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

NCT03557931 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 4345-CL-0015
• Study Type: interventional
• Target: 233
• Locations: 1 country
• Sites: 27

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.

Conditions

Schizophrenia

Keywords

aripiprazole; ziprasidone; lurasidone; schizophrenia; ASP4345; quetiapine; olanzapine; brexpiprazole; risperidone; paliperidone

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (2)

• 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

• Concentration at Trough Level (Ctrough) for ASP4345

  Predose: day 7, day 14, day 21, day 42 and day 84/EoT

Study Arms (3)

ASP4345 50 milligram (mg)

EXPERIMENTAL

Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks.

Drug: ASP4345; Drug: risperidone; Drug: quetiapine; Drug: olanzapine; Drug: ziprasidone; Drug: aripiprazole; Drug: brexpiprazole; Drug: paliperidone; Drug: lurasidone

ASP4345 150 mg

EXPERIMENTAL

Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks.

Drug: ASP4345; Drug: risperidone; Drug: quetiapine; Drug: olanzapine; Drug: ziprasidone; Drug: aripiprazole; Drug: brexpiprazole; Drug: paliperidone; Drug: lurasidone

Placebo

PLACEBO COMPARATOR

Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.

Drug: placebo; Drug: risperidone; Drug: quetiapine; Drug: olanzapine; Drug: ziprasidone; Drug: aripiprazole; Drug: brexpiprazole; Drug: paliperidone; Drug: lurasidone

Interventions

ASP4345 DRUG

oral administration

ASP4345 150 mg; ASP4345 50 milligram (mg)

placebo DRUG

oral administration

Placebo

risperidone DRUG

oral or depot administration

Also known as: Risperdal

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

quetiapine DRUG

oral administration

Also known as: Seroquel

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

olanzapine DRUG

Oral or depot administration

Also known as: Zyprexa

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

ziprasidone DRUG

Oral or depot administration

Also known as: Geodon

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

aripiprazole DRUG

Oral or depot administration

Also known as: Abilify

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

brexpiprazole DRUG

Oral administration

Also known as: Rexulti

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

paliperidone DRUG

Oral or depot administration

Also known as: Invega

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

lurasidone DRUG

Oral administration

Also known as: Latuda

ASP4345 150 mg; ASP4345 50 milligram (mg); Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (27)

CNS Research Science, Inc.

Cerritos, California, 90703, United States

Location

Collaborative Neuroscience Network, LLC

Garden Grove, California, 92845, United States

Location

Synergy East

Lemon Grove, California, 91945, United States

Location

Pacific Research Partners, LLC

Oakland, California, 94607, United States

Location

California Neuropsychopharmacology Clinical Research Institute-LA, LLC

Pico Rivera, California, 90660, United States

Location

California Neuropsychopharmacology Clinical Research Institute, LLC (CNRI-San Diego)

San Diego, California, 92102, United States

Location

Artemis Institute for Clinical Research

San Diego, California, 92103, United States

Location

Sharp Mesa Vista Hospital

San Diego, California, 92123, United States

Location

Collaborative Neuroscience Network, LLC

Torrance, California, 90502, United States

Location

Radiant Research, Inc.

Atlanta, Georgia, 30328, United States

Location

Atlanta Center for Medical Research

Atlanta, Georgia, 30331, United States

Location

Alam Medical Research Inc.

Chicago, Illinois, 60612, United States

Location

Uptown Research Institute

Chicago, Illinois, 60640, United States

Location

Michigan Clinical Research Institute PC

Ann Arbor, Michigan, 48105, United States

Location

Cherry Street Services, Inc.

Grand Rapids, Michigan, 49503, United States

Location

Arch Clinical Trials, LLC

St Louis, Missouri, 63118, United States

Location

Hassman Research Institute

Berlin, New Jersey, 08009, United States

Location

Albuquerque Neuroscience Inc.

Albuquerque, New Mexico, 87109, United States

Location

SPRI Clinical Trials, LLC

Brooklyn, New York, 11235, United States

Location

CNS Research Science, Inc.

Jamaica, New York, 11432, United States

Location

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Manhattan Psychiatric Center's 125th Street Clinic

New York, New York, 10035, United States

Location

Finger Lakes Clinical Research

Rochester, New York, 14618, United States

Location

Midwest Clinical Research Center

Dayton, Ohio, 45417, United States

Location

Community Clinical Research, Inc.

Austin, Texas, 78754, United States

Location

InSite Clinical Research, LLC

DeSoto, Texas, 75115, United States

Location

Pillar Clinical Research, LLC

Richardson, Texas, 75080, United States

Location

Related Publications (1)

• Desai A, Benner L, Wu R, Gertsik L, Uz T, Marek GJ, Zhu T. Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies. Clin Pharmacokinet. 2021 Jan;60(1):79-88. doi: 10.1007/s40262-020-00911-0.

  PMID: 32533536 DERIVED

Related Links

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

MeSH Terms

Conditions

Schizophrenia

Interventions

Risperidone; Quetiapine Fumarate; Olanzapine; ziprasidone; Aripiprazole; brexpiprazole; Paliperidone Palmitate; Lurasidone Hydrochloride

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Piperazines; Quinolones; Quinolines; Isoxazoles; Azoles; Thiazoles; Isoindoles

Limitations and Caveats

ASP4345 metabolites were optional and deemed not necessary.

Results Point of Contact

• Title: Clinical Trial Disclosure
• Organization: Astellas Pharma Global Development, Inc.

astellas.resultsdisclosure@astellas.com

800-888-7704

Study Officials

• Executive Medical Director

  Astellas Pharma Global Development

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2018
• First Posted: June 15, 2018
• Study Start: July 13, 2018
• Primary Completion: October 21, 2019
• Study Completion: October 21, 2019
• Last Updated: November 12, 2024
• Results First Posted: October 27, 2020

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (27)