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

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

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.

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.

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