Trial Outcomes & Findings for Study in Healthy Volunteers to Prove That 2 Rotigotine Patches From Different Manufacturing Processes Deliver Equivalent Drug Amount to the Body. (NCT NCT00881894)

NCT ID: NCT00881894

Last Updated: 2014-10-27

Results Overview

The AUC(0-tz) is the area under the plasma concentration- time curve from zero up to the last analytically quantifiable concentration.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 52 participants
• Primary outcome timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application
• Results posted on: 2014-10-27

Participant Flow

A total of 52, healthy, male subjects has been randomized in order to complete the trial with at least 44 subjects eligible for the Pharmacokinetic Set (PKS). Baseline characteristics refer to the PKS.

Patients with an insufficient patch adhesiveness were excluded from the PKS.

Participant milestones

Measure	Sequence A-B (Test: PR2.1.1 - Reference: PR1.0) Two single applications of rotigotine patches from two different manufacturing processes in the order A-B separated by a washout phase of at least 5 days	Sequence B-A (Reference: PR1.0 - Test: PR2.1.1) Two single applications of rotigotine patches from two different manufacturing processes in the order B-A separated by a washout phase of at least 5 days
Overall Study STARTED	26	26
Overall Study Pharmacokinetic Set (PKS)	23	21
Overall Study COMPLETED	25	23
Overall Study NOT COMPLETED	1	3

Reasons for withdrawal

Measure	Sequence A-B (Test: PR2.1.1 - Reference: PR1.0) Two single applications of rotigotine patches from two different manufacturing processes in the order A-B separated by a washout phase of at least 5 days	Sequence B-A (Reference: PR1.0 - Test: PR2.1.1) Two single applications of rotigotine patches from two different manufacturing processes in the order B-A separated by a washout phase of at least 5 days
Overall Study Consent withdrawn	0	1
Overall Study Other reasons for premature termination	1	2

Baseline Characteristics

Study in Healthy Volunteers to Prove That 2 Rotigotine Patches From Different Manufacturing Processes Deliver Equivalent Drug Amount to the Body.

Baseline characteristics by cohort

Measure	Sequence A-B (Test: PR2.1.1 - Reference: PR1.0) n=23 Participants Two single applications of rotigotine patches from two different manufacturing processes in the order A-B separated by a washout phase of at least 5 days	Sequence B-A (Reference: PR1.0 - Test: PR2.1.1) n=21 Participants Two single applications of rotigotine patches from two different manufacturing processes in the order B-A separated by a washout phase of at least 5 days	Total n=44 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	23 Participants n=5 Participants	21 Participants n=7 Participants	44 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	38.7 years STANDARD_DEVIATION 9.8 • n=5 Participants	39.3 years STANDARD_DEVIATION 9.1 • n=7 Participants	39.0 years STANDARD_DEVIATION 9.3 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	21 Participants n=7 Participants	44 Participants n=5 Participants
Region of Enrollment Germany	23 participants n=5 Participants	21 participants n=7 Participants	44 participants n=5 Participants
Weight	78.98 kg STANDARD_DEVIATION 7.08 • n=5 Participants	79.98 kg STANDARD_DEVIATION 8.20 • n=7 Participants	79.45 kg STANDARD_DEVIATION 7.57 • n=5 Participants

PRIMARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz) is the area under the plasma concentration- time curve from zero up to the last analytically quantifiable concentration.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
AUC(0-tz) of Unconjugated Rotigotine	3.0168 (ng/ mL)*h Standard Deviation 1.4077	3.0635 (ng/ mL)*h Standard Deviation 1.4309

PRIMARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The Cmax is the maximum plasma concentration.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Cmax of Unconjugated Rotigotine	0.14418 ng/ mL Standard Deviation 0.06211	0.15155 ng/ mL Standard Deviation 0.06540

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The AUC(0-∞) is the area under the plasma concentration- time curve from zero up to infinity.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
AUC(0-∞) of Unconjugated Rotigotine	3.12622 (ng/ mL)*h Standard Deviation 1.41536	3.16403 (ng/ mL)*h Standard Deviation 1.43028

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz)Norm (Apparent dose) is the area under the plasma concentration- time curve from zero up to the last analytically quantifiable concentration normalized by apparent dose (mg).

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
AUC(0-tz)Norm (Apparent Dose) of Unconjugated Rotigotine	1.78200 (ng/ mL)*(h/ mg) Standard Deviation 0.71912	1.58900 (ng/ mL)*(h/ mg) Standard Deviation 0.54806

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz)Norm (BW) is the area under the plasma concentration- time curve from zero up to the last analytically quantifiable concentration normalized by body weight (kg).

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
AUC(0-tz)Norm (BW) of Unconjugated Rotigotine	239.241 (ng/ mL)*h*kg Standard Deviation 112.475	243.841 (ng/ mL)*h*kg Standard Deviation 116.640

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The Cmax,Norm (Apparent dose) is the maximum plasma concentration normalized by apparent dose.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Cmax,Norm (Apparent Dose) of Unconjugated Rotigotine	0.085822 (ng/ mL) / mg Standard Deviation 0.032789	0.079619 (ng/ mL) / mg Standard Deviation 0.027178

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The Cmax,Norm (BW) is the maximum plasma concentration normalized by body weight (kg).

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Cmax,Norm (BW) of Unconjugated Rotigotine	11.4391 (ng/ mL)*kg Standard Deviation 4.9667	12.0441 (ng/ mL)*kg Standard Deviation 5.3133

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The Tmax is the time to reach a maximum plasma concentration after patch application.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Tmax of Unconjugated Rotigotine	16.00 hour (h) Full Range 6.18 • Interval 8.0 to 28.0	16.00 hour (h) Full Range 5.26 • Interval 6.0 to 26.0

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24(before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The MRT is the mean residence time.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
MRT of Unconjugated Rotigotine	19.012 hour (h) Standard Deviation 1.809	18.882 hour (h) Standard Deviation 1.802

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The λz is the rate constant of elimination.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
λz of Unconjugated Rotigotine	0.153848 1/ hour (1/h) Standard Deviation 0.037525	0.151239 1/ hour (1/h) Standard Deviation 0.025301

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The t1/2 is the terminal half- life.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
t1/2 of Unconjugated Rotigotine	4.7665 hour (h) Standard Deviation 1.1499	4.7128 hour (h) Standard Deviation 0.8088

SECONDARY outcome

Timeframe: Pharmacokinetic samples were taken predose, after 1, 2, 3, 4, 6, 8, 12, 16, 24 (before patch removal), 25, 26, 28, 30, 32, 36, 40 and 48 hours after patch application.

Population: Pharmacokinetic Set (PKS)

The CL/f is the apparent total body clearance.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
CL/f of Unconjugated Rotigotine	1825.38 L/ h Standard Deviation 1058.21	1822.13 L/ h Standard Deviation 1060.42

SECONDARY outcome

Timeframe: 48 hours

Population: Pharmacokinetic Set (PKS)

Apparent dose of unconjugated rotigotine in mg. The Apparent dose of unconjugated rotigotine was determined from the patches removed on Day 2.

Outcome measures

Measure	Treatment A (Test: PR2.1.1) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=44 Participants Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Apparent Dose	1.676 mg Standard Deviation 0.423	1.890 mg Standard Deviation 0.561

Adverse Events

Treatment A (Test: PR2.1.1)

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Treatment B (Reference: PR1.0)

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Treatment A (Test: PR2.1.1) n=51 participants at risk Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from modified manufacturing process (Test; drug product PR2.1.1); single application of 1 patch for 24 hours	Treatment B (Reference: PR1.0) n=51 participants at risk Rotigotine transdermal patch (4.5 mg/ 10 cm\^2) from originally approved manufacturing process (Reference; drug product PR1.0); single application of 1 patch for 24 hours
Eye disorders Abnormal Sensation in Eye	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Gastrointestinal disorders Nausea	7.8% 4/51 • Number of events 4 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	5.9% 3/51 • Number of events 3 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Gastrointestinal disorders Vomiting	3.9% 2/51 • Number of events 2 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
General disorders Application Site Pruritus	23.5% 12/51 • Number of events 12 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	23.5% 12/51 • Number of events 12 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
General disorders Application Site Cold Feeling	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
General disorders Fatigue	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Infections and infestations Rhinitis	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Nervous system disorders Headache	13.7% 7/51 • Number of events 9 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	9.8% 5/51 • Number of events 5 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Nervous system disorders Somnolence	3.9% 2/51 • Number of events 2 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	5.9% 3/51 • Number of events 3 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Nervous system disorders Syncope Vasovagal	3.9% 2/51 • Number of events 2 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Nervous system disorders Dizziness	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	5.9% 3/51 • Number of events 3 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Nervous system disorders Disturbance in Attention	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Psychiatric disorders Insomnia	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/51 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.	2.0% 1/51 • Number of events 1 • Adverse Events (AEs) were collected within 48 hours. Adverse events are reported for the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of trial medication (N=52). Two subjects terminated the study prematurely after period 1 (1 subject in sequence A-B and 1 in sequence B-A). Therefore the number of subject exposed to each treatment is N=51.

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