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Trial registered on ANZCTR


Registration number
ACTRN12615000925549
Ethics application status
Approved
Date submitted
17/08/2015
Date registered
4/09/2015
Date last updated
24/07/2019
Date data sharing statement initially provided
24/07/2019
Date results information initially provided
24/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Evaluation of Donepezil Transdermal Delivery System (TDS) formulations versus oral Donezepil (Aricept) in healthy volunteers
Scientific title
A Phase 1 Crossover Study to Evaluate the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of Two Formulations of a 7-Day Application Donepezil Transdermal Delivery System (TDS) Compared to Oral Administration of Aricept (Registered Trademark) in Healthy Volunteers
Secondary ID [1] 287287 0
P-15007
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's Disease 295923 0
Condition category
Condition code
Neurological 296182 296182 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1, open-label, cross-over, randomized study in healthy subjects conducted in two parts. Part A of the study is a three-way cross-over, partially randomized (for the first two treatment periods) design to evaluate the PK, safety, tolerability and pharmacodynamics (PD) of two different formulations of donepezil administered from a TDS (Donepezil TDS LF 50 cm2 and Donepezil TDS HF 50 cm2) compared to oral donepezil (Aricept) in healthy subjects. Part B of the study is a two-way cross-over, randomized design to evaluate the adhesive properties, safety, tolerability and PK of a larger patch size donepezil TDS (either Donepezil TDS LF 150cm2 or Donepezil TDS HF 100cm2) with two different backing laminate compositions.

Part A
The following treatments will be administered in Part A of the study:
Treatment A: Donepezil TDS LF 50 cm2 patch: 3 x 50 cm2 patches will be applied (total application area of 150 cm2) and worn for seven days, target dose 10 mg/day. An overlay will be applied to the patches.
Treatment B: Donepezil TDS HF 50 cm2 patch: 2 x 50 cm2 patches will be applied (total application area of 100 cm2) and worn for seven days, target dose 10 mg/day. An overlay will be applied to the patches.
Treatment C: Comparator – donepezil hydrochloride 10 mg (Aricept), as a daily oral dose for seven days.
A washout of at least 15 days between each treatment is allowed.
Part B
Part B will commence after at least the first six subjects have completed Day 11 of Treatment Period 1 in Part A. The TDS
formulations to be assessed in this part of the study will be selected by the sponsor following review of the safety and PK data from the first six subjects in Part A. Based on these results either the two TDS LF or the two TDS HF formulations listed below will be administered in Part B of the study:
Treatment D1: Donepezil TDS LF 150 cm2 patch with backing formulation 1: 1 x 150 cm2 patch will be applied and worn for seven days, target dose 10 mg/day.
Treatment D2: Donepezil TDS LF 150 cm2 patch with backing formulation 2: 1 x 150 cm2 patch will be applied and worn for seven days, target dose 10 mg/day.
Or
Treatment E1: Donepezil TDS HF 100 cm2 patch with backing formulation 1: 1 x 100 cm2 patch will be applied and worn for seven days, target dose 10mg/day.
Treatment E1: Donepezil TDS HF 100 cm2 patch with backing formulation 2: 1 x 100 cm2 patch will be applied and worn for seven days, target dose 10mg/day.
There is a wash-out period of 10 days before starting the second period in Part B. A new set of participants will be recruited for Part B

Part A – Treatments A and B
The following two transdermal patch formulations are being compared in Part A of this study: Donepezil TDS LF 50 cm2 (Treatment A) and Donepezil TDS HF 50 cm2 (Treatment B). Each formulation contains 90 mg donepezil per patch. Both Treatment A and Treatment B are transdermal patch formulations consisting of three layers. These formulations differ from each other with respect to the composition of the middle drug–in-adhesive layer and the donepezil delivery is anticipated to be approximately 3-fold higher for Donepezil TDS HF when compared to the LF formulation.
Part A Treatment C
In Australia Aricept is marketed by Pfizer Australia Pty Ltd. It is indicated for the treatment of mild, moderate and severe Alzheimer’s disease. Donepezil hydrochloride 10 mg (Aricept), as an oral tablet, will be provided in bottles. The site pharmacy will dispense in a single use individualized dosing container according to the dosing schedule.

Part B – Treatments D1, D2, E1, E2
The Donepezil TDS LF formulations to be evaluated in this part of the study have a patch size of 150 cm2 and contain 270 mg donepezil per patch.
The Donepezil TDS HF formulations to be evaluated in this part of the study have a patch size of 100 cm2 and contain 180 mg donepezil per patch.
The TDS LF and HF with backing formulation 1 (Treatments D1 and E1, respectively) are comprised of 5 layers and differ in composition from the Part A TDS treatments by the addition of a thin adhesive layer and a stretchable woven fabric between the top backing layer and the drug-in -adhesive layer.
The TDS LF and HF with backing formulation 2 (Treatments D2 and E2, respectively) are comprised of 3 layers and differ in composition from the Part A TDS treatments by the addition of a stretchable woven fabric in the drug-in-adhesive layer.

Patches will be applied across the back for both parts of the study.
Intervention code [1] 292607 0
Treatment: Drugs
Comparator / control treatment
Donepezil hydrochloride 10 mg (Aricept), as an oral tablet, will be provided in bottles. The site Pharmacy will dispense in a single use individualized dosing container according to the dosing schedule.

Control group
Active

Outcomes
Primary outcome [1] 295858 0
Part A
The primary objective of Part A of the study is:To evaluate the effects of formulation on the PK of two Donepezil TDS formulations, each worn for seven days.

The primary PK variables for comparison in Part A will include:
Cmax, AUC0–8 and AUC0-tau.
Timepoint [1] 295858 0
PK blood samples will be collected at the following times relative to patch application: 0 (pre-dose) 2, 6, 12, 24, 48, 72, 96, 144, 148, 152 and 168 hours following application; and at 12, 24, 48, 96, 144 and 192 hours (1 hour) after TDS removal.
Primary outcome [2] 295859 0
Part B
The primary objective of Part B of the study is:
To evaluate the relative adhesive properties of two formulations of a larger donepezil TDS (100 cm2 or 150cm2 patch size) when applied for seven days.

Adhesion will be assessed via a 5 point scoring scale by trained site staff.
Timepoint [2] 295859 0
Donepezil TDS adhesion will be assessed 0 (immediately after TDS application), 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 and 168 hours after application and before removal of the TDS. A photograph of the patch and the immediate area surrounding the patch is required at each scheduled adhesion assessment time point. In addition, a photograph of the patch will be required when adhesion assessment scores of 1 or higher are first reported or when they occur between scheduled assessments.
Secondary outcome [1] 316732 0
Part A

To evaluate the safety and tolerability (including local skin tolerability) of seven day applications of two formulations of donepezil TDS (50cm2 patch size)
Timepoint [1] 316732 0
Day 0 to Day 11 for treatment period 1 and 2.
Baseline clinical photography of the site area used for treatment is required prior to the treatment on Day 1. Photography is then required at each scheduled local tolerability evaluation time point or if scored a 2 and above on the 8 point categorical scale and/or and for any additional observations such as bruising and bleeding. Local tolerability evaluation will be studied and assessed at the application sites at 4, 12, 24, 48 and 72 hours following removal of the patch.
Secondary outcome [2] 316733 0
Part A
To compare the PK of donepezil and metabolite 6-O-desmethyl donepezil between 50 cm2 TDS applications and oral donepezil (Aricept) tablet administration.
The primary PK variables for comparison in Part A will include:
Cmax and AUC from blood samples.
Timepoint [2] 316733 0
PK blood samples will be collected at the following times relative to patch application: 0 (pre-dose) 2, 6, 12, 24, 48, 72, 96, 144, 148, 152 and 168 hours following application; and at 12, 24, 48, 96, 144 and 192 hours after TDS removal.
Secondary outcome [3] 316975 0
Part A
To compare the time course of RBC AChE activity between 50 cm2 TDS applications and oral donepezil tablet administration (Aricept).
Timepoint [3] 316975 0
For Treatments 1 and 2
Blood samples for the biomarker RBC AChE will be collected at the following times relative to patch application: 0 (pre-dose) and 2, 6 ,12, 24, 48, 72, 96, 144, 148, 152 and 168 hours following application.

For Treatment 3
Blood samples for RBC AChE will be collected at the following times relative to the first dose on Day 1: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 , 12, 24 hours following dosing; at the following time relative to the last dose on Day 7: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 , 12, 24 hours following dosing.
Secondary outcome [4] 316976 0
Part B
To evaluate the safety and tolerability (including local skin tolerability) of seven day applications of two formulations of a larger donepezil TDS (100 cm2 or 150cm2)
This outcome will be asessed following an 8-point categorical scale used by trained study personnel only.
Timepoint [4] 316976 0
Local tolerability will be studied and assessed at the application sites immediately before TDS application and at approximately 0.5 hours, 24, 48 and 72 hours following removal of the patch.
Secondary outcome [5] 316977 0
Part B
To compare the PK of donepezil between the two formulations of the larger patch size Donepezil TDS administered in Part B.
The primary PK variables for comparison in Part B will include:
Cmax and AUC from blood samples.
Timepoint [5] 316977 0
PK blood samples for donepezil will be collected at the following times relative to TDS application: 0 (pre-dose) and at 6, 24, 48, 72, 96, 120, 144 and 168 hours after application and before removal of the TDS.
Secondary outcome [6] 316978 0
Part A and B
To compare the PK of treatments administered in Part A and those administered in Part B.
The primary PK variables for comparison for Part A and Part B will include: Cmax and AUC from blood samples.
Timepoint [6] 316978 0
Part A
PK blood samples for donepezil and the metabolite 6-O-desmethyl donepezil will be collected at the following times relative to patch application: 0 (pre-dose) and 2, 6, 12, 24, 48, 72, 96, 144, 148, 152 and 168 hours (+ 1 hour) following application/dosing; and at 12, 24, 48, 96, 144 and 192 hours after TDS removal or dosing.

Part B
PK blood samples for donepezil will be collected at the following times relative to TDS application: 0 (pre-dose) and at 6 24, 48, 72, 96, 120, 144 and 168 hours after application and before removal of the TDS.

Eligibility
Key inclusion criteria
- Has a Body Mass Index (BMI) between 18-32 kg/m2 (inclusive) as calculated using the site standard procedures.
- 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.
- 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 randomization on Day 1. Permitted medications must be consistent with the current label for oral donepezil (Aricept) tablets.
- Women and men 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.
Minimum age
50 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Plasma donation within twenty eight days of screening or any blood donation or blood loss > 500 mL within three months of screening.
- 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).
- 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.
- 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.
- 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.
- Has a history of or is currently consuming high caffeine levels (greater than ten regular or espresso cups of coffee per day) and/or smoke more than twenty cigarettes per day for more than ten years (ex-smokers can be included in the study if they ceased smoking at least one year from the start of the study)
- 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
- 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.
- Potential for occupational exposure to anticholinesterase agents in the three weeks prior to randomization or prior to the planned Study Exit Visit
- Have a history of allergic reactions to medical grade adhesive tapes, sunscreens, cosmetics, lotions, fragrances, or latex.
- 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.
- 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
- Use of food or beverages containing xanthine derivatives, xanthine-related compounds and/or energy drinks from forty eight hours prior to each patch application until after the last pharmacokinetic blood sample of each treatment period

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)
A screening visit will occur thirty days prior to first dosing in each part of the study. Written informed consent will be obtained by the Investigator prior to any study procedures being performed. Screening assessments will include the following; demographic information, medical/surgical history, physical examination (including height and weight), vital signs, 12-lead electrocardiogram (ECG) and clinical laboratory tests.

The investigator site will be aware which treatment each subject receives the study is not blinded. Allocation is not concealed.

Part A
On Day 0 and/or prior to dosing on Day 1, confirmation of continued eligibility and baseline assessments and measurements will be made. A sufficient number of subjects will be randomized to ensure a minimum of 12 subjects complete this part of the study. Randomization will be stratified by gender: 2 females: 1 male. Eligible subjects will be randomized by gender to one of the two possible treatment sequences (Treatments ABC or Treatments BAC). Subjects will receive their treatment in the order specified in the randomization schedule.

Part B
Part B will commence after at least the first six subjects have completed Day 11 of Treatment Period 1 in Part A. The TDS formulations to be assessed in this part of the study will be selected following review of the safety and PK data from the first six subjects in Part A. On Day 0 and/or prior to dosing on Day 1, confirmation of continued eligibility and baseline assessments and measurements will be made. A sufficient number of subjects will be randomized to ensure a minimum of 12 subjects complete this part of the study.
There are two treatment periods for this part of the study. All subjects will be required to complete both treatment periods. Randomization will be stratified by gender: 2 females to 1 male. Eligible subjects will be randomized by gender to one of the two possible treatment sequences.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
As this is not a powered efficacy study, no formal sample size calculations were performed. A maximum of 36 healthy subjects will be enrolled to ensure a minimum of 12 subjects complete Part A and B of the study and are included in the analysis. A minimum of 12 healthy subjects per study part is adequate to assess the PK and adhesion characteristics of each TDS treatment.
A Statistical Analysis Plan (SAP) will be written after finalizing the Protocol and prior to database lock. The SAP will detail the implementation of all the planned statistical analysis in accordance with the principal features stated in the Protocol. Any deviations from the SAP will be presented in the final clinical study report.
In general, data will be summarized using either descriptive statistics (number of non-missing observations, mean, median, standard deviation (SD), minimum and maximum) or frequency counts and percentages, as appropriate to the type of data. For PK data, descriptive statistics will also include the geometric mean and coefficient of variation.
All data will be summarized and listed separately for each study part.

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)
VIC
Recruitment hospital [1] 4214 0
Nucleus Network - Melbourne

Funding & Sponsors
Funding source category [1] 291856 0
Commercial sector/Industry
Name [1] 291856 0
Corium International, Inc.
Address [1] 291856 0
235 Constitution Drive
Menlo Park, CA 94025, USA
Country [1] 291856 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
INCResearch Australia Pty Ltd
Address
159 Port Road, Hindmarsh, SA 5007, Australia
Country
Australia
Secondary sponsor category [1] 290522 0
Commercial sector/Industry
Name [1] 290522 0
Corium International, Inc.
Address [1] 290522 0
235 Constitution Drive
Menlo Park, CA 94025, USA
Country [1] 290522 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293367 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 293367 0
The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
Ethics committee country [1] 293367 0
Australia
Date submitted for ethics approval [1] 293367 0
Approval date [1] 293367 0
07/05/2015
Ethics approval number [1] 293367 0
158/15

Summary
Brief summary
This is a Phase 1, open-label, cross-over, randomized, study in healthy subjects conducted in two parts. Part A of the study is a three-way cross-over, partially randomized (for the first two treatment periods) design to evaluate the PK, safety, tolerability and PD of donepezil administered from two different formulations of a TDS (Donepezil TDS LF 50 cm2 and Donepezil TDS HF 50 cm2) compared to oral donepezil (Aricept). Part B of the study is a two-way cross-over, randomized design to evaluate the adhesive properties, safety, tolerability and PK of a larger donepezil TDS (either Donepezil TDS LF 150cm2 or Donepezil TDS HF 100cm2) with two different backing laminate compositions.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59574 0
Dr Dr Jason Lickliter
Address 59574 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne, Victoria, Australia, 3004
Country 59574 0
Australia
Phone 59574 0
+613 9076 8900
Fax 59574 0
Email 59574 0
businessdevelopment@nucleusnetwork.com.au
Contact person for public queries
Name 59575 0
Mr Daniel Obando
Address 59575 0
Suite 1, Level 2, 924 Pacific Highway, Gordon NSW 2072
Country 59575 0
Australia
Phone 59575 0
+612 8437 9200
Fax 59575 0
Email 59575 0
daniel.obando@incresearch.com
Contact person for scientific queries
Name 59576 0
Mrs Vaeling Miller
Address 59576 0
Corium International, Inc.
235 Constitution Drive
Menlo Park, CA 94025, USA
Country 59576 0
United States of America
Phone 59576 0
+1 650-298-8255
Fax 59576 0
Email 59576 0
vmiller@coriumintl.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary