Trial Outcomes & Findings for 3-week Study to Evaluate Efficacy and Safety of Ziprasidone With Either Lithium or Divalproex in Acutely Manic Subjects (NCT NCT00312494)

Last Updated: 2021-03-29

Results Overview

YMRS is an 11-item scale (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech \[rate and amount\], language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight) used to assess the severity of manic symptoms and effect of treatment on mania severity. Seven items ranked on scale from 0 to 4; 4 items ranked 0 to 8. Total possible score 0 to 60: higher scores indicate greater severity. Change calculated as mean of (value of YMRS score at observation minus baseline value).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

680 participants

Primary outcome timeframe

Baseline, Week 3

Results posted on

2021-03-29

Participant Flow

Participant milestones

Participant milestones
Measure	Ziprasidone (Higher Dose) Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Overall Study STARTED	232	226	222
Overall Study Received Study Treatment	223	216	217
Overall Study COMPLETED	161	168	179
Overall Study NOT COMPLETED	71	58	43

Reasons for withdrawal

Reasons for withdrawal
Measure	Ziprasidone (Higher Dose) Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Overall Study Randomized; not treated with study drug	9	10	5
Overall Study Adverse Event	33	15	11
Overall Study Lack of Efficacy	4	6	8
Overall Study Laboratory abnormality	1	0	0
Overall Study Lost to Follow-up	8	8	8
Overall Study Withdrawal by Subject	6	9	10
Overall Study Other	10	10	1

Baseline Characteristics

3-week Study to Evaluate Efficacy and Safety of Ziprasidone With Either Lithium or Divalproex in Acutely Manic Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ziprasidone (Higher Dose) n=223 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=216 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=217 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer	Total n=656 Participants Total of all reporting groups
Age, Customized <18 years	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants
Age, Customized Between 18 and 44 years	125 participants n=5 Participants	124 participants n=7 Participants	126 participants n=5 Participants	375 participants n=4 Participants
Age, Customized Between 45 and 64 years	96 participants n=5 Participants	92 participants n=7 Participants	90 participants n=5 Participants	278 participants n=4 Participants
Age, Customized >=65 years	2 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	3 participants n=4 Participants
Sex: Female, Male Female	100 Participants n=5 Participants	108 Participants n=7 Participants	110 Participants n=5 Participants	318 Participants n=4 Participants
Sex: Female, Male Male	123 Participants n=5 Participants	108 Participants n=7 Participants	107 Participants n=5 Participants	338 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Week 3

Population: Intent to Treat population (ITT): all randomized subjects who received at least 1 dose of double-blind medication, who had 1 baseline and at least 1 post-baseline primary efficacy evaluation; excluding data from 2 sites that were closed due to Good Clinical Practices (GCP) deviations.

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline to Week 3 in Young Mania Rating Scale (YMRS)	-10.19 scores on scale Standard Error 0.78	-10.95 scores on scale Standard Error 0.80	-9.47 scores on scale Standard Error 0.83

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2

Population: ITT population excluding data from 2 sites that were closed to GCP deviations; (n)=number of subjects for ziprasidone (higher dose), ziprasidone (lower dose), and placebo, respectively.

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline to Week 1 and Week 2 in YMRS Week 1 (n=202, 205, 200)	-4.38 scores on scale Standard Error 0.65	-4.56 scores on scale Standard Error 0.65	-5.10 scores on scale Standard Error 0.70
Change From Baseline to Week 1 and Week 2 in YMRS Week 2 (n=178, 188, 186)	-7.10 scores on scale Standard Error 0.72	-7.56 scores on scale Standard Error 0.73	-8.24 scores on scale Standard Error 0.76

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3

Population: ITT population excluding data from 2 sites that were closed due to GCP deviations; (n)=number of subjects for ziprasidone (higher dose), ziprasidone (lower dose), and placebo, respectively.

MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal) with anchors at 2-point intervals; total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as mean of (value of MADRS score at observation minus baseline value).

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Scores Week 1 (n=202, 205, 200)	-2.16 scores on scale Standard Error 0.52	-2.47 scores on scale Standard Error 0.49	-1.11 scores on scale Standard Error 0.63
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Scores Week 2 (n=178, 188, 186)	-3.27 scores on scale Standard Error 0.57	-3.24 scores on scale Standard Error 0.55	-1.71 scores on scale Standard Error 0.66
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Scores Week 3 (n=163, 172, 170)	-4.20 scores on scale Standard Error 0.63	-3.79 scores on scale Standard Error 0.64	-2.90 scores on scale Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3

CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Rating ranges from 1 (normal, not at all ill) to 7 (among the most severely ill subjects); higher score = more affected. Change calculated as mean of (value of CGI-S score at observation minus baseline value).

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline in Clinical Global Impression Scale - Severity (CGI-S) Score Week 1 (n=202, 206, 200)	-0.35 scores on scale Standard Error 0.06	-0.43 scores on scale Standard Error 0.06	-0.39 scores on scale Standard Error 0.07
Change From Baseline in Clinical Global Impression Scale - Severity (CGI-S) Score Week 2 (n=178, 188, 186)	-0.70 scores on scale Standard Error 0.08	-0.74 scores on scale Standard Error 0.07	-0.73 scores on scale Standard Error 0.09
Change From Baseline in Clinical Global Impression Scale - Severity (CGI-S) Score Week 3 (n=163, 172, 171)	-0.94 scores on scale Standard Error 0.08	-1.13 scores on scale Standard Error 0.09	-1.00 scores on scale Standard Error 0.09

SECONDARY outcome

Timeframe: Week 1, Week 2, Week 3

CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse); higher score = more affected.

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Clinical Global Impression - Improvement (CGI-I) Scale Scores Week 1 (n=202, 206, 200)	3.34 scores on scale Standard Error 0.09	3.34 scores on scale Standard Error 0.09	3.38 scores on scale Standard Error 0.08
Clinical Global Impression - Improvement (CGI-I) Scale Scores Week 2 (n=178, 188, 186)	3.02 scores on scale Standard Error 0.10	2.91 scores on scale Standard Error 0.09	2.98 scores on scale Standard Error 0.10
Clinical Global Impression - Improvement (CGI-I) Scale Scores Week 3 (n=163, 172, 171)	2.65 scores on scale Standard Error 0.11	2.57 scores on scale Standard Error 0.11	2.72 scores on scale Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline, Week 3

PANSS is a 30-item scale to measure severity of psychopathology (16 items); positive scale (7 items); negative scale (7 items); summarized as positive score, negative score, and total score. Scores rated 1 (absent symptoms) to 7 (extreme); total score range 30 to 210: higher score indicates greater severity. Change calculated as mean of (value of PANSS score at observation minus baseline value).

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score Week 3 total score (n=198, 199, 189)	-4.87 scores on scale Standard Error 1.86	-5.34 scores on scale Standard Error 1.68	-3.44 scores on scale Standard Error 1.84
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score Week 3 positive score (n=198, 199, 189)	-1.94 scores on scale Standard Error 0.52	-2.26 scores on scale Standard Error 0.52	-1.56 scores on scale Standard Error 0.56
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Score Week 3 negative score (n=198, 199, 189)	-0.58 scores on scale Standard Error 0.51	-0.43 scores on scale Standard Error 0.51	-0.20 scores on scale Standard Error 0.52

SECONDARY outcome

Timeframe: Baseline, Week 3

Population: ITT population excluding data from 2 sites that were closed due to GCP deviations.

GAF measures the severity of illness-related impairment in psychological, social, and occupational functioning; rated on a 100-point scale (single score of 1 to 100) with 100 indicating superior functioning. Change calculated as mean of (value of GAF score at observation minus baseline value).

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline in Global Assessment of Functioning (GAF) Score	8.79 scores on scale Standard Error 1.23	9.62 scores on scale Standard Error 1.25	7.79 scores on scale Standard Error 1.22

SECONDARY outcome

Timeframe: Baseline, Week 3

Population: ITT population excluding data from 2 sites that were closed due to GCP deviations.

LIFE-RIFT measures severity of illness-related impairment in 4 domains: work, interpersonal relations, recreation, and global satisfaction; has a total score and individual domain scores. Domain scores range from 1 to 5 (scores ≥ 2 reflect impaired functioning). Total score is sum of the 4 domains with range of 4 (very good) to 20 (very poor): higher scores indicate greater impairment. Change calculated as mean of (value of LIFE-RIFT score at observation minus baseline value).

Outcome measures

Outcome measures
Measure	Ziprasidone (Higher Dose) n=211 Participants Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=210 Participants Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=201 Participants Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Change From Baseline in Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning (LIFE-RIFT) Score	-1.68 scores on scale Standard Error 0.45	-1.58 scores on scale Standard Error 0.50	-1.27 scores on scale Standard Error 0.46

SECONDARY outcome

Timeframe: Baseline

Population: All subjects eligible (optional consent); samples were not to be analyzed as part of the current protocol and the analysis was not to be covered by the statistical analysis plan.

Anonymized pharmacogenomic blood draw to evaluate the pharmacogenomic basis for ziprasidone treatment responsivity.

Outcome measures

Outcome data not reported

Adverse Events

Ziprasidone (Higher Dose)

Serious events: 5 serious events

Other events: 134 other events

Deaths: 0 deaths

Ziprasidone (Lower Dose)

Serious events: 4 serious events

Other events: 99 other events

Deaths: 0 deaths

Placebo

Serious events: 4 serious events

Other events: 82 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Ziprasidone (Higher Dose) n=223 participants at risk Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=216 participants at risk Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=217 participants at risk Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
General disorders Chest pain	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Infections and infestations Cellulitis	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Injury, poisoning and procedural complications Intentional overdose	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Injury, poisoning and procedural complications Overdose	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Injury, poisoning and procedural complications Thermal burn	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Investigations Blood pressure increased	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Anterograde amnesia	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Acute psychosis	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Agitation	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Alcohol abuse	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Bipolar I disorder	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Drug abuse	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Emotional disorder	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Suicide attempt	0.00% 0/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of \< 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), \< 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Ziprasidone (Higher Dose) n=223 participants at risk Ziprasidone 120 to 160 mg daily + Mood Stabilizer	Ziprasidone (Lower Dose) n=216 participants at risk Ziprasidone 40 to 80 mg daily + Mood Stabilizer	Placebo n=217 participants at risk Placebo (matching ziprasidone higher dose or ziprasidone lower dose) + Mood Stabilizer
Gastrointestinal disorders Abdominal discomfort	2.7% 6/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.93% 2/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.92% 2/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Gastrointestinal disorders Diarrhoea	5.4% 12/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	4.6% 10/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	3.2% 7/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Gastrointestinal disorders Dry mouth	2.7% 6/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.4% 3/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Gastrointestinal disorders Nausea	4.9% 11/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	5.1% 11/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	6.0% 13/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Gastrointestinal disorders Salivary hypersecretion	2.2% 5/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.9% 4/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Gastrointestinal disorders Vomiting	5.8% 13/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.8% 6/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.8% 4/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
General disorders Fatigue	4.9% 11/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.4% 3/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Infections and infestations Nasopharyngitis	3.1% 7/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.8% 4/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Infections and infestations Upper respiratory tract infection	2.2% 5/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	3.2% 7/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Metabolism and nutrition disorders Increased appetite	0.45% 1/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Musculoskeletal and connective tissue disorders Arthralgia	1.3% 3/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	1.8% 4/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.8% 6/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Musculoskeletal and connective tissue disorders Pain in extremity	2.2% 5/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	3.2% 7/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.92% 2/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Akathisia	6.7% 15/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	3.7% 8/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Dizziness	7.2% 16/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.8% 6/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Extrapyramidal disorder	4.9% 11/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.9% 4/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Headache	4.5% 10/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	8.8% 19/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	7.4% 16/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Sedation	14.8% 33/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	7.9% 17/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	8.3% 18/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Somnolence	11.7% 26/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	8.8% 19/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Tremor	5.4% 12/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.8% 6/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	3.2% 7/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Agitation	2.7% 6/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.9% 4/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Anxiety	2.2% 5/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.93% 2/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.92% 2/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Psychiatric disorders Insomnia	3.6% 8/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.4% 3/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	2.3% 5/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Nervous system disorders Restlessness	2.7% 6/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	1.4% 3/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.00% 0/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.2% 5/223 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.46% 1/216 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.	0.92% 2/217 Safety population: all randomized subjects who were administered at least 1 dose of double-blind medication; includes data from the 2 sites that were closed due to GCP deviations.