Trial Outcomes & Findings for Bunionectomy Study (0000-063) (NCT NCT00601458)

Last Updated: 2015-04-10

Results Overview

Total dose (amount) of hydromorphone via patient controlled analgesic (PCA) pump required in the 24 hours post-surgery in each of the treatment arms: placebo, pregabalin 300 mg or naproxen 550 mg.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

100 participants

Primary outcome timeframe

First 24 hours following surgery

Results posted on

2015-04-10

Participant Flow

First Patient Entered: 25 July 2007 Last Patient Last Visit: 28 January 2008 1 site

Participant milestones

Participant milestones
Measure	Pregabalin 300 mg Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.
Overall Study STARTED	36	34	30
Overall Study COMPLETED	32	29	28
Overall Study NOT COMPLETED	4	5	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Pregabalin 300 mg Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.
Overall Study Dosing Error	1	0	0
Overall Study Incomplete Data	0	2	0
Overall Study Protocol Violation	3	2	1
Overall Study Early Termination	0	1	1

Baseline Characteristics

Bunionectomy Study (0000-063)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pregabalin 300 mg n=32 Participants Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg n=29 Participants Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo n=28 Participants Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Total n=89 Participants Total of all reporting groups
Age, Continuous	40.3 years STANDARD_DEVIATION 14.1 • n=5 Participants	40.6 years STANDARD_DEVIATION 13.5 • n=7 Participants	38.8 years STANDARD_DEVIATION 11.6 • n=5 Participants	39.9 years STANDARD_DEVIATION 13.1 • n=4 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	23 Participants n=7 Participants	23 Participants n=5 Participants	73 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	16 Participants n=4 Participants
Body Weight	72.3 Kilograms STANDARD_DEVIATION 18.1 • n=5 Participants	76.7 Kilograms STANDARD_DEVIATION 17.2 • n=7 Participants	77.2 Kilograms STANDARD_DEVIATION 16.9 • n=5 Participants	75.3 Kilograms STANDARD_DEVIATION 17.4 • n=4 Participants
Lidocaine Use	15.0 Milliliters STANDARD_DEVIATION 2.3 • n=5 Participants	15.9 Milliliters STANDARD_DEVIATION 2.7 • n=7 Participants	14.6 Milliliters STANDARD_DEVIATION 1.6 • n=5 Participants	15.2 Milliliters STANDARD_DEVIATION 2.2 • n=4 Participants
Propofol Use	348.4 Milligrams STANDARD_DEVIATION 132.9 • n=5 Participants	364.5 Milligrams STANDARD_DEVIATION 122.8 • n=7 Participants	353.9 Milligrams STANDARD_DEVIATION 105.8 • n=5 Participants	355.4 Milligrams STANDARD_DEVIATION 121.1 • n=4 Participants

PRIMARY outcome

Timeframe: First 24 hours following surgery

Total dose (amount) of hydromorphone via patient controlled analgesic (PCA) pump required in the 24 hours post-surgery in each of the treatment arms: placebo, pregabalin 300 mg or naproxen 550 mg.

Outcome measures

Outcome measures
Measure	Pregabalin 300 mg n=32 Participants Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg n=29 Participants Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo n=28 Participants Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.
Total Patient Controlled Analgesic (PCA) Hydromorphone Consumption Over the 24 Hours Post-surgery	2.94 milligrams Interval 2.0 to 5.35	2.07 milligrams Interval 0.8 to 4.6	5.96 milligrams Interval 4.5 to 7.7

SECONDARY outcome

Timeframe: First 24 hours following surgery

Time (in hours) to first patient controlled analgesic (PCA) pump use after surgery in each of the treatment arms: placebo, pregabalin 300 mg or naproxen 550 mg.

Outcome measures

Outcome measures
Measure	Pregabalin 300 mg n=32 Participants Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg n=29 Participants Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo n=28 Participants Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.
Time to First Request of PCA Hydromorphone	7.3 Hours Interval 5.8 to 9.4	9.1 Hours Interval 7.1 to 13.6	5.8 Hours Interval 5.1 to 7.4

Adverse Events

Pregabalin 300 mg

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Naproxen Sodium 550 mg

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Results disclosure agreements

Principal investigator is a sponsor employee Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Pregabalin 300 mg n=36 participants at risk Active Comparator: Arm 1: Pregabalin 300 mg Pregabalin (300 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, pregabalin (150 mg) was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.	Naproxen Sodium 550 mg n=34 participants at risk Active Comparator: Arm 2: Naproxen sodium 550 mg Naproxen sodium (550 mg) treatment was administered approximately 1 hour prior to surgery. Postoperatively, naproxen sodium was dosed starting at 12 hours following T=0 and every 12 hours until 36 hours following T=0.	Placebo n=30 participants at risk Placebo treatment was administered approximately 1 hour prior to surgery. Postoperatively, placebo was dosed starting at 8 hours following T=0 and every 8 hours until 40 hours following T=0.
Musculoskeletal and connective tissue disorders Pain In Extremity	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Dizziness	16.7% 6/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	14.7% 5/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	10.0% 3/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Eye disorders Vision Blurred	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Abdominal Pain	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Constipation	5.6% 2/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	5.9% 2/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Diarrhoea	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Dry Mouth	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Nausea	44.4% 16/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	41.2% 14/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	70.0% 21/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Gastrointestinal disorders Vomiting	19.4% 7/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	26.5% 9/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	60.0% 18/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Chills	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Pain	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	5.9% 2/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
General disorders Pyrexia	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Investigations Blood Pressure Decreased	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Investigations Oxygen Saturation Decreased	5.6% 2/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	10.0% 3/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Metabolism and nutrition disorders Anorexia	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Musculoskeletal and connective tissue disorders Back Pain	5.6% 2/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Musculoskeletal and connective tissue disorders Muscle Spasms	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Headache	22.2% 8/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	13.3% 4/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Somnolence	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Nervous system disorders Tremor	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Psychiatric disorders Insomnia	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Renal and urinary disorders Dysuria	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Reproductive system and breast disorders Vulvovaginal Dryness	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Respiratory, thoracic and mediastinal disorders Epistaxis	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Respiratory, thoracic and mediastinal disorders Hypoxia	5.6% 2/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	3.3% 1/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal Pain	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	6.7% 2/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Skin and subcutaneous tissue disorders Blood Blister	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	13.3% 4/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Skin and subcutaneous tissue disorders Pruritus	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	14.7% 5/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	16.7% 5/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.
Skin and subcutaneous tissue disorders Rash	2.8% 1/36 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	2.9% 1/34 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.	0.00% 0/30 • AEs were collected from the time the subject signed consent until 14 days following the last dose of study mediciation. AE were assessed by clinical evaluation including vital signs, physical examination. medical history, clinical laboratory safety assessment (chemistry, hematology, urinalysis) and ECG at time points specified in the study. Subjects were queried at each visit for any clinical adverse experiences that may have occurred since the previous visit.