Trial Outcomes & Findings for The Use of Rotigotine for Treatment of Reducing Signs and Symptoms of Fibromyalgia in Adults. (NCT NCT00464737)

Last Updated: 2015-06-22

Results Overview

The average daily pain score is calculated using an 11-point Likert scale, ranging from 0 (no pain) to 10 (worst pain ever experienced).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

230 participants

Primary outcome timeframe

Baseline, Last 2 weeks of the 12-week Treatment Phase

Results posted on

2015-06-22

Participant Flow

The Full Analysis Set (FAS) contains all randomized subjects who received at least 1 dose of trial medication, and had at least 1 post-Baseline Likert pain score. The Per Protocol Set contains all subjects in the FAS who completed at least 2 weeks of the Maintenance Phase and had no major protocol deviations.

Participant flow is based on the 230 randomized subjects however 1 subject randomized to Rotigotine 4 mg/24 hrs did not receive study medication and was excluded from the Safety Set. Thus 229 subjects are included in summaries of baseline characteristics and adverse events. The excluded subject was a 47-year old female enrolled in the United States

Participant milestones

Participant milestones
Measure	Placebo Placebo	Rotigotine 4 mg Rotigotine 4 mg/24 hrs	Rotigotine 8 mg Rotigotine 8 mg/24 hrs
Overall Study STARTED	82	74	74
Overall Study COMPLETED	50	42	19
Overall Study NOT COMPLETED	32	32	55

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo	Rotigotine 4 mg Rotigotine 4 mg/24 hrs	Rotigotine 8 mg Rotigotine 8 mg/24 hrs
Overall Study Adverse Event	12	17	33
Overall Study Lack of Efficacy	7	7	4
Overall Study Withdrawal by Subject	5	3	5
Overall Study Protocol Violation	1	1	5
Overall Study Non-compliance	0	1	1
Overall Study Lost to Follow-up	5	2	5
Overall Study Other: Subject's schedule doesn't permit	1	0	0
Overall Study Other: Subject left town; family illness	1	0	0
Overall Study Other: Study demands too great	0	1	0
Overall Study Other: Personal family reasons	0	0	1
Overall Study Other: Subject's disability per sponsor	0	0	1

Baseline Characteristics

The Use of Rotigotine for Treatment of Reducing Signs and Symptoms of Fibromyalgia in Adults.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=82 Participants Placebo	Rotigotine 4 mg n=73 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=74 Participants Rotigotine 8 mg/24 hrs	Total n=229 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	81 Participants n=5 Participants	73 Participants n=7 Participants	73 Participants n=5 Participants	227 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Age, Continuous	46.4 years STANDARD_DEVIATION 10.7 • n=5 Participants	47.5 years STANDARD_DEVIATION 10.3 • n=7 Participants	47.0 years STANDARD_DEVIATION 11.6 • n=5 Participants	47.0 years STANDARD_DEVIATION 10.8 • n=4 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	65 Participants n=7 Participants	68 Participants n=5 Participants	209 Participants n=4 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	8 Participants n=7 Participants	6 Participants n=5 Participants	20 Participants n=4 Participants
Region of Enrollment United States	82 participants n=5 Participants	73 participants n=7 Participants	74 participants n=5 Participants	229 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Last 2 weeks of the 12-week Treatment Phase

Population: Of the 82 (Placebo), 74 (Rotigotine 4 mg), and 74 (Rotigotine 8 mg) patients randomized, 81, 70 and 72 patients respectively are included in the summary of the last 2 weeks of the 12-week Treatment Phase, based on the Full Analysis Set.

The average daily pain score is calculated using an 11-point Likert scale, ranging from 0 (no pain) to 10 (worst pain ever experienced).

Outcome measures

Outcome measures
Measure	Placebo n=81 Participants Placebo	Rotigotine 4 mg n=70 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=72 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Average Daily Pain Score to the Last 2 Weeks of the 12-week Treatment Phase (Based on the Full Analysis Set)	-1.12 Score on a scale Standard Deviation 1.83	-1.27 Score on a scale Standard Deviation 1.86	-0.83 Score on a scale Standard Deviation 1.70

PRIMARY outcome

Timeframe: Baseline, Last 2 weeks of the 12-week Treatment Phase

Population: Of the 82 (Placebo), 74 (Rotigotine 4 mg), and 74 (Rotigotine 8 mg) patients randomized, 50, 33 and 22 patients respectively are included in the summary of the last 2 weeks of the 12-week Treatment Phase, based on the Per Protocol Set.

The average daily pain score is calculated using an 11-point Likert scale, ranging from 0 (no pain) to 10 (worst pain ever experienced).

Outcome measures

Outcome measures
Measure	Placebo n=50 Participants Placebo	Rotigotine 4 mg n=33 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=22 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Average Daily Pain Score to the Last 2 Weeks of the 12-week Treatment Phase (Based on the Per Protocol Set)	-1.28 score on a scale Standard Deviation 1.79	-2.09 score on a scale Standard Deviation 2.07	-1.57 score on a scale Standard Deviation 2.27

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

Population: Of the 82 (Placebo), 74 (Rotigotine 4 mg), and 74 (Rotigotine 8 mg) patients randomized, 80, 64 and 63 patients respectively are included in this summary based on the Full Analysis Set and have the Last Assessment in the 12-week Treatment Phase.

The Fibromyalgia Impact Questionnaire (FIQ) Total Score ranges from 0 to 100 with higher scores corresponding to a greater impact of fibromyalgia

Outcome measures

Outcome measures
Measure	Placebo n=80 Participants Placebo	Rotigotine 4 mg n=64 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=63 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Fibromyalgia Impact Questionnaire (FIQ) Total Score to the Last Assessment in the 12-week Treatment Phase	-14.9 Score on a scale Standard Deviation 15.6	-13.4 Score on a scale Standard Deviation 13.7	-12.8 Score on a scale Standard Deviation 18.1

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

Population: Based on the observed outcome for the primary efficacy variable for this study, an abbreviated clinical study report was produced. Summaries were not produced for all pre-planned outcome measures and thus these results are not available. This summary was not produced for the abbreviated clinical study report.

Total Myalgic Score ranges from 0 to 54 with higher scores corresponding to a greater level of pain.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, Last 2 weeks of the 12-week Treatment Phase

Sleep scale - the subject rated quality of sleep, from 0 (very good sleep) to 10 (very poor sleep)

Outcome measures

Outcome measures
Measure	Placebo n=81 Participants Placebo	Rotigotine 4 mg n=70 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=72 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Average Daily Interference With Sleep to the Last 2 Weeks of the 12-week Treatment Phase	-0.95 Score on a scale Standard Deviation 2.01	-0.82 Score on a scale Standard Deviation 2.03	-0.48 Score on a scale Standard Deviation 2.09

SECONDARY outcome

Timeframe: Baseline, Last 2 weeks of the 12-week Treatment Phase

General activity scale - the subject rated how the pain had interfered with general activity, from 0 (did not interfere) to 10 (completely interfered)

Outcome measures

Outcome measures
Measure	Placebo n=81 Participants Placebo	Rotigotine 4 mg n=70 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=72 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Daily Interference With General Activity to the Last 2 Weeks of the 12-week Treatment Phase	-1.11 Score on a scale Standard Deviation 2.05	-1.19 Score on a scale Standard Deviation 1.82	-0.88 Score on a scale Standard Deviation 2.10

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

Population: Of the 82 (Placebo), 74 (Rotigotine 4 mg), and 74 (Rotigotine 8 mg) patients randomized, 76, 58, and 51 patients respectively are included in this summary based on the Full Analysis Set and have the Last Assessment in the 12-week Treatment Phase.

The PGIC is a 7-point self-administered categorical rating scale in which the subject rated the change in pain since starting trial medication (from much worse \[score of 1\] to much better \[score of 7\]).

Outcome measures

Outcome measures
Measure	Placebo n=76 Participants Placebo	Rotigotine 4 mg n=58 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=51 Participants Rotigotine 8 mg/24 hrs
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Much better	8 Patients	10 Patients	9 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Moderately better	14 Patients	14 Patients	7 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Mildly better	25 Patients	12 Patients	11 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase No change	16 Patients	17 Patients	12 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Mildly worse	5 Patients	3 Patients	5 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Moderately worse	7 Patients	1 Patients	5 Patients
Patient Global Impression of Change (PGIC) Assessment From Baseline to the Last Assessment in the 12-week Treatment Phase Much worse	1 Patients	1 Patients	2 Patients

SECONDARY outcome

Timeframe: Baseline, Last 2 weeks of the 12-week Treatment Phase

An 11-point Likert scale was used for subjects to assess pain, from 0 (no pain) to 10 (worst pain ever experienced).

Outcome measures

Outcome measures
Measure	Placebo n=81 Participants Placebo	Rotigotine 4 mg n=70 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=72 Participants Rotigotine 8 mg/24 hrs
Change From Baseline in Morning and Evening Pain Scores to the Last 2 Weeks of the 12-week Treatment Phase Morning Pain Score	-1.07 Score on a scale Standard Deviation 1.91	-1.30 Score on a scale Standard Deviation 1.91	-0.78 Score on a scale Standard Deviation 1.78
Change From Baseline in Morning and Evening Pain Scores to the Last 2 Weeks of the 12-week Treatment Phase Evening Pain Score	-1.17 Score on a scale Standard Deviation 1.82	-1.24 Score on a scale Standard Deviation 1.90	-0.88 Score on a scale Standard Deviation 1.89

SECONDARY outcome

Timeframe: 12-week Treatment Phase

Subjects recorded use of rescue medication for pain in the diary daily in the evening with a Yes/No response. Use of alcohol to treat pain in the past 24 hours was recorded with a Yes/No response.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: End of the Maintenance Phase/Week 12

Population: The number of patients in the Placebo group has been presented as 0 as this outcome measure is not applicable for this treatment group. Of the 73 (Rotigotine 4 mg) and 74 (Rotigotine 8 mg) patients respectively in the Safety Set, a total of 41 and 20 patients respectively at the end of Maintenance Phase/Week 12 have this assessment.

Outcome measures

Outcome measures
Measure	Placebo Placebo	Rotigotine 4 mg n=41 Participants Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=20 Participants Rotigotine 8 mg/24 hrs
Rotigotine Plasma Concentration at the End of the Maintenance Phase/Week 12	—	0.2388 ug/ML Standard Deviation 0.2337	0.2981 ug/ML Standard Deviation 0.2973

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

The Hospital Anxiety and Depression Scale (HADS) is a self-administered instrument for detecting anxiety and depression in medical outpatients. Scores range from 0 to 21 for each subscale with higher scores reflecting a greater level of anxiety or depression.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

All scores range from 0 to 10 with higher scores corresponding to a greater level of symptom severity.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, Last assessment in the 12-week Treatment Phase

The Beck Depression Inventory-II is a 21-item questionnaire. Each item is scored on a scale of 0 to 3 with a total score ranging from 0 to 63. A higher total score is associated with more severe depressive symptoms.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12-week Treatment Phase

Impulse control disorders (ICDs) are a set of psychiatric disorders in which a person is unable to control strong and often harmful impulses. They are assessed in this study using the Jay Modified Minnesota Impulsive Disorders Interview (Jay Modified MIDI), which focuses on the five most common ICDs that may be associated with dopamine agonist use: compulsive buying, compulsive gambling, compulsive eating, hypersexuality and punding (performing repetitive and/or mechanical tasks).

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 53 other events

Deaths: 0 deaths

Rotigotine 4 mg

Serious events: 1 serious events

Other events: 55 other events

Deaths: 0 deaths

Rotigotine 8 mg

Serious events: 1 serious events

Other events: 65 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=82 participants at risk Placebo	Rotigotine 4 mg n=73 participants at risk Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=74 participants at risk Rotigotine 8 mg/24 hrs
General disorders Chest pain	0.00% 0/82 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	1.4% 1/73 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Hepatobiliary disorders Cholelithiasis	0.00% 0/82 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	1.4% 1/74 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Infections and infestations Pneumonia	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Injury, poisoning and procedural complications Ankle fracture	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Injury, poisoning and procedural complications Lung injury	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Injury, poisoning and procedural complications Rib fracture	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Intracranial hypotension	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Nerve compression	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Trigeminal neuralgia	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.2% 1/82 • Number of events 2 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.

Other adverse events

Additional Information

UCB Clinical Trial Call Center

UCB

Phone: +1 877 822 9493

Results disclosure agreements

Principal investigator is a sponsor employee UCB has \> 60 days but \<= 180 days to review results communications prior to public release and may delete information that is confidential and compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=82 participants at risk Placebo	Rotigotine 4 mg n=73 participants at risk Rotigotine 4 mg/24 hrs	Rotigotine 8 mg n=74 participants at risk Rotigotine 8 mg/24 hrs
Gastrointestinal disorders Abdominal pain upper	2.4% 2/82 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/73 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Gastrointestinal disorders Constipation	6.1% 5/82 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/73 • Number of events 5 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/74 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Gastrointestinal disorders Diarrhoea	7.3% 6/82 • Number of events 7 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/73 • Number of events 5 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	10.8% 8/74 • Number of events 8 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Gastrointestinal disorders Dry mouth	3.7% 3/82 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/73 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	9.5% 7/74 • Number of events 7 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Gastrointestinal disorders Nausea	22.0% 18/82 • Number of events 25 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	46.6% 34/73 • Number of events 46 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	64.9% 48/74 • Number of events 63 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Gastrointestinal disorders Vomiting	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	17.8% 13/73 • Number of events 15 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	24.3% 18/74 • Number of events 22 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
General disorders Application site irritation	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	8.2% 6/73 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/74 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
General disorders Application site pruritus	4.9% 4/82 • Number of events 5 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	4.1% 3/73 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	14.9% 11/74 • Number of events 11 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
General disorders Fatigue	2.4% 2/82 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	6.8% 5/73 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	1.4% 1/74 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Infections and infestations Sinusitis	7.3% 6/82 • Number of events 7 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	2.7% 2/73 • Number of events 2 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	0.00% 0/74 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Infections and infestations Upper respiratory tract infection	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	9.6% 7/73 • Number of events 7 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	2.7% 2/74 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Musculoskeletal and connective tissue disorders Muscle spasms	6.1% 5/82 • Number of events 5 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	2.7% 2/73 • Number of events 2 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Dizziness	7.3% 6/82 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	13.7% 10/73 • Number of events 10 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	10.8% 8/74 • Number of events 10 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Headache	14.6% 12/82 • Number of events 17 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	17.8% 13/73 • Number of events 18 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	16.2% 12/74 • Number of events 15 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Nervous system disorders Somnolence	7.3% 6/82 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	11.0% 8/73 • Number of events 9 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	9.5% 7/74 • Number of events 9 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Psychiatric disorders Anxiety	2.4% 2/82 • Number of events 2 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	1.4% 1/73 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Psychiatric disorders Insomnia	4.9% 4/82 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	8.2% 6/73 • Number of events 10 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	9.5% 7/74 • Number of events 9 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/82 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	4.1% 3/73 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 7 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Skin and subcutaneous tissue disorders Pruritus	1.2% 1/82 • Number of events 1 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.5% 4/73 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.
Skin and subcutaneous tissue disorders Rash	6.1% 5/82 • Number of events 6 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	4.1% 3/73 • Number of events 3 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.	5.4% 4/74 • Number of events 4 The Safety Set (SS) is comprised of all subjects who received at least 1 dose of trial medication.