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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: ASP4345
* Drug: placebo
* Drug: risperidone
* Drug: quetiapine
* Drug: olanzapine
* Drug: ziprasidone
* Drug: aripiprazole
* Drug: brexpiprazole
* Drug: paliperidone
* Drug: lurasidone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline and week 12/end of treatment (EoT) | 
| Number of Participants With Adverse Event (AE) | 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. | Baseline up to end of study (EoS) (week 14) | 
| Number of Participants With Clinically Significant Differences in Columbia-Suicide Severity Rating Scale (C-SSRS) Values | 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). | Baseline up to EoS (week 14) | 
| Number of Participants With Clinically Significant Differences in Abnormal Involuntary Movement Scale (AIMS) Values | 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. | Baseline, week 6 and week 12 | 
| Number of Participants With Clinically Significant Differences in Simpson Angus Scale (SAS) Values | 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. | Baseline, week 6 and week 12 | 
| Number of Participants With Clinically Significant Differences in Barnes Akathisia Rating Scale (BARS) Values | 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. | Baseline, week 6 and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline and week 12/EoT | 
| Concentration at Trough Level (Ctrough) for ASP4345 | Ctrough concentration for ASP4345 was reported. | Predose: day 7, day 14, day 21, day 42 and day 84/EoT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aripiprazole, ziprasidone, lurasidone, schizophrenia, ASP4345, quetiapine, olanzapine, brexpiprazole, risperidone, paliperidone