Pharmacokinetic Interaction Study Between Eslicarbazepine Acetate and Carbamazepine

• Sponsor: Bial - Portela C S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02284854
• Collaborator: (none)
• Enrollment: 43
• Arms: 2
• Duration (Months): 4

Study Details

Study Description

Brief Summary

Open-label study in two parallel groups of 20 healthy subjects each. Group A assessed the effect of CBZ on ESL pharmacokinetics, and Group B assessed the effect of ESL on CBZ pharmacokinetics.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: BIA 2-093; Drug: Carbamazepine	Phase 1

Detailed Description

Open-label study in two parallel groups of 20 healthy subjects each. Group A assessed the effect of CBZ on ESL pharmacokinetics, and Group B assessed the effect of ESL on CBZ pharmacokinetics. Each patient participated in the study for approximately 9 weeks. The clinical portion of the study was completed in approximately 3 months. Subjects received the treatments during 35 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic Interaction Study Between Eslicarbazepine Acetate and Carbamazepine in Healthy Subject
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily	Drug: BIA 2-093; Other Names: Eslicarbazepine acetate ESL ; Drug: Carbamazepine; Other Names: CBZ
Experimental: Group B Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily	Drug: BIA 2-093; Other Names: Eslicarbazepine acetate ESL ; Drug: Carbamazepine; Other Names: CBZ

Outcome Measures

Primary Outcome Measures

1. Cmax (BIA 2-093) - the Maximum Plasma Concentration [Day 7 to 35]

   Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg

2. Cmax (CBZ) - the Maximum Plasma Concentration [Day 28 to 35]

   Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg

3. Cmax (CBZE) - the Maximum Plasma Concentration [Day 28 to 35]

   Reference - Day 28 following twice-daily oral administration of CBZ 400 mg twice-daily Test - Day 35 following twice-daily oral administration of CBZ 400 mg twice-daily CBZE - carbamazepine-epoxide is the active metabolite of CBZ

4. AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093 [Day 7 to 35]

   Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg

5. AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ [Day 28 to 35]

   Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg

6. AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE [Day 28 to 35]

   Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg CBZE - carbamazepine-epoxide is the active metabolite of CBZ

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male and female subjects aged 18 to 45 years inclusive;

• Body mass index (BMI) between 18 and 30 kg/m2 inclusive;

• Healthy as determined by pre-study medical history, physical examination, vital signs, and 12-lead electrocardiogram (ECG); negative tests for Hepatitis B surface Antigen (HBsAg), anti-HCVAb and Human Immunodeficiency Virus (HIV)-1 and HIV-2 Ab at screening;

• Clinical laboratory test results clinically acceptable at screening and admission to each treatment period;

• Negative screen for alcohol and drugs of abuse at screening and admission to each treatment period;

• Non-smokers or ex-smokers;

• Able and willing to give written informed consent;

• If female, not of childbearing potential by reason of surgery or, if of childbearing potential, she used a double-barrier method of contraception: 1 male barrier method [male condom] plus 1 female barrier method (diaphragm, spermicide, or intrauterine device);

• If female, had a negative urine pregnancy test at screening and admission to each treatment period.

Exclusion Criteria:

• Clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders; have a clinically relevant surgical history;

• History of relevant atopy or any drug hypersensitivity (including known hypersensitivity to ESL or other carboxamide derivatives [e.g., carbamazepine, oxcarbazepine] or any of its excipients; known hypersensitivity to drugs structurally related to carbamazepine [e.g.: tricyclic antidepressants] or any of its excipients);

• Second or third-degree atrioventricular blockade not corrected with a pace-maker or any other clinically significant abnormality in the 12-lead ECG as determined by the investigator;

• History of alcoholism or drug abuse;

• Consumed more than 14 units1 of alcohol a week;

• Significant infection or known inflammatory process on screening or admission to each treatment period;

• Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to each treatment period;

• Use of medicines within two weeks of admission to first period that may affect the safety or other study assessments, in the investigator's opinion;

• Had donated or received any blood or blood products within the 3 months prior to screening;

• Vegetarians, vegans or have other medical dietary restrictions;

• Could not communicate reliably with the investigator; was unlikely to co-operate with the requirements of the study;

• Unwilling or unable to give written informed consent;

• If female, was pregnant or breast-feeding;

• If female, was of childbearing potential and did not use an accepted effective contraceptive method or used hormonal contraceptives;

• Had received an investigational drug within 3 months of screening or was currently participating in another study.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Bial - Portela C S.A.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bial - Portela C S.A.
• ClinicalTrials.gov Identifier: NCT02284854
• Other Study ID Numbers: BIA-2093-129
• First Posted: Nov 6, 2014
• Last Update Posted: Jan 8, 2015
• Last Verified: Jan 1, 2015

• Additional relevant MeSH terms: Epilepsy; Carbamazepine; Eslicarbazepine acetate

Study Results

Participant Flow

Arm/Group Title	Group A	Group B
Arm/Group Description	Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Period Title: Overall Study
STARTED	23	20
COMPLETED	18	20
NOT COMPLETED	5	0

Baseline Characteristics

Arm/Group Title	Group A	Group B	Total
Arm/Group Description	Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + 400 mg twice-daily	Total of all reporting groups
Overall Participants	23	20	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	23 100%	20 100%	43 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	10 43.5%	7 35%	17 39.5%
Male	13 56.5%	13 65%	26 60.5%

Outcome Measures

1. Primary Outcome

Title	Cmax (BIA 2-093) - the Maximum Plasma Concentration
Description	Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg
Time Frame	Day 7 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A
Arm/Group Description	Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	18
Cmax ESL (D7 ESL 800mg)	18601 (3164)
Cmax ESL (D35 ESL 800mg)	14591 (1800)

2. Primary Outcome

Title	Cmax (CBZ) - the Maximum Plasma Concentration
Description	Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg
Time Frame	Day 28 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group B
Arm/Group Description	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	20
Cmax CBZ (D28 CBZ 400 mg twice-daily)	10414 (1896)
Cmax CBZ (D35 CBZ 400 mg twice-daily)	9719 (2019)

3. Primary Outcome

Title	Cmax (CBZE) - the Maximum Plasma Concentration
Description	Reference - Day 28 following twice-daily oral administration of CBZ 400 mg twice-daily Test - Day 35 following twice-daily oral administration of CBZ 400 mg twice-daily CBZE - carbamazepine-epoxide is the active metabolite of CBZ
Time Frame	Day 28 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group B
Arm/Group Description	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	20
Cmax CBZE (D28 CBZ 400 mg twice-daily)	1562 (429)
Cmax CBZE (D35 CBZ 400 mg twice-daily)	1560 (332)

4. Primary Outcome

Title	AUC0-t (BIA 2-093) - Area Under the Curve to Last Measurable Concentration for BIA 2-093
Description	Reference - Day 7 following once-daily oral administration of ESL 800 mg Test - Day 35 following once-daily oral administration of ESL 800 mg
Time Frame	Day 7 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A
Arm/Group Description	Day 1 to Day 8 - BIA 2-093 800 mg Day 9 to Day 14 - BIA 2-093 800 mg + CBZ 200 mg Day 15 to Day 22 - BIA 2-093 800 mg + CBZ 400 mg Day 23 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	18
AUC0-t ESL (D7 ESL 800mg)	276836 (43062)
AUC0-t ESL (D35 ESL 800mg)	188648 (23897)

5. Primary Outcome

Title	AUC0-t (CBZ) - Area Under the Curve to Last Measurable Concentration for CBZ
Description	Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg
Time Frame	Day 28 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group B
Arm/Group Description	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	20
AUC0-t CBZ (D28 CBZ 400 mg twice-daily)	104494 (16344)
AUC0-t CBZ (D35 CBZ 400 mg twice-daily)	94394 (17230)

6. Primary Outcome

Title	AUC0-t (CBZE) - Area Under the Curve to Last Measurable Concentration for CBZE
Description	Reference - Day 28 following twice-daily oral administration of CBZ 400 mg Test - Day 35 following twice-daily oral administration of CBZ 400 mg CBZE - carbamazepine-epoxide is the active metabolite of CBZ
Time Frame	Day 28 to 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group B
Arm/Group Description	Day 1 to Day 8 - CBZ 200 mg Day 9 to Day 14 - CBZ 400 mg Day 15 to Day 29 - CBZ 400 mg twice-daily Day 30 to Day 35 - BIA 2-093 800 mg + CBZ 400 mg twice-daily
Measure Participants	20
AUC0-t CBZE (D28 CBZ 400 mg twice-daily)	15322 (3857)
AUC0-t CBZE (D35 CBZ 400 mg twice-daily)	14953 (3121)

Adverse Events

Arm/Group Title	CBZ 200 mg		CBZ 400 mg		CBZ 400 mg Twice-daily		ESL 800 mg + CBZ 400 mg Twice-daily		ESL 800 mg		ESL 800 mg + CBZ 200 mg		ESL 800 mg + CBZ 400 mg		Before Treatment		After Treatment
Arm/Group Description	Group B CBZ 200 mg		Group B CBZ 400 mg		Group B CBZ 400 mg twice-daily		Group A + B ESL 800 mg + CBZ 400 mg twice-daily		Group A ESL 800 mg		Group A ESL 800 mg + CBZ 200 mg		Group A ESL 800 mg + CBZ 400 mg		Group A and B Before treatment		Group A and B After treatment
All Cause Mortality
	CBZ 200 mg		CBZ 400 mg		CBZ 400 mg Twice-daily		ESL 800 mg + CBZ 400 mg Twice-daily		ESL 800 mg		ESL 800 mg + CBZ 200 mg		ESL 800 mg + CBZ 400 mg		Before Treatment		After Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	CBZ 200 mg		CBZ 400 mg		CBZ 400 mg Twice-daily		ESL 800 mg + CBZ 400 mg Twice-daily		ESL 800 mg		ESL 800 mg + CBZ 200 mg		ESL 800 mg + CBZ 400 mg		Before Treatment		After Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	CBZ 200 mg		CBZ 400 mg		CBZ 400 mg Twice-daily		ESL 800 mg + CBZ 400 mg Twice-daily		ESL 800 mg		ESL 800 mg + CBZ 200 mg		ESL 800 mg + CBZ 400 mg		Before Treatment		After Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/20 (55%)		9/20 (45%)		12/20 (60%)		21/39 (53.8%)		14/23 (60.9%)		10/21 (47.6%)		10/19 (52.6%)		0/43 (0%)		4/38 (10.5%)
Blood and lymphatic system disorders
Lymphadenopathy	0/20 (0%)		1/20 (5%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		3/19 (15.8%)		0/43 (0%)		0/38 (0%)
Cardiac disorders
Palpitations	0/20 (0%)		1/20 (5%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Ear and labyrinth disorders
Tinnitus	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Eye disorders
Vision blurred	0/20 (0%)		0/20 (0%)		0/20 (0%)		3/39 (7.7%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/20 (0%)		0/20 (0%)		1/20 (5%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Abdominal pain	1/20 (5%)		0/20 (0%)		1/20 (5%)		2/39 (5.1%)		0/23 (0%)		0/21 (0%)		2/19 (10.5%)		0/43 (0%)		1/38 (2.6%)
Constipation	0/20 (0%)		0/20 (0%)		1/20 (5%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Diarrhoea	0/20 (0%)		1/20 (5%)		0/20 (0%)		2/39 (5.1%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Dry mouth	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		1/23 (4.3%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Dyspepsia	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Flatulence	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Hypoaesthesia oral	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		1/21 (4.8%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Nausea	1/20 (5%)		1/20 (5%)		1/20 (5%)		3/39 (7.7%)		2/23 (8.7%)		0/21 (0%)		2/19 (10.5%)		0/43 (0%)		0/38 (0%)
Toothache	0/20 (0%)		0/20 (0%)		1/20 (5%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Vomiting	0/20 (0%)		0/20 (0%)		0/20 (0%)		2/39 (5.1%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
General disorders
Asthenia	3/20 (15%)		4/20 (20%)		7/20 (35%)		5/39 (12.8%)		7/23 (30.4%)		3/21 (14.3%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Feeling drunk	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Malaise	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		1/38 (2.6%)
Oedema peripheral	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Pyrexia	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Infections and infestations
Nasopharyngitis	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Rhinitis	0/20 (0%)		1/20 (5%)		2/20 (10%)		1/39 (2.6%)		0/23 (0%)		1/21 (4.8%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Investigations
Alanine aminotransferase increased	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Gamma-glutamyltransferase increased	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Inspiratory capacity abnormal	0/20 (0%)		0/20 (0%)		1/20 (5%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)		0/20 (0%)		1/20 (5%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Myalgia	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Neck pain	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Sensation of heaviness	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		1/38 (2.6%)
Torticollis	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Nervous system disorders
Disturbance in attention	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Dizziness	3/20 (15%)		0/20 (0%)		4/20 (20%)		8/39 (20.5%)		0/23 (0%)		4/21 (19%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Dysgeusia	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Dystonia	0/20 (0%)		0/20 (0%)		1/20 (5%)		5/39 (12.8%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Headache	5/20 (25%)		2/20 (10%)		3/20 (15%)		9/39 (23.1%)		4/23 (17.4%)		1/21 (4.8%)		2/19 (10.5%)		0/43 (0%)		2/38 (5.3%)
Paraesthesia	1/20 (5%)		0/20 (0%)		2/20 (10%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Presyncope	0/20 (0%)		0/20 (0%)		1/20 (5%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Sciatica	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		1/38 (2.6%)
Somnolence	4/20 (20%)		1/20 (5%)		5/20 (25%)		5/39 (12.8%)		4/23 (17.4%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Speech disorder	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Tremor	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Psychiatric disorders
Insomnia	1/20 (5%)		1/20 (5%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		1/38 (2.6%)
Reproductive system and breast disorders
Dysmenorrhoea	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Menstrual discomfort	1/20 (5%)		0/20 (0%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/20 (0%)		0/20 (0%)		1/20 (5%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/20 (0%)		0/20 (0%)		1/20 (5%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Night sweats	0/20 (0%)		1/20 (5%)		0/20 (0%)		0/39 (0%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Rash erythematous	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		1/21 (4.8%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Sweat gland disorder	0/20 (0%)		0/20 (0%)		0/20 (0%)		2/39 (5.1%)		0/23 (0%)		0/21 (0%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Vascular disorders
Hot flush	0/20 (0%)		0/20 (0%)		0/20 (0%)		2/39 (5.1%)		0/23 (0%)		1/21 (4.8%)		0/19 (0%)		0/43 (0%)		0/38 (0%)
Orthostatic hypotension	0/20 (0%)		0/20 (0%)		0/20 (0%)		1/39 (2.6%)		0/23 (0%)		0/21 (0%)		1/19 (5.3%)		0/43 (0%)		0/38 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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