A Study to Assess the Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment in Subjects With Schizophrenia on Stable Doses of Antipsychotic Medication

• Sponsor: Astellas Pharma Global Development, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03557931
• Collaborator: (none)
• Enrollment: 233
• Locations: 27
• Arms: 3
• Actual Duration (Months): 15.3
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo using change from baseline in MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score (excluding social cognition domain). The primary estimand used a Hypothetical Strategy and compared participants as though the participant had continued on the assigned treatment and to evaluate the safety and tolerability of ASP4345 compared to placebo. This study also evaluated the effects of ASP4345 compared to placebo on functional capacity using the University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) total score and evaluated the pharmacokinetic profile of ASP4345.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: ASP4345; Drug: placebo; Drug: risperidone; Drug: quetiapine; Drug: olanzapine; Drug: ziprasidone; Drug: aripiprazole; Drug: brexpiprazole; Drug: paliperidone; Drug: lurasidone	Phase 2

Detailed Description

Participants received oral doses of ASP4345 or matching placebo QD (once daily) for 12 weeks. All participants were administered the first dose of blinded study drug at the site following randomization and provided with web-based applications that provided supplemental cognitive training and recorded treatment compliance. Participants returned to the clinic weekly for safety, efficacy, and/or pharmacokinetic procedures. Participants continued the participant's antipsychotic treatment for the entire study and were followed for 14 days after the participant's last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 233 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group Study to Assess the Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment in Subjects With Schizophrenia on Stable Doses of Antipsychotic Medication
• Actual Study Start Date: Jul 13, 2018
• Actual Primary Completion Date: Oct 21, 2019
• Actual Study Completion Date: Oct 21, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ASP4345 50 milligram (mg) Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Drug: ASP4345; oral administration; Drug: risperidone; oral or depot administration; Other Names: Risperdal ; Drug: quetiapine; oral administration; Other Names: Seroquel ; Drug: olanzapine; Oral or depot administration; Other Names: Zyprexa ; Drug: ziprasidone; Oral or depot administration; Other Names: Geodon ; Drug: aripiprazole; Oral or depot administration; Other Names: Abilify ; Drug: brexpiprazole; Oral administration; Other Names: Rexulti ; Drug: paliperidone; Oral or depot administration; Other Names: Invega ; Drug: lurasidone; Oral administration; Other Names: Latuda
Experimental: ASP4345 150 mg Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.	Drug: ASP4345; oral administration; Drug: risperidone; oral or depot administration; Other Names: Risperdal ; Drug: quetiapine; oral administration; Other Names: Seroquel ; Drug: olanzapine; Oral or depot administration; Other Names: Zyprexa ; Drug: ziprasidone; Oral or depot administration; Other Names: Geodon ; Drug: aripiprazole; Oral or depot administration; Other Names: Abilify ; Drug: brexpiprazole; Oral administration; Other Names: Rexulti ; Drug: paliperidone; Oral or depot administration; Other Names: Invega ; Drug: lurasidone; Oral administration; Other Names: Latuda
Placebo Comparator: Placebo Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Drug: placebo; oral administration; Drug: risperidone; oral or depot administration; Other Names: Risperdal ; Drug: quetiapine; oral administration; Other Names: Seroquel ; Drug: olanzapine; Oral or depot administration; Other Names: Zyprexa ; Drug: ziprasidone; Oral or depot administration; Other Names: Geodon ; Drug: aripiprazole; Oral or depot administration; Other Names: Abilify ; Drug: brexpiprazole; Oral administration; Other Names: Rexulti ; Drug: paliperidone; Oral or depot administration; Other Names: Invega ; Drug: lurasidone; Oral administration; Other Names: Latuda

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12/End of Treatment (EoT) in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Neurocognitive Composite Score [Baseline and week 12/end of treatment (EoT)]

   The MCCB is a cognitive battery to assess 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, reasoning and problem solving). The MCCB neurocognitive composite score is a standardized mean of the six domain scores (excluding social cognition). Raw scores are converted to age and sex adjusted t-scores which are standardized to normative data, and have a mean of 50 and standard deviation of 10 in the general healthy population. A higher score indicates less impairment.

2. Number of Participants With Adverse Event (AE) [Baseline up to end of study (EoS) (week 14)]

   Treatment emergent adverse event (TEAE) is defined as an AE observed after starting administration of the study drug and 28 days after the last dose of study drug. A study drug-related TEAE is defined as any TEAE with at least possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, metabolic parameters etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant.

3. Number of Participants With Clinically Significant Differences in Columbia-Suicide Severity Rating Scale (C-SSRS) Values [Baseline up to EoS (week 14)]

   The C-SSRS is a questionnaire used for suicide risk assessment. Affirmative or negative responses are provided to items 1 to 5 for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods [not plan] without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and items 6 to 10 for suicide behavior (6. Preparatory acts or behavior, 7. Aborted attempt, 8. Interrupted attempt, 9. Actual attempt, 10. Completed suicide).

4. Number of Participants With Clinically Significant Differences in Abnormal Involuntary Movement Scale (AIMS) Values [Baseline, week 6 and week 12]

   AIMS is a 14-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 to 14 are yes/no questions regarding the global judgement and dental status of the participant. The total score is the sum of the scores for the 14 items and the possible total score ranges from 0 to 44. A higher total score is indicative of more severe dyskinetic movements.

5. Number of Participants With Clinically Significant Differences in Simpson Angus Scale (SAS) Values [Baseline, week 6 and week 12]

   SAS scale consists of 10 items including 7 items that address bradykinesia-rigidity and additional single items for tremor, glabellar tap, and salivation. Each item represents a specific physical condition and is rated on a 5-point category rating scale ranging from 0 (complete absence of the condition) to 4 (the condition is present to an extreme degree).The total score is obtained by adding the scores for the 10 individual items making the maximum possible score is 40. Higher scores are indicative of more severe Parkinsonian-type symptoms.

6. Number of Participants With Clinically Significant Differences in Barnes Akathisia Rating Scale (BARS) Values [Baseline, week 6 and week 12]

   BARS is used to rate observable, restless movements of drug induced akathisia and subjective awareness of restlessness and any distress associated with the akathisia. BARS consists of the following 4 items: objective assessment of akathisia symptoms, subjective assessment of the participants's awareness of inner restlessness, distress restlessness, and global clinical assessment of akathisia. First three items are rated on a 4-point scale ranging from 0 (no abnormal movements or absence of inner restlessness or no distress) to 3 (severe akathisia or awareness of intense compulsion to move most of the time or severe distress). The last item, the global clinical assessment of akathisia, is rated on a 6-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). Total BARS score ranges from 0 to 14 with a higher score representing worse results.

Secondary Outcome Measures

1. Change From Baseline to Week 12/EoT in University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) Total Score [Baseline and week 12/EoT]

   The UPSA-2-ER assesses the functional abilities of the participant with schizophrenia in 6 domains: household management, communication, financial skills, transportation, comprehension/planning and medication management. The UPSA-2-ER total score has a range from 0 to 105. A higher score indicates less impairment.

2. Concentration at Trough Level (Ctrough) for ASP4345 [Predose: day 7, day 14, day 21, day 42 and day 84/EoT]

   Ctrough concentration for ASP4345 was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria and confirmed by the Mini-International Neuropsychiatric Interview version 7.02

• Subject has a stable clinical course as suggested by the following:

• no psychiatric hospitalization within the last 4 months,

• no symptom-related changes in psychotropic medications (as defined in the concomitant medication section) within 4 weeks prior to baseline for oral medications and within 2 months for depot medications,

• and core positive symptoms no worse than moderate in severity and no evidence of a current severe major depressive episode (moderately severe depression is allowed)

• Subject has a stable living situation

• Subject's extrapyramidal symptoms are no worse than mild in severity

• Subject must be in ongoing maintenance (i.e., at least 4 weeks prior to day 1 for oral medications and within 2 months for depot medications) on up to 2 antipsychotic therapies (oral or depot) other than clozapine

• Subject has a body mass index range of 18.5 to 45.0 kg/m2

• Female subject must either:

• Be of nonchildbearing potential:

• Postmenopausal (defined as at least 1 year without menses) prior to screening or

• Documented as surgically sterile

• Or, if of childbearing potential

• Agrees not to try to become pregnant during the study and for 28 days after the final study drug administration

• And has a negative blood pregnancy test at screening and a negative urine pregnancy test at day 1,

• and if heterosexually active, agrees to consistently use 1 form of highly effective birth control starting at screening and throughout the study period and for 28 days after the final study drug administration

• Female subjects must agree not to breastfeed starting at screening and throughout the study period, and for 28 days after the final study drug administration

• Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration

• A sexually active male subject with female partner(s) who is of childbearing potential is eligible if:

• Agrees to use male condom starting at screening and throughout the study period, and for 28 days after the final study drug administration

• Male subject must not donate sperm starting at screening and throughout the study period, and for 28 days after the final study drug administration

• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 90 days after the final study drug administration

• Subject agrees not to participate in another interventional study while participating in the present study, defined as signing the informed consent form until completion of the last study visit

• Subject has a negative urine drug screen for drugs of abuse at screening and day 1, excluding cannabis and documented prescribed benzodiazepines

Exclusion Criteria:

• Subject has a known or suspected hypersensitivity to ASP4345 or any components of the formulation

• Subject has had previous exposure with ASP4345

• Subject has a history of suicide attempt or suicidal behavior within 1 year prior to screening or has any suicidal ideation that meets criteria at a level of 4 or 5 by using the Columbia Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to commit suicide

• Subject has any clinically significant liver chemistry test result (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) or a result > 1.5 times above the upper limit of normal (ULN) at screening or repeated within

1 week prior to potential randomization (day 1). In such a case, the assessment may be repeated once

• Subject has any history or evidence of any clinically significant allergic, cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, history of seizure disorder, renal and/or other major disease or malignancy

• Subject has any clinically significant abnormality of the physical examination, electrocardiogram (ECG) and clinical laboratory tests at screening or at admission to the study (day 1)

• Subject has known kidney disease and a glomerular filtration rate (GFR) < 60 mL/min per meter squared at screening and subjects will be discontinued from treatment only for decreases in the GFR that are clinically relevant

• Subject has a resting systolic blood pressure > 180 mmHg or < 90 mmHg, and a resting diastolic blood pressure > 100 mmHg at screening. These assessments may be repeated once, after a reasonable time period, at the investigator's discretion (but within the screening period)

• Subject has a mean corrected QTcF > 450 msec (for male subjects) and > 470 msec (for female subjects) at screening or at randomization. If the mean QTcF exceeds the limits above, one additional triplicate ECG can be taken on day 1

• Subject has a history in the 6 months prior to screening of consuming more than 14 units of alcoholic beverages per week for males and more than 7 units of alcoholic beverages per week for females. (Note 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits)

• Subject is currently using prohibited medications and is unable to washout, including over-the-counter products and agrees not to consume grapefruit and/or grapefruit juice

• Subject is currently using clozapine for treatment of schizophrenia

• Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies (immunoglobulin M) (anti-HAV [IgM]) or hepatitis C virus antibodies (anti- HCV) at Screening or has history of a positive test for human immunodeficiency virus type 1(HIV-1) and/or type 2 (HIV-2)

• Subject who has had electroconvulsive therapy within the 6 months prior to screening.

• Subject has a history of head injury with clinically significant sequelae, including loss of consciousness for 1 hour or greater

• Subject has received investigational study drug within 28 days or 5 half-lives, whichever is longer, prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CNS Research Science, Inc.	Cerritos	California	United States	90703
2	Collaborative Neuroscience Network, LLC	Garden Grove	California	United States	92845
3	Synergy East	Lemon Grove	California	United States	91945
4	Pacific Research Partners, LLC	Oakland	California	United States	94607
5	California Neuropsychopharmacology Clinical Research Institute-LA, LLC	Pico Rivera	California	United States	90660
6	California Neuropsychopharmacology Clinical Research Institute, LLC (CNRI-San Diego)	San Diego	California	United States	92102
7	Artemis Institute for Clinical Research	San Diego	California	United States	92103
8	Sharp Mesa Vista Hospital	San Diego	California	United States	92123
9	Collaborative Neuroscience Network, LLC	Torrance	California	United States	90502
10	Radiant Research, Inc.	Atlanta	Georgia	United States	30328
11	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
12	Alam Medical Research Inc.	Chicago	Illinois	United States	60612
13	Uptown Research Institute	Chicago	Illinois	United States	60640
14	Michigan Clinical Research Institute PC	Ann Arbor	Michigan	United States	48105
15	Cherry Street Services, Inc.	Grand Rapids	Michigan	United States	49503
16	Arch Clinical Trials, LLC	Saint Louis	Missouri	United States	63118
17	Hassman Research Institute	Berlin	New Jersey	United States	08009
18	Albuquerque Neuroscience Inc.	Albuquerque	New Mexico	United States	87109
19	SPRI Clinical Trials, LLC	Brooklyn	New York	United States	11235
20	CNS Research Science, Inc.	Jamaica	New York	United States	11432
21	New York State Psychiatric Institute	New York	New York	United States	10032
22	Manhattan Psychiatric Center's 125th Street Clinic	New York	New York	United States	10035
23	Finger Lakes Clinical Research	Rochester	New York	United States	14618
24	Midwest Clinical Research Center	Dayton	Ohio	United States	45417
25	Community Clinical Research, Inc.	Austin	Texas	United States	78754
26	InSite Clinical Research, LLC	DeSoto	Texas	United States	75115
27	Pillar Clinical Research, LLC	Richardson	Texas	United States	75080

Sponsors and Collaborators

• Astellas Pharma Global Development, Inc.

Investigators

• Study Director: Executive Medical Director, Astellas Pharma Global Development

Study Documents (Full-Text)

• Study Protocol - Aug 17, 2018
• Statistical Analysis Plan - Aug 22, 2019

More Information

Additional Information:

• Link to results on the Astellas Clinical Study Results website.

Publications

None provided.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT03557931
• Other Study ID Numbers: 4345-CL-0015
• First Posted: Jun 15, 2018
• Last Update Posted: May 10, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Astellas Pharma Global Development, Inc.: aripiprazole; ziprasidone; lurasidone; schizophrenia; ASP4345; quetiapine; olanzapine; brexpiprazole; risperidone; paliperidone
• Additional relevant MeSH terms: Schizophrenia; Cognitive Dysfunction; Olanzapine; Risperidone; Aripiprazole; Quetiapine Fumarate; Paliperidone Palmitate; Ziprasidone; Lurasidone Hydrochloride; Brexpiprazole

Study Results

Participant Flow

Pre-assignment Detail	Participants who were 18 to 55 years of age (inclusive at screening) with stable schizophrenia or schizoaffective disorder with mild extrapyramidal symptoms on up to 2 antipsychotic therapies and who met inclusion criteria and none of the exclusion criteria were enrolled.

Arm/Group Title	Placebo	ASP4345 50 Milligrams (mg)	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Period Title: Overall Study
STARTED	100	65	68
COMPLETED	69	46	55
NOT COMPLETED	31	19	13

Baseline Characteristics

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg	Total
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.	Total of all reporting groups
Overall Participants	100	65	68	233
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.8 (9.1)	42.7 (9.2)	42.8 (9.9)	42.8 (9.3)
Sex: Female, Male (Count of Participants)
Female	27 27%	23 35.4%	20 29.4%	70 30%
Male	73 73%	42 64.6%	48 70.6%	163 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 14%	3 4.6%	4 5.9%	21 9%
Not Hispanic or Latino	86 86%	62 95.4%	64 94.1%	212 91%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1%	1 1.5%	0 0%	2 0.9%
Asian	2 2%	1 1.5%	4 5.9%	7 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	72 72%	48 73.8%	47 69.1%	167 71.7%
White	24 24%	14 21.5%	17 25%	55 23.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1%	1 1.5%	0 0%	2 0.9%
MATRICS Consensus Cognitive Battery (MCCB) Neurocognitive Composite Score (T-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T-score]	32.6 (13.3)	34 (10.7)	33.7 (12.3)	33.3 (12.3)
UPSA-2-ER Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	74.4 (16.7)	80.2 (13.2)	78.1 (15.5)	77.2 (15.5)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12/End of Treatment (EoT) in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Neurocognitive Composite Score
Description	The MCCB is a cognitive battery to assess 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, reasoning and problem solving). The MCCB neurocognitive composite score is a standardized mean of the six domain scores (excluding social cognition). Raw scores are converted to age and sex adjusted t-scores which are standardized to normative data, and have a mean of 50 and standard deviation of 10 in the general healthy population. A higher score indicates less impairment.
Time Frame	Baseline and week 12/end of treatment (EoT)

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) consisted of all participants who were randomized and received at least 1 dose of study drug and had at least 1 postbaseline MCCB measurement. FAS population with available data at baseline and week12/EoT.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	67	45	51
Least Squares Mean (Standard Error) [T-score]	1.15 (0.65)	1.34 (0.79)	0.87 (0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ASP4345 50 mg
	Comments	Mixed model repeated measures (MMRM) analysis model is performed with change from baseline (least square (LS) Mean estimate for observed value from separate model using observed values) at week 12 as response; treatment, site (pooled where necessary), visit, treatment*visit, and visit*baseline as fixed effects, and baseline as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.858
	Comments
	Method	MMRM Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 90%; -1.51 to 1.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.02
	Estimation Comments
Other Statistical Analysis		Cohen's d Effect Size was defined as: (t-value for the least squares mean pairwise difference of ASP4345 50 mg vs placebo) * sqrt(1/n[PLACEBO] + 1/n[ASP4345]). The Cohen's d Effect Size value for ASP4345 50 mg vs placebo is 0.035.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, ASP4345 150 mg
	Comments	MMRM analysis model is performed with change from baseline (LS Mean estimate for observed value from separate model using observed values) at week 12 as response; treatment, site (pooled where necessary), visit, treatment*visit, and visit*baseline as fixed effects, and baseline as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 90%; -1.93 to 1.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments
Other Statistical Analysis		Cohen's d Effect Size was defined as: (t-value for the least squares mean pairwise difference of ASP4345 150 mg vs placebo) * sqrt(1/n[PLACEBO] + 1/n[ASP4345]). The Cohen's d Effect Size value for ASP4345 150 mg vs placebo is - 0.053.

2. Primary Outcome

Title	Number of Participants With Adverse Event (AE)
Description	Treatment emergent adverse event (TEAE) is defined as an AE observed after starting administration of the study drug and 28 days after the last dose of study drug. A study drug-related TEAE is defined as any TEAE with at least possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, metabolic parameters etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant.
Time Frame	Baseline up to end of study (EoS) (week 14)

Outcome Measure Data

Analysis Population Description

The safety analysis set (SAF) consisted of all participants who took at least 1 dose of study drug.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	100	65	68
TEAE	45 45%	28 43.1%	28 41.2%
Drug-Related TEAEs	11 11%	13 20%	11 16.2%
Serious TEAEs	1 1%	3 4.6%	1 1.5%
Drug-Related Serious TEAE	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Number of Participants With Clinically Significant Differences in Columbia-Suicide Severity Rating Scale (C-SSRS) Values
Description	The C-SSRS is a questionnaire used for suicide risk assessment. Affirmative or negative responses are provided to items 1 to 5 for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods [not plan] without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and items 6 to 10 for suicide behavior (6. Preparatory acts or behavior, 7. Aborted attempt, 8. Interrupted attempt, 9. Actual attempt, 10. Completed suicide).
Time Frame	Baseline up to EoS (week 14)

Outcome Measure Data

Analysis Population Description

SAF population

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	100	65	68
Number [participants]	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Number of Participants With Clinically Significant Differences in Abnormal Involuntary Movement Scale (AIMS) Values
Description	AIMS is a 14-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 to 14 are yes/no questions regarding the global judgement and dental status of the participant. The total score is the sum of the scores for the 14 items and the possible total score ranges from 0 to 44. A higher total score is indicative of more severe dyskinetic movements.
Time Frame	Baseline, week 6 and week 12

Outcome Measure Data

Analysis Population Description

SAF population with available data at each time point.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	93	62	65
Baseline	0 0%	0 0%	0 0%
Week 6	0 0%	0 0%	0 0%
Week 12	0 0%	0 0%	0 0%

5. Primary Outcome

Title	Number of Participants With Clinically Significant Differences in Simpson Angus Scale (SAS) Values
Description	SAS scale consists of 10 items including 7 items that address bradykinesia-rigidity and additional single items for tremor, glabellar tap, and salivation. Each item represents a specific physical condition and is rated on a 5-point category rating scale ranging from 0 (complete absence of the condition) to 4 (the condition is present to an extreme degree).The total score is obtained by adding the scores for the 10 individual items making the maximum possible score is 40. Higher scores are indicative of more severe Parkinsonian-type symptoms.
Time Frame	Baseline, week 6 and week 12

Outcome Measure Data

Analysis Population Description

SAF population with available data at each time point.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	93	62	65
Baseline	0 0%	0 0%	0 0%
Week 6	0 0%	0 0%	0 0%
Week 12	0 0%	0 0%	0 0%

6. Primary Outcome

Title	Number of Participants With Clinically Significant Differences in Barnes Akathisia Rating Scale (BARS) Values
Description	BARS is used to rate observable, restless movements of drug induced akathisia and subjective awareness of restlessness and any distress associated with the akathisia. BARS consists of the following 4 items: objective assessment of akathisia symptoms, subjective assessment of the participants's awareness of inner restlessness, distress restlessness, and global clinical assessment of akathisia. First three items are rated on a 4-point scale ranging from 0 (no abnormal movements or absence of inner restlessness or no distress) to 3 (severe akathisia or awareness of intense compulsion to move most of the time or severe distress). The last item, the global clinical assessment of akathisia, is rated on a 6-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). Total BARS score ranges from 0 to 14 with a higher score representing worse results.
Time Frame	Baseline, week 6 and week 12

Outcome Measure Data

Analysis Population Description

SAF population with available data at each time point.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	93	62	66
Baseline	0 0%	0 0%	0 0%
Week 6	0 0%	0 0%	0 0%
Week 12	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Change From Baseline to Week 12/EoT in University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) Total Score
Description	The UPSA-2-ER assesses the functional abilities of the participant with schizophrenia in 6 domains: household management, communication, financial skills, transportation, comprehension/planning and medication management. The UPSA-2-ER total score has a range from 0 to 105. A higher score indicates less impairment.
Time Frame	Baseline and week 12/EoT

Outcome Measure Data

Analysis Population Description

FAS population with available data at baseline and at week 12/EoT.

Arm/Group Title	Placebo	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	55	40	44
Least Squares Mean (Standard Error) [units on a scale]	3.11 (1.06)	3.86 (1.23)	2.56 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ASP4345 50 mg
	Comments	Analysis of covariance (ANCOVA) model is performed with change from baseline (LS Mean estimate for observed value from separate model using observed values) at the Week 12 timepoint as response, treatment and site (pooled where necessary) and baseline as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.639
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 90%; -1.90 to 3.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.60
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, ASP4345 150 mg
	Comments	ANCOVA model is performed with change from baseline (LS Mean estimate for observed value from separate model using observed values) at the Week 12 timepoint as response, treatment and site (pooled where necessary) and baseline as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.721
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 90%; -3.11 to 2.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.54
	Estimation Comments

8. Secondary Outcome

Title	Concentration at Trough Level (Ctrough) for ASP4345
Description	Ctrough concentration for ASP4345 was reported.
Time Frame	Predose: day 7, day 14, day 21, day 42 and day 84/EoT

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set (PKAS) consisted of all participants who took at least 1 dose of study drug and who had at least 1 plasma concentration. PKAS population with available data at each time point.

Arm/Group Title	ASP4345 50 mg	ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.	Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
Measure Participants	54	60
Day 7 Pre-dose	175.041 (159.345)	483.84 (452.65)
Day 14 Pre-dose	182.903 (165.499)	428.88 (516.14)
Day 21 Pre-dose	172.040 (128.812)	384.48 (331.71)
Day 42 Pre-dose	207.145 (167.127)	471.78 (546.00)
Day 84 Pre-dose	204.914 (154.615)	433.56 (427.12)

Adverse Events

Time Frame	Baseline up to EoS (week 14)
Arm/Group Title	Placebo		ASP4345 50 mg		ASP4345 150 mg
Arm/Group Description	Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.		Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.		Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.
All Cause Mortality
	Placebo		ASP4345 50 mg		ASP4345 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		0/65 (0%)		0/68 (0%)
Serious Adverse Events
	Placebo		ASP4345 50 mg		ASP4345 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/100 (1%)		3/65 (4.6%)		1/68 (1.5%)
Injury, poisoning and procedural complications
Head injury	0/100 (0%)	0	1/65 (1.5%)	1	0/68 (0%)	0
Psychiatric disorders
Psychotic disorder	0/100 (0%)	0	1/65 (1.5%)	1	1/68 (1.5%)	1
Suicidal ideation	1/100 (1%)	2	0/65 (0%)	0	0/68 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/100 (0%)	0	1/65 (1.5%)	1	0/68 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		ASP4345 50 mg		ASP4345 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/100 (3%)		5/65 (7.7%)		7/68 (10.3%)
Nervous system disorders
Dizziness	0/100 (0%)	0	1/65 (1.5%)	1	4/68 (5.9%)	4
Headache	3/100 (3%)	3	4/65 (6.2%)	4	3/68 (4.4%)	3

Limitations/Caveats

ASP4345 metabolites were optional and deemed not necessary.

More Information

Certain Agreements

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

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.