Trial to Evaluate the Pharmacokinetics, Safety, and Tolerability of Rotigotine in Healthy Korean Subjects

Study Overview
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Brief Summary
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The objective of this trial is to investigate the PK (Pharmacokinetic) of repeated-dose applications of the Rotigotine transdermal patch in healthy young male and female Korean subjects to be submitted to MFDS for new drug application approval.

Official Title
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A Single-site, Randomized, Double-blind, Placebo-controlled, Repeated-dose Trial to Evaluate the Pharmacokinetics, Safety, and Tolerability of Rotigotine in 2 Different Dosages (2 mg / 24 Hours [10 cm2], 4 mg / 24 Hours [20 cm2]) in Healthy Korean Subjects

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: Rotigotine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male or female and aged between 19 and 45 years of age (inclusive) Subject is healthy (no clinically relevant findings in any of the investigations of the pre-examination) as judged by the investigator Subject is of normal body weight as determined by a Body Mass Index (BMI) between 18 and 28 kg / m² Subject is Korean (both parents are pure Korean) Exclusion Criteria: Subject has had a history of drug or alcohol abuse within the last 2 years Subject has had a history of transient ischemic attack or stroke within the last 12 months Subject has a history or current condition of Epilepsy and / or seizures Subject has a history of significant skin hypersensitivity to adhesives or other transdermal products or recently unsolved Contact Dermatitis Subject has a history or present condition of an Atopic or Eczematous Dermatitis, Psoriasis, and / or an active skin disease Female subject is pregnant or lactating Subject has any medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the subject's ability to participate in this trial Subject has a QTcB (according to Bazett´s formula) interval of ≥ 450 ms for female or ≥ 430 ms for male or any other clinically relevant Electrocardiogram (ECG) finding Subject has any clinically relevant abnormality in the physical examination, or any clinically relevant deviation from the normal range in the clinical chemistry, hematology, or urinalysis Subject has a relevant hepatic dysfunction (total Bilirubin > 2 mg /dL or Alanine Aminotransferase [ALT] or Aspartate Aminotransferase [AST] greater than 2 times the upper limit of the normal reference range) Subject has a positive test for Human Immunodeficiency Virus antibodies (HIV)-1/2Ab, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Virus Antibody (HCV-Ab) Subject has a positive test for alcohol or drugs Subject consumes more than 150 g of alcohol / week Subject has made a blood donation or had a comparable blood loss (> 400 ml) within the last 3 months Subject smokes more than 5 cigarettes per day or has done so within previous 6 months Subject has a clinically relevant allergy Subject is taking any medication (excluding oral hormonal contraceptive) currently or within 2 weeks prior to the first day of dosing (with the exception of Acetaminophen [up to 1000 mg per day per os] which may have been taken up to 48 hours prior to commencement of dosing) Female subject is currently taking an oral hormonal contraceptive but less than 2 months Subject has a symptomatic orthostatic hypotension with a decrease of Blood Pressure (BP) from supine to standing position of ≥ 20 mmHg in systolic BP or of ≥ 10 mmHg in diastolic BP after 1 and / or 3 minutes Subject has a pulse rate at rest less than 45 beats per minute or more than 100 beats per minute (measured in supine position) Subject has a systolic Blood Pressure (BP) lower than 100 mmHg or higher than 150 mmHg or diastolic BP higher than 95 mmHg (measured in supine position) Subject has a current or a history of clinically relevant motor disturbance, impairment of memory, sleep disturbance or neurodegenerative disease (e.g. , Alzheimer Dementia, Diffuse, Lewy Body Dementia, Amyotrophic Lateral Sclerosis [ALS], Multiple Sclerosis) Subject has taken herbal medicine therapy within the last 2 weeks Subject consumes more than 3 cups (more than 450 ml) of caffeinated beverages per day within the last 2 weeks

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rotigotine group<br> | Drug: Rotigotine<br>* Day 1-3: 2 mg patch once daily Day 4-6: 4 mg patch once daily<br>* Other names: Neupro;|
| Placebo Comparator: Placebo group<br>Placebo matched to rotigotine will be administered in the same way as within the Rotigotine group. | Other: Placebo<br>* Placebo patches matching with Rotigotine 2 mg patches and 4 mg patches. Frequency: Day 1-3: 2 mg patch once daily Day 4-6: 4 mg patch once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Plasma concentrations of total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state (AUC (0-24), ss) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state (AUC (0-24), ss) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by Body Weight (AUC (0-24), ss, norm (BW)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by Body Weight (AUC (0-24), ss, norm (BW)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration (Cmax) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration (Cmax) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by Body Weight (Cmax, norm (BW)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by Body Weight (Cmax, norm (BW)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by apparent-dose (AUC (0-24), ss, norm (apparent-dose)) of unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by apparent-dose (AUC (0-24), ss, norm (apparent-dose)) of total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by apparent-dose (Cmax, norm (apparent-dose)) of unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by apparent-dose (Cmax, norm (apparent-dose)) of total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by drug content (AUC (0-24), ss, norm (mgdc)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Area under the plasma concentration-time curve from 0 to 24 hours at steady-state normalized by drug content (AUC (0-24), ss, norm (mgdc)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by drug content of patch (Cmax, norm (mgdc)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Maximum plasma concentration normalized by drug content of patch (Cmax, norm (mgdc)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Terminal half-life (t ½) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Terminal half-life (t ½) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Time to reach maximum plasma concentration during a dosing interval at steady-state (t max, ss) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Time to reach maximum plasma concentration during a dosing interval at steady-state (t max, ss) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance (CL/f) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance (CL/f) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance normalized by Body Weight (CL/f norm (BW)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance normalized by Body Weight (CL/f norm (BW)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance normalized by apparent-dose (CL/f norm (apparent-dose)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent total body clearance normalized by apparent-dose (CL/f norm (apparent-dose)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent volume of distribution (Vz/f) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent volume of distribution (Vz/f) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent volume of distribution normalized by Body Weight (Vz/f norm (BW)) for unconjugated Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Apparent volume of distribution normalized by Body Weight (Vz/f norm (BW)) for total Rotigotine |  | Day 3 and Day 6 predose, and 1, 2, 3, 4, 6, 8, 12, 16, 24 hours after patch application at Day 3 and 6 and 25, 26, 28, 30, 33 and 36, 48, 60, 72 hours after patch application on Day 6 | 
| Plasma concentration at steady-state directly before patch removal (C (24), ss) for total Despropyl Rotigotine |  | Directly before patch removal at Day 2 to Day 7 | 
| Plasma concentration at steady-state directly before patch removal (C (24), ss) for total Desthienyl Rotigotine |  | Directly before patch removal at Day 2 to Day 7 | 
| Plasma concentration at steady-state 30 hours after last patch application (C (30 h), ss) for total Despropyl Rotigotine |  | At day 7 at 30 hours after last patch application | 
| Plasma concentration at steady-state 30 hours after last patch application (C (30 h), ss) for total Desthienyl Rotigotine |  | At day 7 at 30 hours after last patch application | 
| Amount excreted into urine from 0 to 24 hours at steady-state (Ae (0-24), ss) for unconjungated Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 
| Amount excreted into urine from 0 to 24 hours at steady-state (Ae (0-24), ss) for total Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 
| Amount excreted into urine from 0 to 24 hours at steady-state (Ae (0-24), ss) for total Despropyl Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 
| Amount excreted into urine from 0 to 24 hours at steady-state (Ae (0-24), ss) for total Desthienyl Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 
| Renal Clearance (CLR) for unconjugated Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 
| Renal Clearance (CLR) for total Rotigotine |  | Day 3 and Day 6 from 0 to after 24 hours of patch application | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Rotigotine, Pharmacokinetics, Healthy subjects