety data collected during the immediately preceding cohort, with the data indicating that the dose had been tolerated.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88534 0
Dr Lara Hatchuel
Address 88534 0
L1, B Block,QEII MedicalCentre,HospitalAvenue, Nedlands, WA 6009
Country 88534 0
Australia
Phone 88534 0
+61 8 63825100
Fax 88534 0
Email 88534 0
[email protected]
Contact person for public queries
Name 88535 0
Mr James Song
Address 88535 0
Teikoku Pharma USA, Inc
1718 Ringwood Ave
San Jose, CA 95131
Country 88535 0
United States of America
Phone 88535 0
+1 408 501 1821
Fax 88535 0
Email 88535 0
[email protected]
Contact person for scientific queries
Name 88536 0
Mr James Song
Address 88536 0
Teikoku Pharma USA Inc.
1718 Ringwood Ave
San Jose, CA 95131
Country 88536 0
United States of America
Phone 88536 0
+1 408 501 1821
Fax 88536 0
Email 88536 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's a healthy volunteer study and the individual participant data will not be valuable to the participants or to others outside of the sponsor.


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.