Trial Outcomes & Findings for A Study of the Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis (NCT NCT00477672)

Last Updated: 2017-05-17

Results Overview

Antipsychotic Efficacy was defined as a decrease in the severity and/or frequency of hallucinations and/or delusions. This is measured as the change from baseline (Day 1) to Day 42 in the Scale for the Assessment of Positive Symptoms - Hallucinations and Delusions scales (SAPS-H+D) score for the ITT Analysis Set. The possible total score is 0 to 100 and a negative change in score indicates improvement. Analysis Method: Analysis of Covariance (ANCOVA) and missing data was imputed using Last Observation Carried Forward (LOCF) method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

298 participants

Primary outcome timeframe

Each study visit (i.e. Days 1, 8, 15, 29 and 42)

Results posted on

2017-05-17

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Overall Study STARTED	98	101	99
Overall Study COMPLETED	91	85	83
Overall Study NOT COMPLETED	7	16	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Overall Study Adverse Event	3	5	6
Overall Study Death	0	1	0
Overall Study Disease progression	0	1	0
Overall Study Physician Decision	1	0	0
Overall Study Protocol noncompliance	0	2	0
Overall Study Consent withdrawn	2	5	10
Overall Study Discretion of Sponsor	1	2	0

Baseline Characteristics

A Study of the Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=98 Participants Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg n=99 Participants Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg n=98 Participants Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks	Total n=295 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Age, Categorical Between 18 and 65 years	27 Participants n=99 Participants	30 Participants n=107 Participants	23 Participants n=206 Participants	80 Participants n=7 Participants
Age, Categorical >=65 years	71 Participants n=99 Participants	69 Participants n=107 Participants	75 Participants n=206 Participants	215 Participants n=7 Participants
Age, Continuous	69.6 years STANDARD_DEVIATION 9.67 • n=99 Participants	69.0 years STANDARD_DEVIATION 8.61 • n=107 Participants	69.4 years STANDARD_DEVIATION 7.84 • n=206 Participants	69.3 years STANDARD_DEVIATION 8.71 • n=7 Participants
Sex: Female, Male Female	47 Participants n=99 Participants	36 Participants n=107 Participants	24 Participants n=206 Participants	107 Participants n=7 Participants
Sex: Female, Male Male	51 Participants n=99 Participants	63 Participants n=107 Participants	74 Participants n=206 Participants	188 Participants n=7 Participants
Region of Enrollment United States	44 participants n=99 Participants	45 participants n=107 Participants	45 participants n=206 Participants	134 participants n=7 Participants
Region of Enrollment India	10 participants n=99 Participants	10 participants n=107 Participants	10 participants n=206 Participants	30 participants n=7 Participants
Region of Enrollment Europe	44 participants n=99 Participants	44 participants n=107 Participants	43 participants n=206 Participants	131 participants n=7 Participants

PRIMARY outcome

Timeframe: Each study visit (i.e. Days 1, 8, 15, 29 and 42)

Population: This is the "Intent to Treat" population, defined as patients who received at least one dose of study drug, and had both the baseline SAPS assessment and at least one post-baseline SAPS assessment.

Outcome measures

Outcome measures
Measure	Placebo n=95 Participants Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg n=96 Participants Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg n=91 Participants Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Antipsychotic Efficacy Change from Baseline	-5.9 Score on the SAPS H+D scale 95% Confidence Interval 7.90 • Interval -7.3 to -4.5	-5.8 Score on the SAPS H+D scale 95% Confidence Interval 9.77 • Interval -7.2 to -4.3	-6.7 Score on the SAPS H+D scale 95% Confidence Interval 7.87 • Interval -8.1 to -5.2
Antipsychotic Efficacy Difference of Least Squares Mean versus Placebo	NA Score on the SAPS H+D scale Calculation is a comparison of active arm versus placebo.	0.1 Score on the SAPS H+D scale Interval -1.7 to 2.0	-0.8 Score on the SAPS H+D scale Interval -2.7 to 1.1

SECONDARY outcome

Timeframe: Each study visit (i.e. Days 1, 8, 15, 29 and 42)

Population: This is the "Per Protocol" population, which includes subjects in the ITT analysis set, who were free of important protocol deviations, as defined before database lock and unblinding. Subjects were analyzed according to the treatment actually received.

Motor symptoms were measured using the change from baseline (Day 1) to Day 42 in the combined score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living) and Part III (Motor Examination) using the per-protocol (PP) analysis set. The possible total score is 0 to 160 and a negative change in score indicates improvement. Analysis Method: ANCOVA, and missing data was imputed using LOCF. The UPDRS Parts II+III score was analyzed by constructing 2-sided 95% confidence intervals (CIs) on the difference between each pimavanserin dose group and placebo mean change from baseline. Non-inferiority was concluded if the upper limit of the CI was less than or equal to 5.

Outcome measures

Outcome measures
Measure	Placebo n=90 Participants Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg n=88 Participants Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg n=85 Participants Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Motor Symptoms Change From Baseline (Negative = Improvement) Change from Baseline	-2.94 Score on UPDRS-II+III Interval -5.08 to -0.8	-1.41 Score on UPDRS-II+III Interval -3.58 to 0.76	-3.13 Score on UPDRS-II+III Interval -5.34 to -0.91
Motor Symptoms Change From Baseline (Negative = Improvement) Difference of Least Square Mean versus Placebo	NA Score on UPDRS-II+III Calculation is a comparison of active arm versus placebo.	1.53 Score on UPDRS-II+III Interval -1.24 to 4.31	-0.19 Score on UPDRS-II+III Interval -2.99 to 2.62

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 34 other events

Deaths: 0 deaths

Pimavanserin 10 mg

Serious events: 5 serious events

Other events: 29 other events

Deaths: 0 deaths

Pimavanserin 40 mg

Serious events: 5 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=98 participants at risk Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg n=99 participants at risk Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg n=98 participants at risk Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Gastrointestinal disorders Nausea	4.1% 4/98 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.0% 4/99 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	8.2% 8/98 • Number of events 10 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Gastrointestinal disorders Constipation	3.1% 3/98 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.0% 4/99 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	5.1% 5/98 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
General disorders Edema	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	2.0% 2/99 • Number of events 3 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	7.1% 7/98 • Number of events 7 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Injury, poisoning and procedural complications Fall	11.2% 11/98 • Number of events 12 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	5.1% 5/99 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.1% 4/98 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Nervous system disorders Dizziness	4.1% 4/98 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	7.1% 7/99 • Number of events 7 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	7.1% 7/98 • Number of events 7 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Nervous system disorders Headache	6.1% 6/98 • Number of events 6 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.0% 4/99 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.1% 4/98 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Psychiatric disorders Confusional state	3.1% 3/98 • Number of events 3 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	5.1% 5/99 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	5.1% 5/98 • Number of events 5 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Vascular disorders Orthostatic hypotension	9.2% 9/98 • Number of events 10 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	4.0% 4/99 • Number of events 4 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	2.0% 2/98 • Number of events 2 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.

Additional Information

Roger Mills, MD

ACADIA Pharmaceuticals Inc.

Phone: 858-202-7563

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator may publish the study results, relative to his/her own patients, only after review, comment and approval by the sponsor. No publication of confidential information shall be made without the sponsor's prior written consent. At least 60 days prior to submitting a manuscript or prior to any public presentation, a copy of the manuscript or presentation will be provided to the sponsor for review and comment. The sponsor has 60 days to review and comment.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=98 participants at risk Placebo tablet, once daily by mouth, 6 weeks	Pimavanserin 10 mg n=99 participants at risk Pimavanserin tartrate (ACP-103) 10 mg, tablet, once daily by mouth, 6 weeks	Pimavanserin 40 mg n=98 participants at risk Pimavanserin tartrate (ACP-103) 40 mg, tablet, once daily by mouth, 6 weeks
Blood and lymphatic system disorders Anemia	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Cardiac disorders Myocardial infarction	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Gastrointestinal disorders Gastrointestinal hemorrhage	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Infections and infestations Bronchitis	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Infections and infestations Cellulitis	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Infections and infestations Sepsis	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Nervous system disorders Encephalopathy	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Nervous system disorders Headache	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Nervous system disorders Syncope	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Psychiatric disorders Confusional state	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Psychiatric disorders Dementia	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Psychiatric disorders Hallucination	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Psychiatric disorders Mental status changes	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/99 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/98 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.
Surgical and medical procedures Inguinal hernia repair	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	1.0% 1/99 • Number of events 1 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.	0.00% 0/98 • 6 weeks From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 8, 15, 29, 42 and Day 70 or 4 weeks after the last dose for subjects who do not continue into the open-label, extension protocol.