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Trial registered on ANZCTR


Registration number
ACTRN12616000349448
Ethics application status
Approved
Date submitted
23/12/2015
Date registered
17/03/2016
Date last updated
12/09/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
To evaluate the effects of formulation on the PK of different Memantine TDS formulations, worn for seven, four or three days, applied to the backs of healthy subjects
Scientific title
A Phase 1 Crossover Study to Evaluate the Pharmacokinetics (PK) and Safety of Two Formulations of a 7-Day Application of Memantine Transdermal Delivery System (TDS) Compared to Oral Administration of NAMENDA XR and to assess TDS adhesion in Healthy 50-80 year old Volunteers
Secondary ID [1] 288188 0
Nil known
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer’s Disease 297091 0
Condition category
Condition code
Neurological 297331 297331 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A
Treatment A: Formulation A - Memantine TDS 362, 50 cm2 22 mg/day target dose (comprising three x patches for a total application area of 150 cm2) worn for seven days, four or three days.
Treatment B: Formulation B - Memantine TDS 360, 50 cm2 18 mg/day target dose (comprising three x patches for a total application area of 150 cm2) worn for seven days.
Treatment C: Comparator – (Memantine Hydrochloride) 28 mg (NAMENDA XR), as a daily oral dose for seven days.
Part B
Treatment D1: Memantine TDS 362 with backing laminate 1, 150 cm2 22 mg/day target dose (comprising one x patch, total application area 150 cm2) worn for three days.
There will be a washout period of ast least 15 days between treatments.
(Monitoring to adherence not required since the IP is a patch formulation).
Patch is applied to the backs of subjects
Part C
Treatment D1: Memantine TDS 362 with backing laminate 1, 150 cm2 22 mg/day target dose will be applied to the back and worn for three days. The patch will be removed on Day 4. A new Memantine TDS 362 treatment will be applied to the opposite side of the previous patch and will be worn for seven days.
Part D
Treatment D1: Memantine TDS 362 with backing laminate 1, 150 cm2 22 mg/day target dose worn for seven days
Intervention code [1] 293489 0
Treatment: Drugs
Intervention code [2] 293490 0
Treatment: Devices
Comparator / control treatment
Namenda XR '(Treatment C)'
Control group
Active

Outcomes
Primary outcome [1] 296895 0
Part A Primary Outcomes
Pharmacokinetic
The primary PK variables for comparison will include:
* Cmax (maximum observed plasma concentration)
* AUC0–8 (area under the plasma concentration-time curve from 0 to infinity)
* AUC0-tau (area under the plasma concentration-time curve from time 0 to the end of the dosing interval)





Timepoint [1] 296895 0
Samples taken at the following time points relative to the first dose on Day 1: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24 hours (+/- 1 hour) following dosing;
and at the following time relative to the last dose on Day 7: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24, 48, 96, 144 and 192 hours (+/- 1 hour) following dosing.
Primary outcome [2] 297036 0
Part B Primary Outcomes
TDS Performance
The individual and cumulative adhesion scores (CAS) of the large patch size Memantine TDS 362 (150 cm2).
Timepoint [2] 297036 0
Memantine TDS adhesion will be assessed 0 (immediately after TDS application), 4, 8, 12, 16, 24, 36, 48, 60, and 72 (+/- 30 minutes) after application and before removal of the TDS.
Primary outcome [3] 299598 0
Part C's composite primary outcome is to evaluate the safety of Memantine TDS 362 (150 cm2) and to assess the Local tolerability for Memantine TDS 362.
Timepoint [3] 299598 0
Part C:
Safety evaluation will include clinical laboratory assessments (hematology, serum chemistry and urinalysis), vital signs, ECG, physical examination findings, and reported AEs for up to ten days.
Local Tolerability will be studied and assessed at the application sites after the TDS patch is applied at each scheduled adhesion assessment time point (every 12 hours +/- 1 hour from application) and at 4, 12, 24, 48 and 72 hours following removal of the patch.
Part C:
Adhesion will be assessed immediately after application (0-hour) and at the following scheduled time-points: 4, 8, 12, 24, and then every 6, 12 hours (+/- 30 minutes) after application, and before removal
Secondary outcome [1] 319640 0
Part A Secondary Outcomes
Safety
The safety variables for comparison in Part A of the study will include:
* Clinical laboratory assessments (hematology, serum chemistry and urinalysis), vital signs, ECG, physical examination findings, reported AEs and serious adverse events (SAEs) of 7-day application of Memantine TDS 362 (50 cm2) and 360 (50 cm2), or a 3 day or a 4-day application of Memantine TDS 362 (50 cm2) when compared to daily oral dosing of NAMENDA XR for seven days.
* Local tolerability scores (irritation) for Memantine TDS 362 (50 cm2) and 360 (50 cm2).
Timepoint [1] 319640 0
Part A Secondary Objectives:
Safety assessments made daily throughout each patch wear period
Secondary outcome [2] 319897 0
Part B Secondary Outcomes
Safety
The safety variables for comparison in Part B of the study will include:
* Clinical laboratory assessments (hematology, serum chemistry and urinalysis), vital signs, ECG, physical examination findings, and reported AEs and SAEs of 3-day application of the large patch size Memantine TDS 362.
* Local tolerability scores (irritation) for the large patch size Memantine TDS 362.
Timepoint [2] 319897 0
Part B Secondary Objectives:
Safety assessments made daily throughout 3 day patch wear
Secondary outcome [3] 321008 0
Pharmacokinetic
The PK variables for comparison in Part B of the study will include but are not limited to:
* Cmax
* AUC0–8
* AUC0-tau
Plasma samples are analysed
Timepoint [3] 321008 0
Samples taken at the following time points relative to the first dose on Day 1: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24 hours (+/- 1 hour) following dosing; and at the following time relative to the last dose on Day 3: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24, 48, 96, 144 and 192 hours (+/- 1 hour) following dosing.
Secondary outcome [4] 321009 0
Pharmacokinetic
In Part A, the secondary PK variables for the characterization of the PK of the Memantine TDS 362 (50 cm2), Memantine TDS 360 (50 cm2) and NAMENDA XR will include but are not limited to:
* lambda z (first-order terminal-phase rate constant)
* t1/2 (apparent terminal elimination half-life)
* Ctau (minimum plasma concentration at the end of the dosage interval)
* tmax (time to reach the maximum plasma concentration)
* AUC0-t (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration)
*Cavg (average plasma concentration over the dosage interval)
* % fluctuation (100 x (Cmax-Ctau)/Ctau)
Timepoint [4] 321009 0
Samples taken at the following time points relative to the first dose on Day 1: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24 hours (+/- 1 hour) following dosing; and at the following time relative to the last dose on Day 7: 0 (pre-dose) and 1, 2, 3, 4, 6, 8 (+/- 5 minutes), 12, 24, 48, 96, 144 and 192 hours (+/- 1 hour) following dosing.
Secondary outcome [5] 327653 0
Part D secondary outcome include the assessment of patch adhesion of the Memantine TDS 362 (150 cm2). Patch adhesion will be assessed using The individual and cumulative adhesion scores (CAS) of the large patch size Memantine TDS 362 (150 cm2).
Timepoint [5] 327653 0
Part D: Adhesion will be assessed immediately after application (0-hour) and at the following scheduled time-points: 4, 8, 12, 24, and then every 12 hours (+/- 30 minutes) after application, and before removal
Secondary outcome [6] 327654 0
Part D's composite primary outcome is to evaluate the safety of Memantine TDS 362 (150 cm2) and to assess the Local tolerability for Memantine TDS 362.
Timepoint [6] 327654 0
Part D:
Safety evaluation will include clinical laboratory assessments (hematology, serum chemistry and urinalysis), vital signs, ECG, physical examination findings, and reported AEs for up to ten days.
Local Tolerability will be studied and assessed at the application sites after the TDS patch is applied at each scheduled adhesion assessment time point (every 12 hours +/- 1 hour from application) and at 4, 12, 24, 48 and 72 hours following removal of the patch.
Secondary outcome [7] 327655 0
Part C Primary Outcome is to assess patch adhesion of the Memantine TDS 362 (150 cm2). Patch adhesion will be assessed using The individual and cumulative adhesion scores (CAS) of the large patch size Memantine TDS 362 (150 cm2).
Timepoint [7] 327655 0
Part C: Adhesion will be assessed immediately after application (0-hour) and at the following scheduled time-points: 4, 8, 12, 24, and then every 6, 12 hours (+/- 30 minutes) after application, and before removal

Eligibility
Key inclusion criteria
Part A and B - Inclusion Criteria
A. General
* Caucasian male or female with light/pale skin aged 50 to 80 years (inclusive) on the day of randomization.
* Has a Body Mass Index (BMI) between 18-34 kg/m^2 (inclusive) as calculated using the site standard procedures.
* 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.
B. Contraception and Concomitant Medications
* 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.
* If the subject is receiving allowed medications for the treatment of non-excluded medical conditions, must be stable for at least 28 days before randomization on Day 1. Any medications not at stable dose for at least 28 days, must be discontinued with a 5 x half-life washout and Sponsor approval prior to randomization on Day 1. Permitted medications must be consistent with the current label for oral Memantine (Namenda XR) tablets.
* Negative 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.
Minimum age
50 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria
A .General
* Participation in another clinical study with an investigational product or device within sixty days prior to screening.
* Plasma donation within 28 days of screening or any blood donation or blood loss greater than 500 mL within three months of screening.
* Has skin color or tone that may not allow reliable evaluation of irritation.
* Unwilling to abstain from strenuous physical exercise and from alcohol consumption for forty eight hours prior to scheduled PK blood draws at the clinic visits.
* 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.
* 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, moles and/or similar abnormalities at the intended application sites which would affect absorption of the Investigational Product.
* Unwilling to refrain from using tanning salons, saunas, or sunbathe during the conduct of the study. Unwilling to also refrain from shaving of application site, waxing of application site, or using lotion hair remover on or near application site from twenty one days before patch application and during the conduct of the study.
* Smoke more than twenty cigarettes per day
B. Medical History
* 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.
* Significant cardiovascular disease, including moderate or severe congestive heart failure (ejection fraction of less than 40%) or clinically significant stenosis or occlusion of a carotid or vertebral artery.
* Significant or chronic lung disease, including Chronic Obstructive Pulmonary Disease (COPD) and severe or unstable asthma.
* Diabetes complicated with retinopathy (by history), neuropathy (by history or physical examination), or nephropathy (by serum creatinine greater than ULN or proteinuria greater than0.2 g/L). Uncomplicated, stable diabetes that is well controlled and actively managed is not exclusionary.
* 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.
* History of severe allergy/hypersensitivity reactions or on-going allergy/hypersensitivity reactions, or history of hypersensitivity to Memantine or other drugs of the N-methyl-D-aspartate (NMDA) antagonist class.
* History of cancer within five years of screening or between screening and randomization. Subjects with history of non-metastatic basal cell carcinoma of the skin, carcinoma in situ of the cervix or non-progressive prostate cancer may be enrolled with prior approval from Corium.
* Transient Ischemic Attack (TIA) or stroke in the last three years.
* History of suspected alcohol or drug dependence within two years of screening, or who are positive for urine drug test at the screening or one day before investigational product administration (with the exception of nicotine dependence, which is permitted).
* Myocardial infarction, hospitalization for unstable angina or arrhythmia or unexplained syncope within one year of screening.
* Clinically important infection, including chronic, persistent or acute infection, within three months of screening or between screening and randomization.
* Any medical or surgical procedure or trauma within 28 days of Day 1.
* 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.
* Exhibiting symptoms suggestive of bladder outflow obstruction as determined by the Investigator.
* Have a history of allergy or sensitivity or hypersensitivity to the ingredients in the TDS patches including glues/adhesives, topical alcohol, medical grade adhesive tapes, sunscreens, cosmetics, lotions, fragrances, and/or latex, which in the opinion of the Principal Investigator, would compromise the safety of the subject or the study.
C. Concomitant Medications and Procedural Contraindications
* 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;
* Use of any topical products with or without medicinal ingredient (including but not limited to perfumes, body lotions, sunscreens, spray or patch oils, creams and alcohol) on the back 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;
* Prior or current use of Memantine hydrochloride or to piperidine derivatives and related drugs (not applicable to Part A subjects returning for Part C)
D. Physical Examination, Vital Signs, ECG, Laboratories and Imaging.
* 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.
* Clinically significant hypertension defined as systolic blood pressure of greater than 160 mmHg and/or diastolic blood pressure of greater than 95 mmHg. Out-of-range results can be confirmed with a double repeat used to determine eligibility.
* Any clinically significant abnormality in ECG rhythm, conduction or morphology, including but not limited to:
* Clinically significant PR (PQ) interval prolongation
(PR greater than 220 ms);
* Intermittent second or third degree atrioventricular (AV) block (AV block II Mobitz Type I, Wenckebach, while asleep or in deep rest is not exclusionary)
* Incomplete, full or intermittent bundle branch block (QRS greater than 115 msec with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy)
* Abnormal T wave morphology suggesting ischemic heart disease.
* Prolonged QTcF of greater than 450 msec (males), greater than 470 msec (females) or family history of long QT syndrome, or shortened QTcF of less than 360 msec or family history of short QT syndrome.
* AST (aspartate transaminase) of ALT (alanine transaminase) levels greater than 1.5 ULN at screening, or between screening and baseline.
* Screening creatinine clearance of less than 50 mL/min as determined by the Cockcroft-Gault formula.
* Clinically significant abnormal findings in laboratory tests of coagulation, or hematology or has a screening hemoglobin value of less than 113 g/L.
* A positive pregnancy test at screening or between screening and randomization (fertile females only).
* Heart rate equal to 50 bpm

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
This study is partially randomized. The first twelve subjects were randomized and the remaining subjects will not be randomzied.
The study consists of 4 participants groups. Each group consists of 2 or 3 treatment periods.
Group 1
Treatment Period 1 – TDS 7 day adhesion, randomised to TDS 360 or TDS 362
Treatment Period 2 – Namenda XR 7 day dosing (non-randomised)
Treatment Period 3 – TDS 3 day adhesion, TDS 362 only (non-randomised)
Group 2
Treatment Period 1- TDS 7 day adhesion, randomised to TDS 360 or TDS 362
Treatment Period 2 – Namenda XR 7 day dosing (non-randomised)
Treatment Period 3 – TDS 3 day adhesion, TDS 362 only (non-randomised)
Group 3
Treatment Period 1 - Namenda XR 7 day dosing (non-randomised)
Treatment Period 2- TDS 4 day adhesion, TDS 362 only (non-randomised)
Group 4
Treatment Period 1- Namenda XR 7 day dosing (non-randomised)
Treatment Period 2 - TDS 3 day adhesion, TDS 362 only (non-randomised)

Treatment A: Formulation A - Memantine TDS 362, 50 cm2 22 mg/day target dose (comprising three x patches for a total application area of 150 cm2) worn for seven days, four or three days.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Baseline and Demographic Data
Baseline and demographic data will be summarized.
Safety Analysis
Adverse events, laboratory data, vital signs, ECG data and skin irritation scores will be summarized.

Pharmacokinetic Analysis
Plasma Memantine concentrations and resultant pharmacokinetic parameters across study subjects and treatments will be summarised.

Performance Analysis
Individual TDS adhesion scores (0-4) for each patch and for Cumulative adhesion scores (CAS) (Part B) will be summarized.

Part A: Sample size of at least twelve subjects to complete is considered adequate to estimate the Memantine PK from TDS in human subjects and to select the dose and formulation for treatment in a larger group of subjects. In addition this sample size will provide adequate PK data to establish the delivery profile of Memantine TDS in human subjects compared to Memantine PK following oral Memantine (NAMENDA XR).
Part B: Sample size of at least 12 subjects enrolled should provide sufficient data to meet the adhesion assessment objectives.
Part C: Sample size of at least six subjects recruited and enrolled will provide sufficient data to meet the tolerability and adhesion assessment objectives.
Part D: Sample size of at least six subjects recruited and enrolled will provide sufficient data to meet the tolerability and adhesion assessment objectives
As this is not a powered efficacy study, no formal sample size calculations were performed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
29/09/2015
Date of last participant enrolment
Anticipated
16/06/2016
Actual
23/06/2016
Date of last data collection
Anticipated
Actual
18/08/2016
Sample size
Target
48
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 4985 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 12472 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 292583 0
Commercial sector/Industry
Name [1] 292583 0
Corium International
Country [1] 292583 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Corium International, Inc.
Address
235 Constitution Drive, Menlo Park, CA 94025
Country
United States of America
Secondary sponsor category [1] 291306 0
None
Name [1] 291306 0
Address [1] 291306 0
Country [1] 291306 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294068 0
Bellberry Limited
Ethics committee address [1] 294068 0
Ethics committee country [1] 294068 0
Australia
Date submitted for ethics approval [1] 294068 0
26/08/2015
Approval date [1] 294068 0
24/09/2015
Ethics approval number [1] 294068 0
Application No: 2015-08-577

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62290 0
Dr Sam Salman
Address 62290 0
Linear Clinical Research Limited
QEII Medical Centre
First Floor, B Block Hospital Avenue
Nedlands WA 6009


Country 62290 0
Australia
Phone 62290 0
+61 (8) 6382 5100
Fax 62290 0
+61 (8) 9381 4453
Email 62290 0
[email protected]
Contact person for public queries
Name 62291 0
Sarah Marriott
Address 62291 0
INC Research
Suite 1, Level 2
924 Pacific Highway, Gordon, NSW, 2072
Country 62291 0
Australia
Phone 62291 0
+61 (2) 8437 9256
Fax 62291 0
+61 (2) 8437 9299
Email 62291 0
[email protected]
Contact person for scientific queries
Name 62292 0
Sarah Marriott
Address 62292 0
INC Research
Suite 1, Level 2
924 Pacific Highway, Gordon, NSW, 2072
Country 62292 0
Australia
Phone 62292 0
+61 (2) 8437 9256
Fax 62292 0
+61 (2) 8437 9299
Email 62292 0
[email protected]

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