None listed
Conditions
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.
Interventions
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 an
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.
Sponsors
INCResearch Australia Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
50 Years to 80 Years
Healthy volunteers
Yes
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.
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.
Outcome results
None listed