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Trial registered on ANZCTR


Registration number
ACTRN12616000348459
Ethics application status
Approved
Date submitted
8/03/2016
Date registered
17/03/2016
Date last updated
28/07/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
An interventional study to evaluate the effects of formulation and dose on the Pharmacokinetics (PK, the measure of how the human body prcessed a substance) of up to four Donezepil Transdermal Delivery System (TDS, a patch that delivers a drug) formulations (50 cm2 patch size), worn for seven days, applied to the backs of healthy female participants.
Scientific title
A Phase 1 Parallel Study to Evaluate the Pharmacokinetics (PK),
Pharmacodynamics (PD) and Safety of Formulations of a 7-Day Application Donepezil
Transdermal Delivery System (TDS) in Healthy Female Volunteers
Secondary ID [1] 288611 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer’s Disease 297759 0
Condition category
Condition code
Neurological 297942 297942 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
5mg TDS Treatment Period
Treatment A: Donepezil TDS Formulation 1: 1 x 60 cm2 patch (contains 115.2 mg/patch donepezil HCl) will be applied and worn for seven days. An overlay will be applied to the patch.
Treatment B: Donepezil TDS Formulation 2: 1 x 60 cm2 patch (contains 150 mg/patch donepezil HCl) will be applied and worn for seven days. An overlay will be applied to the patch.
Treatment C: Donepezil TDS Formulation 3: 1 x 60 cm2 patch (contains 126 mg/patch donepezil HCl) will be applied and worn for seven days. An overlay will be applied to the patch.

All formulations contain a rate controlling membrane made of microporous polypropylene, but the treatments differ in the composition of the drug-in adhesive layer:
Treatment A: contains acrylic adhesive, crospovidone, sodium bicarbonate, glycerine, and two or three additional vehicles selected from triethyl citrate, sorbitan monolaurate, and lauryl lactate as inactive ingredients, with donepezil hydrochloride as the active ingredient.
Treatment B: contains acrylic adhesive , colloidal silicon dioxide and/or Crospovidone, Eudragit EPO, glycerine and additional 2 or 3 vehicles or enhancers selected from triethyl citrate, , and lauryl lactate as inactive ingredients, with donepezil hydrochloride as the active ingredient.
Treatment C: contains acrylic adhesive , colloidal silicon dioxide, Eudragit EPO, glycerine and additional 2 or 3 vehicles or enhancers selected from triacetin, sorbitan monolaurate, and lauryl lactate as inactive ingredients, with donepezil hydrochloride as the active ingredient.

All formulations will be applied as one patch worn continuously for 7 days, applied to the lower back (preferred location is vertically along the spine) by a trained member of site staff.
Participants will remain in the study facility for the duration of patch application and will constantly monitored to ensure compliance.

10mg TDS Treatment Period
The treatment determined (by interim PK and safety analysis) to be the lead formulation will be selected and applied as 2 x 60cm2, 5mg/ day target dose (comprising of two individual patches, with total target dose 10mg/ day) worn continuously for seven days.
Patches will be applied to the lower back (preferred location is vertically along the spine) by a trained member of site staff.
Participants will remain in the study facility for the duration of patch application and will constantly monitored to ensure compliance.
Intervention code [1] 294011 0
Treatment: Drugs
Comparator / control treatment
Sub-study
Treatment E: Comparator – Donepezil hydrochloride 5 mg (Aricept 'Registered Trademark'), as a daily oral dose, for seven days.
Participants who were treated with the donepezil TDS formulation determined (by interim PK and safety analysis) to be the lead formulation will be invited to participate in the sub-study. Participants who consent to participate in the sub-study will receive an oral dose of Aricept ('Registered Trademark') following a 7-day washout period.
5mg Aricept ('Registered Trademark') will also be used for three days as a lead-in dose to the 10mg dose treatment periods.

Treatment F: Comparator - Donepezil hydrochloride 10 mg (Aricept 'Registered Trademark'), as a daily oral dose, for seven days, following a 3-day lead-in period of dosing with Donepezil hydrochloride 5 mg (Aricept 'Registered Trademark').
Participants who were treated with the donepezil TDS formulation determined (by interim PK and safety analysis) to be the lead formulation will be invited to participate in the sub-study. Participants who consent to participate in the sub-study will receive an oral dose of Aricept ('Registered Trademark') following a 21-day washout period.

Participants who received 5mg TDS treatment who choose to participate in the sub-study will be treated with Comparator Treatment E, 5mg Aricept ('Registered Trademark').
Participants who received 10 TDS treatment who choose to participate in the sub-study will be treated with Comparator Treatment F, 10mg Aricept ('Registered Trademark').
Control group
Active

Outcomes
Primary outcome [1] 297463 0
To evaluate the effects of formulation and dose on the pharmacokinetics (PK) of Donepezil transdermal delivery systems (TDS) applied for seven days.
Plasma samples will be collected and the following PK parameters will be assessed: Cmax (maximum plasma concentration); Ctau (plasma concentration at end of dosing interval); AUC0-t=infinity (area under the plasma concentration-time curve from time 0 to infinity); AUCtau (area under the plasma concentration-time curve from time 0 to the end of the dosing interval); tmax (time to reach maximum plasma concetration); deltaz (first-order terminal-phase rate constant); and t1/2 (apparent terminal elimination half-life).
Timepoint [1] 297463 0
For the TDS Treatment Periods:
Baseline; 2, 6, (+/- 5 minutes), 12, 24, 48, 72, 96, 120, 144, 148, 152 and 168 hours (+/- 1 hour) following TDS application; at 12, 24, 48, 96, 144, and at 168 (if the washout period is 7 days) or at 192, 240 and 288 (if the washout period is longer) hours (+/-1 hour) after TDS removal.
Secondary outcome [1] 321121 0
To evaluate the safety and tolerability (including local skin tolerability) of seven day applications of each Donepezil TDS (60 cm2 patch size) treatment, as well as to data obtained from the oral arms of this study.
Local tolerability evaluation will be performed by trained site staff using an eight-point Dermal Response Score scale: 0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = definite erythema, readily visible; minimal edema or minimal papular response; 3 = erythema and papules; 4 = definite edema; 5 = erythema, edema and papules; 6 = vesicular eruption; 7 = strong reaction spreading beyond application site. Other effects will also be rated: 0 = no other effects; 1 = slight glazing; 2 = marked glazing; 3 = glazing with peeling and cracking; 4 = glazing with fissures; 5 = film of dried serous exudate covering all or part of the patch site; 6 = small petechial erosions and/or scabs. Not applicable for oral treatment periods.
Timepoint [1] 321121 0
Local tolerability evaluation will be studied and assessed at the application sites at Baseline, then 4, 12, 24, 48 and 72 hours following removal of the patch.
Secondary outcome [2] 321130 0
To compare the PK of donepezil and metabolite 6-O-desmethyl donepezil between formulations of Donepezil TDS (60 cm2 patch size) and the oral arms of this study. This will be assessed with plasma samples.
Timepoint [2] 321130 0
For the TDS Treatment Periods:
Baseline; 2, 6, (+/- 5 minutes), 12, 24, 48, 72, 96, 120, 144, 148, 152 and 168 hours (+/- 1 hour) following TDS application; at 12, 24, 48, 96, 144, and at 168 (if the washout period is 7 days) or at 192, 240 and 288 (if the washout period is longer) hours (+/-1 hour) after TDS removal.

For the oral treatment periods:
Relative to the first dose on Day 1: Baseline; 1, 2, 3, 4, 6, 8 (+/-5 minutes), 12, 24 (+/- 1 hour) hours post-dose. Relative to the last dose on Day 7: pre-dose; 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24, 48, 96, 144, and at 168 (if the washout period is 7 days) or at 192 (if the washout period is longer) hours (+/- 1 hour) post-dose.
Secondary outcome [3] 321131 0
To compare the time course of RBC AChE (red blood cell acetylcholinesterase) activity between formulations of Donepezil TDS (60 cm2 patch size) and the oral arm of this study. Whole blood samples will be collected to assess this outcome.
Timepoint [3] 321131 0
For the TDS Treatment Periods:
Baseline; 2, 6, (+/- 5 minutes), 12, 24, 48, 72, 96, 120, 144, 148, 152 and 168 hours (+/- 1 hour) following TDS application.

For the oral treatment periods:
Relative to the first dose on Day 1: baseline; 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24 (+/- 1 hour) hours post-dose. Relative to the last dose on Day 7: pre-dose; 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24 (+/- 1 hour) hours post-dose.
Secondary outcome [4] 321701 0
To assess TDS adhesion.
Trained site staff will score adhesion at the specified timepoints using the folling scale:
0 = greater than or equal to 90% adhered (essentially no lift off of the skin)
1 = greater than or equal 75% to <90% adhered (some edges only lifting off the skin)
2 = greater than or equal 50% to < 75% adhered (less than half of the system lifting off the skin)
3 = < 50% adhered but not detached (more than half the system lifting off of the
skin without falling off)
4 = 0% adhered - patch detached (patch completely off the skin.

Photographs are to be taken of the TDS patches: after application (but prior to overlay), post application of the overlay, at each scheduled adhesion assessment time point, prior to additional tape (if needed) and after taping.
Timepoint [4] 321701 0
Adhesion will be assessed every 12 hours +/- 1 hour from the time the TDS is applied until it is removed (i.e. 12, 24, 36, 48, 60, 72, 84, 96,108, 120, 132, 144, 156 and 168 hours after the TDS is applied).

Eligibility
Key inclusion criteria
1. Caucasian female aged 50 to 80 years (inclusive) on the day of treatment allocation.
2. Has a Body Mass Index (BMI) between 18-32 kg/m^2 (inclusive) as calculated using the site standard procedures.
3. Must be willing and able to understand and participate in all scheduled evaluations by
providing a signed and dated written informed consent prior to the initiation of any study
procedures.
4. Women of child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for ninety days following completion of therapy. Postmenopausal status will be verified by the absence of
the menstrual cycle for twelve consecutive months or medical documentation of an
oophorectomy or hysterectomy or bilateral tubal ligation and follicle-stimulating hormone
(FSH) blood test at screening. FSH must be > 25.8 mIU/mL.
5. Willing and able to discontinue all nonsteroidal anti-inflammatory drugs (NSAID) or
COX-2 analgesic therapy, thirty days prior to Day 1 and until completion of the Study Exit
Visit. This includes over-the-counter (OTC) pain medications and topical analgesics that
contain an NSAID or COX-2. The use of NSAIDs or COX-2 medications at any time
during the study and through to completion of the Study Exit Visit is prohibited and
contraindicated.
6. If the subject is receiving allowed medications for the treatment of non-excluded medical conditions, the dose must be stable for at least twenty eight days before treatment allocation on Day 1. Permitted medications must be consistent with the current label for oral donepezil (Aricept 'Registered Trademark) tablets.
Minimum age
50 Years
Maximum age
80 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Dosing with an investigational product within sixty days prior to screening.
2. Plasma donation within twenty eight days of screening or any blood donation or blood loss > 500 mL within three months of screening.
3. Has skin color or tone that may not allow reliable evaluation of irritation.
4. Unwilling to abstain from new strenuous physical exercise and from alcohol consumption for forty eight hours prior to scheduled PK blood draws at the clinic visits (subjects can maintain their normal exercise routine).
5. Has intolerance to venipuncture and/or inability to comply with the extensive blood
sampling required for this study or does not have suitable veins in both arms.
6. Has cuts, scratches/abrasions, scars, breaks in the skin surface, recent tattoos (within last six months) at the application site, skin with excessive hair, indications of sunburn,
excessive skin tanning, stretch marks and/or similar abnormalities at the intended
application sites which would affect absorption of the Investigational Product.
7. Must refrain from using tanning salons, saunas, or sun bathing during the conduct of the
study. Must also avoid shaving of application site, waxing of application site, or use of
lotion hair remover on or near application site from 48 hours before patch application and
during the conduct of the study.
8. Must abstain from food or beverages containing grapefruit, starfruit, pomegranate, limes,
seville oranges, pomelo and food or beverages containing > 5% the aforementioned fruits
(examples are: fruit drinks, fruit punches, fruit cocktails, fruit aides) fourteen days prior to
the first patch application and throughout the study.
9. Subjects with a history of or who are currently consuming high caffeine levels (greater
than ten regular or espresso cups of coffee per day); heavy smokers who smoke more
than twenty cigarettes per day. Exception will be made for lighter smokers and subjects
on stable doses of nicotine patches.
10. Presence of any major psychiatric disorder if, in the opinion of the Investigator, the
psychiatric disorder or symptom is likely to confound interpretation of drug
effect/tolerability, or affect the subject’s ability to complete the study.
11. Significant cardiovascular disease, including moderate or severe congestive heart failure (ejection fraction of < 40%) or clinically significant stenosis or occlusion of a carotid or vertebral artery.
12. Significant or chronic lung disease, including Chronic Obstructive Pulmonary Disease
(COPD) and severe or unstable asthma.
13. Diabetes complicated with retinopathy (by history), neuropathy (by history or physical
examination), or nephropathy (by serum creatinine > ULN or proteinuria > 0.2 g/L).
Uncomplicated, stable diabetes that is well controlled and actively managed is not
exclusionary.
14. Known or suspected systemic infection, including human immunodeficiency virus (HIV),
hepatitis B virus (HBV) or hepatitis C virus (HCV), or tuberculosis (TB) or qualitative
syphilis test as judged by the Investigator at screening.
15. History of severe allergy/hypersensitivity reactions or on-going allergy/hypersensitivity
reactions, or history of hypersensitivity to donepezil or other drugs of the cholinesterase
inhibitor class.
16. Potential for occupational exposure to anticholinesterase agents in the three weeks prior to treatment allocation or prior to the planned Study Exit Visit
17. History of cancer within five years of screening or between screening and treatment allocation, with the exception of non-metastatic basal cell carcinoma of the skin, carcinoma in situ of the cervix or non-progressive prostate cancer.
18. Transient Ischemic Attack (TIA) or stroke in the last three years.
19. History of suspected alcohol or drug dependence within two years of screening, or positive urine drug test at the screening or one day before investigational product administration (with the exception of nicotine dependence, which is permitted).
20. Myocardial infarction, hospitalization for unstable angina or arrhythmia or unexplained
syncope within one year of screening.
21. Clinically important infection, including chronic, persistent or acute infection, within three months of screening or between screening and treatment allocation.
22. Any medical or surgical procedure or trauma within twenty eight days of Day 1.
23. Current serious or unstable clinically important illness, including avascular necrosis,
respiratory, cardiovascular, gastrointestinal, endocrinologic, immunologic, hematologic or
other major disease that is likely to deteriorate or affect the subject’s safety or ability to
complete the study, as judged by the Investigator.
24. Exhibiting symptoms suggestive of bladder outflow obstruction as determined by the
Investigator.
25. Have a history of allergic reactions to medical grade adhesive tapes, sunscreens, cosmetics, lotions, fragrances, or latex.
26. Use of adjuvant analgesics, including antidepressants, anticonvulsants, selective serotonin re-uptake inhibitors (SSRIs) and serotonin-norepinephrine re-uptake inhibitors (SNRIs). The use of antidepressant therapy for depressive illness is permitted if judged to be clinically acceptable by the Investigator.
27. Use of muscle relaxants, anti-Parkinsonian or neuroleptic medications.
28. Use of any topical medication in the areas intended for patch application within fourteen days prior to the first patch application and throughout the study;
29. Use of any topical products without medicinal ingredient (including but not limited to
perfumes, body lotions, sunscreens, spray or patch oils, creams and alcohol) on the area
intended for patch application within forty eight hours prior to the first patch application
until after the last sample collection of each period. Topical application of products without
significant systemic absorption are allowed in areas other than the ones intended for patch
application;
30. Use of herbal and dietary supplements within seven days prior to the first patch application and throughout the study.
31. Use of St. John’s Wort within twenty eight days prior to the first patch application and
throughout the study.
32. Use of food or beverages containing xanthine derivatives, xanthine-related compounds
and/or energy drinks from forty eight hours prior to each patch application.
33. Prior or current use of donepezil hydrochloride within 60 days of dosing.
34. Clinically important abnormality in physical examination, vital signs or clinical laboratory
test at screening that could affect the subject’s safety or ability to complete the study, as
judged by the Investigator.
35. Clinically significant hypertension defined as systolic blood pressure of > 160 mmHg
and/or diastolic blood pressure of > 95 mmHg. Out-of-range results can be confirmed with
a double repeat to determine eligibility.
36. Any clinically significant abnormality in ECG rhythm, conduction or morphology,
including but not limited to:
37. Clinically significant PR (PQ) interval prolongation (PR > 220 ms);
38. Intermittent second or third degree atrioventricular (AV) block (AV block II Mobitz Type
I, Wenckebach, while asleep or in deep rest is not exclusionary)
39. Incomplete, full or intermittent bundle branch block (QRS < 115 msec with normal QRS
and T wave morphology is acceptable if there is no evidence of left ventricular
hypertrophy)
40. Abnormal T wave morphology suggesting ischemic heart disease.
41. Prolonged QTcF of > 470 msec or family history of long QT syndrome, or shortened QTcF of < 360 msec or family history of short QT syndrome.
42. Aspartatetransaminase (AST) or alaninetransaminase (ALT) levels > 1.5 ULN at
screening, or between screening and baseline.
43. Screening creatinine clearance of < 50 mL/min as determined by the Cockcroft-Gault
formula.
44. Clinically significant abnormal findings in laboratory tests of coagulation, or hematology
or has a screening hemoglobin value of less than 113 g/L.
45. A positive pregnancy test at screening or between screening and treatment allocation (fertile females only).
46. Positive urine drug screen for drugs of abuse (list as per protocol) unless there is
documentation that the subject has been prescribed the corresponding medication and the medication is otherwise acceptable for the study.
47. Heart rate less than or equal to 50 bpm.

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 involves contacting the holder of the allocation schedule who is the off-site pharmacist.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The master randomization schedule will be made of randomly permuted blocks of appropriate sizes, as determined by the statistician producing the master randomization schedules. The schedules will be generated through the Statistical Analysis System (SAS) software, version 9.3.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
A sample size of eight subjects for each formulation for the first treatment period was selected to assess Donepezil TDS delivery in vivo in human subjects, and to select a treatment group to take through the entire study.
Further subjects may be enrolled if replacement subjects are required to ensure sufficient numbers are available for each of the four treatment periods.
As this is not a powered efficacy study, no formal sample size calculations were performed
for the main study or the optional sub-study. Sample size is based on feasibility.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
11/03/2016
Date of last participant enrolment
Anticipated
31/05/2016
Actual
27/05/2016
Date of last data collection
Anticipated
Actual
21/06/2016
Sample size
Target
24
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5336 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 12798 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 292972 0
Commercial sector/Industry
Name [1] 292972 0
Corium International
Country [1] 292972 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
INCResearch Australia Pty Ltd
Address
159 Port Road,
Hindmarsh SA 5007
Country
Australia
Secondary sponsor category [1] 291744 0
None
Name [1] 291744 0
Address [1] 291744 0
Country [1] 291744 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294473 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 294473 0
The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
Ethics committee country [1] 294473 0
Australia
Date submitted for ethics approval [1] 294473 0
19/02/2016
Approval date [1] 294473 0
29/02/2016
Ethics approval number [1] 294473 0

Summary
Brief summary
This research project is being conducted to look at the Pharmacokinetics (PK, how the human body processes a substance), Pharmacodynamics (PD, how body systems are affected by a substance), and Safety of up to Four Formulations of a 7-Day Application of Donepezil Transdermal Delivery System (TDS, a patch) in Healthy Female Volunteers. It is anticipated that Donepezil TDS could be a treatment for Alzheimer's Disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63822 0
Dr Jason Lickliter
Address 63822 0
Nucleus Network, Level 5, Burnet Tower, AMREP Precinct, 89 Commercial Road, Melbourne VIC 3004
Country 63822 0
Australia
Phone 63822 0
+61 3 9076 8906
Fax 63822 0
Email 63822 0
[email protected]
Contact person for public queries
Name 63823 0
Sarah Marriott
Address 63823 0
INCResearch, Suite 1, Level 2, 924 Pacific Highway, Gordon, NSW, 2072
Country 63823 0
Australia
Phone 63823 0
+61 481 002 409
Fax 63823 0
Email 63823 0
[email protected]
Contact person for scientific queries
Name 63824 0
David Fuller
Address 63824 0
INCResearch, Suite 1, Level 2, 924 Pacific Highway, Gordon, NSW, 2072
Country 63824 0
Australia
Phone 63824 0
+ 61 450 965 709
Fax 63824 0
Email 63824 0
[email protected]

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