Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03557931
Recruitment Status : Completed
First Posted : June 15, 2018
Last Update Posted : December 11, 2019
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:
The purpose of this study is 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 will use a Hypothetical Strategy and compare 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 will also evaluate 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 evaluate the pharmacokinetic profile of ASP4345 and its metabolites, if necessary.

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

Layout table for study information
Study Type : Interventional  (Clinical Trial)
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 : July 13, 2018
Actual Primary Completion Date : October 16, 2019
Actual Study Completion Date : October 16, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: ASP4345 low dose
daily dose of ASP4345 in patients with cognitive impairment associated with schizophrenia on stable doses of antipsychotic medication
Drug: ASP4345
oral administration

Drug: risperidone
oral or depot administration
Other Name: Risperdal

Drug: quetiapine
oral administration
Other Name: Seroquel

Drug: olanzapine
Oral or depot administration
Other Name: Zyprexa

Drug: ziprasidone
Oral or depot administration
Other Name: Geodon

Drug: aripiprazole
Oral or depot administration
Other Name: Abilify

Drug: brexpiprazole
Oral administration
Other Name: Rexulti

Drug: paliperidone
Oral or depot administration
Other Name: Invega

Drug: lurasidone
Oral administration
Other Name: Latuda

Experimental: ASP4345 high dose
daily dose of ASP4345 in patients with cognitive impairment associated with schizophrenia on stable doses of antipsychotic medication
Drug: ASP4345
oral administration

Drug: risperidone
oral or depot administration
Other Name: Risperdal

Drug: quetiapine
oral administration
Other Name: Seroquel

Drug: olanzapine
Oral or depot administration
Other Name: Zyprexa

Drug: ziprasidone
Oral or depot administration
Other Name: Geodon

Drug: aripiprazole
Oral or depot administration
Other Name: Abilify

Drug: brexpiprazole
Oral administration
Other Name: Rexulti

Drug: paliperidone
Oral or depot administration
Other Name: Invega

Drug: lurasidone
Oral administration
Other Name: Latuda

Placebo Comparator: Placebo
daily dose in patients with cognitive impairment associated with schizophrenia on stable doses of antipsychotic medication
Drug: placebo
oral administration

Drug: risperidone
oral or depot administration
Other Name: Risperdal

Drug: quetiapine
oral administration
Other Name: Seroquel

Drug: olanzapine
Oral or depot administration
Other Name: Zyprexa

Drug: ziprasidone
Oral or depot administration
Other Name: Geodon

Drug: aripiprazole
Oral or depot administration
Other Name: Abilify

Drug: brexpiprazole
Oral administration
Other Name: Rexulti

Drug: paliperidone
Oral or depot administration
Other Name: Invega

Drug: lurasidone
Oral administration
Other Name: Latuda




Primary Outcome Measures :
  1. Change from baseline to week 12/end of treatment (EoT) for ASP4345 compared to placebo for the MATRICS Consensus Cognitive Battery neurocognitive composite score (excluding social cognition domain) [ Time Frame: baseline to week 12 ]
    The MATRICS Consensus Cognitive Battery (MCCB) is a cognitive battery to assess 7 domains recommended by the MATRICS initiative (ie, 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. Safety and tolerability assessed as nature, frequency and severity of adverse events [ Time Frame: up to 14 weeks ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  3. Number of participants with vital sign abnormalities and/or AEs [ Time Frame: up to 12 weeks ]
    Number of participants with potentially clinically significant vital sign values

  4. Number of participants with laboratory abnormalities and/or AEs [ Time Frame: up to 12 weeks ]
    Number of participants with potentially clinically significant laboratory values

  5. Safety assessed by 12-lead electrocardiogram (ECG) [ Time Frame: up to 12 weeks ]
    ECGs will be recorded with the subject in the supine position, after the subject has been lying down for approximately 5 minutes. There should be at least 5 minutes between ECG measurements in case a repeat is needed. Any clinically significant adverse changes on the ECG will be reported as AEs.

  6. Safety and tolerability assessed by C-SSRS [ Time Frame: up to 14 weeks ]
    The Columbia-Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation rating scale which identifies ideation behaviors that may be indicative of an individual's intent to commit suicide. The maximum suicidal ideation category (1-5 on C-SSRS) present at the assessment.

  7. Safety assessed by metabolic parameter: weight [ Time Frame: up to 12 weeks ]
    Weight will be summarized by ASP4345 treatment group and pooled placebo

  8. Safety assessed by metabolic parameter: waist circumference [ Time Frame: up to 12 weeks ]
    Waist circumference will be summarized by ASP4345 treatment group and pooled placebo

  9. Safety assessed by metabolic parameter: cholesterol [ Time Frame: up to 14 weeks ]
    Cholesterol will be summarized by ASP4345 treatment group and pooled placebo

  10. Safety assessed by metabolic parameter: triglycerides [ Time Frame: up to 14 weeks ]
    Triglycerides will be summarized by ASP4345 treatment group and pooled placebo

  11. Safety assessed by metabolic parameter: high density lipoprotein (HDL) [ Time Frame: up to 11 weeks ]
    High Density Lipoprotein (HDL) will be summarized by ASP4345 treatment group and pooled placebo

  12. Safety assessed by metabolic parameter: fasting glucose [ Time Frame: up to 12 weeks ]
    Fasting glucose will be summarized by ASP4345 treatment group and pooled placebo

  13. Safety assessed by metabolic parameter: hemoglobin A1C (HbA1C) [ Time Frame: up to 14 weeks ]
    Hemoglobin A1C will be summarized by ASP4345 treatment group and pooled placebo

  14. Safety and tolerability assessed for movement disorder using AIMS [ Time Frame: up to 12 weeks ]

    AIMS: Abnormal Involuntary Movement Scale. The AIMS aids in the early detection of tardive dyskinesia as well as providing a method for on going surveillance. The AIMS is a checklist and uses a 5 point rating scale for recording scores for 7 body areas: face, lips, jaw, tongue, upper extremities, lower extremities and trunk.

    Scores of 2 or higher indicate a diagnosis of tardive dyskinesia. Shifts from baseline at each treatment visit will be shown as follows: [<2 to <2 (no change, not present); <2 to ≥2 (worsening); ≥2 to < 2 (improvement); ≥2 to ≥2 (no change, present).


  15. Safety and tolerability assessed for movement disorder using SAS [ Time Frame: up to 12 weeks ]

    SAS: Simpson Angus Scale. The SAS is a 10 item scale used to rate adverse neurological effects of antipsychotic medications more broadly. It involves direct observation and a brief neurological examination. Rating requires the investigator to observe the participant's gait and check for tremor, excessive salivation and rigidity in the arms, shoulder and neck. Each item is rated from 0 to 4 and a total score can be obtained.

    Scores will be categorized as [<3 (normal); 3-5 (minimal); 6-11 (clinically significant); 12-17 (severe); ≥18 (extreme)


  16. Safety and tolerability assessed for movement disorder using BARS [ Time Frame: up to 12 weeks ]

    BARS: Barnes Akathisia Rating Scale. The BARS is a rating scale that is used to assess the severity of drug induced akathisia.

    Scored from 0 (absent) to 5 (severe akathisia)



Secondary Outcome Measures :
  1. Change from baseline to week 12/EoT for ASP4345 compared to placebo for the UPSA-2-ER instrument. [ Time Frame: baseline to week 12 ]
    The University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) was developed to assess the functional abilities of the subject 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. Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): Minimum Concentration (Ctrough) [ Time Frame: up to 12 weeks ]
    Ctrough will be derived from the pharmacokinetic (PK) plasma samples collected



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03557931


Locations
Show Show 27 study locations
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
Layout table for investigator information
Study Director: Executive Medical Director Astellas Pharma Global Development
Layout table for additonal information
Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03557931    
Other Study ID Numbers: 4345-CL-0015
First Posted: June 15, 2018    Key Record Dates
Last Update Posted: December 11, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
URL: https://www.clinicalstudydatarequest.com/

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
aripiprazole
ziprasidone
lurasidone
schizophrenia
ASP4345
quetiapine
olanzapine
brexpiprazole
risperidone
paliperidone
Additional relevant MeSH terms:
Layout table for MeSH terms
Schizophrenia
Cognitive Dysfunction
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Cognition Disorders
Neurocognitive Disorders
Olanzapine
Risperidone
Aripiprazole
Quetiapine Fumarate
Paliperidone Palmitate
Ziprasidone
Lurasidone Hydrochloride
Brexpiprazole
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Antidepressive Agents
Dopamine Agonists
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists