Dose Escalating Study of Rotigotine in Pediatric Subjects With Restless Legs Syndrome

• Sponsor: UCB BIOSCIENCES, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01495793
• Collaborator: (none)
• Enrollment: 42
• Locations: 12
• Arm: 1
• Duration (Months): 29
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a multicenter, open-label, dose-escalation, Phase 2A study with multiple administrations of the rotigotine transdermal system. The study was conducted in adolescent subjects (13 to <18 years of age) with idiopathic Restless Legs Syndrome (RLS).

Condition or Disease	Intervention/Treatment	Phase
Restless Legs Syndrome	Drug: Rotigotine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Multicenter, Open-Label, 2-Group, Dose Escalation Study of Monotherapy Administration of Rotigotine in Pediatric Subjects With Idiopathic Restless Legs Syndrome
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rotigotine In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.	Drug: Rotigotine; Rotigotine transdermal patch: Dose (size): 0.5 mg/24 h (2.5 cm^2)- 1 mg/24 h (5 cm^2)- 2 mg/24 h (10 cm^2)- 3 mg/24 h (15 cm^2) The patch has to be applied continuously for 24h. After 24h, the patch has to be removed and a new one applied.

Outcome Measures

Primary Outcome Measures

1. Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

2. Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

3. Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

4. Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

5. Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

6. Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

7. Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

8. Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2) [0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28]

   VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject or parent/legal representative is considered reliable and capable of adhering to the protocol

• Subject is male or female, and is ≥13 and <18 years of age at Visit 2/Baseline

• Subject weighs ≥40 kg at Visit 2/Baseline

• Subject's Body Mass Index (BMI) is less than the 95th percentile for his or her age at Visit 2/Baseline

• Subject meets the diagnosis of RLS based on the proposed 2011 Revised International Restless Legs Syndrome Study Group Diagnostic Criteria

• Subject's RLS symptoms cause significant distress or impairment

• At Visit 2/Baseline, subject has a Periodic Limb Movement Index (PLMI) ≥5 during at least 1 of the 5 nights prior to Baseline as measured by the activity monitors

• At Visit 2/Baseline, subject has a score of ≥15 on the IRLS Rating Scale

• At Visit 2/Baseline, subject scores ≥4 points on the Clinical Global Impression (CGI) Item 1 assessment

• Subject receiving supplemental iron has been on a stable dose for at least 3 months prior to Visit 1/Screening Period

Exclusion Criteria:

• Previously participated in this study or received previous treatment with rotigotine

• Participated in another study of an investigational medicinal product (IMP) or a medical device within the last 3 months prior to Visit 1/Screening Period or is currently participating in another study of an IMP or a medical device

• Subject's RLS symptoms are restricted only to the ankles or knees

• RLS symptoms are due to renal insufficiency (uremia) or iron deficiency anemia

• Previous treatment with dopamine agonists within a period of 14 days prior to Visit 2/Baseline or L-dopa within 7 days prior to Visit 2/Baseline

• Failed to respond to previous dopaminergic therapy

• Any medical or psychiatric condition, which in the opinion of the investigator, would jeopardize or compromise the subject's well being or ability to participate

• Subject has a lifetime history of suicide attempt or has suicidal ideation in the past 6 months

• Evidence of an impulse control disorder (ICD)

• History or current symptoms of sleep apnea, narcolepsy, sleep attacks/sudden onset of sleep, or myoclonus epilepsy

• Concomitant diseases such as peripheral neuropathy, muscle fasciculation, painful legs and moving toes, fibromyalgia, rheumatoid arthritis, or sickle cell disease

• Serum ferritin level <15 ng/mL

• Subject has not attempted at least 1 non-pharmacological intervention for the management of RLS (eg, sleep hygiene, exercise)

• Prior history of psychotic episodes

• History of chronic alcohol or drug abuse within 12 months prior Screening Period

• Clinically relevant cardiac dysfunction and/or arrhythmias

• Hemoglobin level below the lower limit of normal

• Clinically relevant renal dysfunction (serum creatinine >1.5 mg/dL)

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level greater than or equal to 2 times the upper limit of normal

• History or presence of clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesion (which may be melanoma), melanoma, or a history of melanoma

• Currently receiving or has received treatment with any of the following within 28 days prior to Visit 2/Baseline: neuroleptics, antidepressants, anxiolytic drugs, opioids, monoamine oxidase (MAO) inhibitors, or sedative antihistamines

• Currently receiving treatment with any of the following: benzodiazepines, hypnotics, anticonvulsants, central alpha-adrenergic agonists, or melatonin; unless treatment is for RLS only, in which case a Wash-Out Period of at least 14 days prior to Visit 2/Baseline is required

• Currently receiving stimulant therapy for attention deficit hyperactivity disorder (ADHD); a Wash-Out Period of at least 7 days prior to Visit 2/Baseline is required

• Pregnant, nursing, or is a woman of childbearing potential who is not surgically sterile, or does not consistently use 2 combined medically acceptable methods of contraception (including at least 1 barrier method), unless not sexually active

• Unwilling to abstain from caffeine after 4pm each evening within 7 days prior to Visit 2/Baseline and for the duration of the study

• Pursues shift work or performs other continuous non-disease-related life conditions, which do not allow regular sleep at night

• Subject has a QT correction (QTc) interval of ≥500 ms at Visit 1/Screening Period or Visit 2/Baseline. Bazett's correction method must be used for the correction of the QT interval

• Symptomatic orthostatic hypotension with a decrease of blood pressure (BP) from supine to standing position of ≥20 mmHg in systolic blood pressure (SBP) or of ≥10 mmHg in diastolic blood pressure (DBP) taken from the 5 minute supine and 1 and/or 3 minute standing measurements

• A known hypersensitivity to any of the components of the study medication, such as a history of significant skin hypersensitivity to adhesives, known hypersensitive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sp1004 006	Little Rock	Arkansas	United States
2	Sp1004 012	Los Angeles	California	United States
3	Sp1004 009	Orange	California	United States
4	Sp1004 005	Washington	District of Columbia	United States
5	Sp1004 014	Spring Hill	Florida	United States
6	Sp1004 013	Indianapolis	Indiana	United States
7	Sp1004 001	Destrehan	Louisiana	United States
8	Sp1004 015	Saint Louis	Missouri	United States
9	Sp1004 007	West Seneca	New York	United States
10	Sp1004 002	Cincinnati	Ohio	United States
11	Sp1004 016	West Chester	Pennsylvania	United States
12	Sp1004 003	Austin	Texas	United States

Sponsors and Collaborators

• UCB BIOSCIENCES, Inc.

Investigators

• Study Director: UCB Clinical Trial Call Center, 1-877-822-9493 (UCB)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: UCB BIOSCIENCES, Inc.
• ClinicalTrials.gov Identifier: NCT01495793
• Other Study ID Numbers: SP1004; 2014-004383-37
• First Posted: Dec 20, 2011
• Last Update Posted: Apr 4, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by UCB BIOSCIENCES, Inc.: Rotigotine; Restless Legs Syndrome; RLS; Children; Adolescents
• Additional relevant MeSH terms: Psychomotor Agitation; Restless Legs Syndrome; Syndrome; Rotigotine

Study Results

Participant Flow

Recruitment Details	This was a multicenter study in which 42 subjects were enrolled and 24 treated at 8 sites in the USA.
Pre-assignment Detail	In total 42 subjects signed the informed consent and were enrolled into the study (Enrolled Set). 24 of these subjects were treated with medication. The sample size of 24 subjects was sufficient to target a 95% confidence interval and the calculation was based on a previous study. Participant Flow refers to the 24 treated subjects (Safety Set).

Arm/Group Title	Rotigotine
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Period Title: Overall Study
STARTED	24
COMPLETED	22
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Rotigotine
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.3 (1.3)
Age, Customized (Number) [Number]
13 years	2 8.3%
14 years	6 25%
15 years	6 25%
16 years	4 16.7%
17 years	6 25%
Sex: Female, Male (Count of Participants)
Female	15 62.5%
Male	9 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 16.7%
Not Hispanic or Latino	20 83.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	8 33.3%
White	16 66.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.39 (6.89)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	65.70 (10.72)
BMI (Body Mass Index) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.388 (3.133)

Outcome Measures

1. Primary Outcome

Title	Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)
Description	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	6
Least Squares Mean (95% Confidence Interval) [L/h (liter per hour)]	676.86

2. Primary Outcome

Title	Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)
Description	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	10
Least Squares Mean (95% Confidence Interval) [L/h (Liter per hour)]	671.72

3. Primary Outcome

Title	Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)
Description	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	11
Least Squares Mean (95% Confidence Interval) [L/h (Liter per hour)]	937.56

4. Primary Outcome

Title	Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)
Description	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	9
Least Squares Mean (95% Confidence Interval) [L/h (Liter per hour)]	1088.77

5. Primary Outcome

Title	Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)
Description	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	6
Least Squares Mean (95% Confidence Interval) [L (Liter)]	5403.16

6. Primary Outcome

Title	Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)
Description	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	10
Least Squares Mean (95% Confidence Interval) [L (Liter)]	6220.79

7. Primary Outcome

Title	Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)
Description	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	11
Least Squares Mean (95% Confidence Interval) [L (Liter)]	7114.01

8. Primary Outcome

Title	Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)
Description	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
Time Frame	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.

Arm/Group Title	Rotigotine (PKPPS)
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Measure Participants	9
Least Squares Mean (95% Confidence Interval) [L (Liter)]	6037.92

Adverse Events

Time Frame	This summary includes TEAEs from the Titration period, Taper period and Safety Follow-up (Day 1 up to 69 days).
Arm/Group Title	Rotigotine
Arm/Group Description	In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
All Cause Mortality
	Rotigotine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rotigotine
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Other (Not Including Serious) Adverse Events
	Rotigotine
	Affected / at Risk (%)	# Events
Total	15/24 (62.5%)
Gastrointestinal disorders
Diarrhoea	1/24 (4.2%)	1
Nausea	7/24 (29.2%)	11
Vomiting	2/24 (8.3%)	2
General disorders
Application site pruritus	4/24 (16.7%)	4
Application site irritation	1/24 (4.2%)	1
Irritability	1/24 (4.2%)	1
Immune system disorders
Allergy to arthropod sting	1/24 (4.2%)	1
Food allergy	1/24 (4.2%)	1
Infections and infestations
Cellulitis	1/24 (4.2%)	1
Fungal infection	1/24 (4.2%)	1
Influenza	1/24 (4.2%)	1
Nasopharyngitis	2/24 (8.3%)	3
Pharyngitis	1/24 (4.2%)	1
Upper respiratory tract infection	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Stress fracture	1/24 (4.2%)	1
Animal bite	1/24 (4.2%)	1
Road traffic accident	1/24 (4.2%)	1
Wound	1/24 (4.2%)	1
Investigations
Blood bilirubin increased	2/24 (8.3%)	2
Metabolism and nutrition disorders
Anorexia	1/24 (4.2%)	1
Increased appetite	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/24 (4.2%)	1
Muscular weakness	1/24 (4.2%)	1
Musculoskeletal chest pain	1/24 (4.2%)	1
Muscukoseletal pain	1/24 (4.2%)	1
Neck pain	1/24 (4.2%)	1
Pain in extremity	1/24 (4.2%)	1
Nervous system disorders
Somnolence	1/24 (4.2%)	1
Syncope	1/24 (4.2%)	1
Headache	2/24 (8.3%)	2
Migraine	1/24 (4.2%)	1
Dizzines	2/24 (8.3%)	2
Sudden onset of sleep	1/24 (4.2%)	2
Reproductive system and breast disorders
Dysmenorrhoea	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders
Acne	1/24 (4.2%)	1
Urticaria	1/24 (4.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.