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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: Rotigotine; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rotigotine group	Drug: Rotigotine; Day 1-3: 2 mg patch once daily Day 4-6: 4 mg patch once daily; Other Names: Neupro
PLACEBO_COMPARATOR: Placebo group; Placebo matched to rotigotine will be administered in the same way as within the Rotigotine group.	Other: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: UCB Pharma
• Investigators: Study Director: UCB, Inc., +1 877 822 9493

Publications and helpful links

General Publications

• Kim BH, Yu KS, Jang IJ, Soo Lim K, Kim JR, Elshoff JP, Andreas JO, Braun M, Cawello W. Pharmacokinetic properties and tolerability of rotigotine transdermal patch after repeated-dose application in healthy korean volunteers. Clin Ther. 2015 Apr 1;37(4):902-12. doi: 10.1016/j.clinthera.2015.01.013. Epub 2015 Mar 16.

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (ACTUAL): February 1, 2007
• Study Completion (ACTUAL): February 1, 2007

Study Registration Dates

• First Submitted: October 14, 2013
• First Submitted That Met QC Criteria: October 16, 2013
• First Posted (ESTIMATE): October 17, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): October 20, 2014
• Last Update Submitted That Met QC Criteria: October 17, 2014
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Parkinson's Disease; Healthy subjects; Rotigotine
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agonists; Dopamine Agents; Rotigotine
• Other Study ID Numbers: SP0885