A Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP4345 in Patients With Schizophrenia

NCT02720263 | Completed Phase 1

• 1 other identifier: 4345-CL-0002
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of multiple ascending oral doses of ASP4345 in patients with schizophrenia. In addition, this study will evaluate the pharmacokinetics of multiple ascending oral doses of ASP4345 in patients with schizophrenia.

Conditions

Schizophrenia

Keywords

Schizophrenia; ASP4345

Outcome Measures

Primary Outcomes (34)

• Safety and tolerability assessed as nature, frequency and severity of adverse events

  Up to Day 21

• Change from baseline in supine blood pressure as a measure of safety and tolerability

  Baseline and Day 21

• Change from baseline in pulse as a measure of safety and tolerability

  Baseline and Day 21

• Change from baseline in oral body temperature as a measure of safety and tolerability

  Baseline and Day 21

• Safety and tolerability assessed by an orthostatic challenge test

  Incidence of positive orthostatic challenge tests will be summarized.

  Up to Day 14

• Number of participants with abnormal laboratory values and/or adverse events related to treatment

  Clinical laboratory tests include hematology, biochemistry and urinalysis.

  Up to Day 21

• Safety and tolerability assessed by routine 12-lead electrocardiogram (ECG)

  The overall interpretation of 12-lead electrocardiogram (ECG) results (normal, abnormal not clinically significant and abnormal clinically significant) will be summarized.

  Up to Day 18

• Safety and tolerability assessed by continuous 12-lead ECG recording

  ECGs will be collected using a 12-lead ECG continuous monitoring system which records continuous digital data.

  Up to Day 14

• Safety and tolerability assessed by abuse liability using an Addiction Research Center Inventory (ARCI-49)

  ARCI-49 is a 49-item short form standardized questionnaire for abuse potential liability.

  Up to Day 17

• Safety and tolerability assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)

  The C-SSRS is a scale that assesses the full spectrum of suicidality: suicidal ideation, intensity of ideation, suicidal behaviors and actual attempts.

  Up to Day 18

• Safety and tolerability assessed by Bond-Lader Visual Analog Scale (VAS)

  The VAS will be used to rate patients' feelings in terms of 16 dimensions. The dimensions will be presented as 100 mm lines, the 2 extremes of the emotion (i.e., alert - drowsy) written at each end.

  Up to Day 17

• Safety and tolerability assessed by metabolic syndrome: weight circumference

  Up to Day 14

• Safety and tolerability assessed by metabolic syndrome: cholesterol

  Up to Day 21

• Safety and tolerability assessed by metabolic syndrome: triglycerides

  Up to Day 21

• Safety and tolerability assessed by metabolic syndrome: glucose level

  Up to Day 21

• Safety and tolerability assessed by weight

  Up to Day 14

• Safety and tolerability assessed by movement disorder: Abnormal Involuntary Movement Scale (AIMS)

  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.

  Up to Day 14

• Safety and tolerability assessed by movement disorder: Simpson Angus Scale (SAS)

  The SAS is a 10-item scale used to rate adverse neurological effects of antipsychotic medications more broadly. Each item is rated from 0 to 4 and a total score will be obtained.

  Up to Day 14

• Safety and tolerability assessed by movement disorder: Barnes Akathisia Rating Scale (BARS)

  The BARS is a rating scale used to assess the severity of drug-induced akathisia.

  Up to Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): tlag

  Time prior to the time corresponding to the first measurable (nonzero) concentration (tlag)

  Day 1

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): tmax

  Time of maximum concentration (tmax)

  Day 1 and Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): Cmax

  Maximum concentration (Cmax)

  Day 1 and Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): AUCtau

  Area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau)

  Day 1 and Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): Ctrough

  Concentration immediately prior to dosing at multiple dosing (Ctrough)

  Days 2 through 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): t1/2

  Terminal elimination half-life (t1/2)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): MRTinf

  Mean residence time extrapolated to time infinity (MRTinf)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): terminal elimination rate constant

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): Vz/F

  Apparent volume of distribution during the terminal elimination phase after single extravascular dosing (Vz/F)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): CL/F

  Apparent total systemic clearance after extravascular dosing (CL/F)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): Rac(AUC)

  Accumulation index area under the concentration-time curve (Rac(AUC))

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (plasma): PTR

  Peak trough ratio (PTR)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (urine): Aetau

  Cumulative amount of study drug excreted into urine from the time of dosing to the start of the next dosing interval (Aetau)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (urine): Aetau%

  Percentage of study drug dose excreted into urine from the time of dosing to the start of the next dosing interval (Aetau%)

  Day 14

• Pharmacokinetics of ASP4345 and its metabolites, if necessary (urine): CLR

  Renal clearance (CLR)

  Day 14

Study Arms (3)

Double-Blind ASP4345 Multiple Dose Levels

EXPERIMENTAL

ASP4345 will be administered orally as a single daily dose on days 1 through 14 with water. On days 1, 7, and 14, ASP4345 will be administered under fasting conditions. On days 2-6 and 8-13, ASP4345 will be administered under fed conditions.

Drug: ASP4345

Double-Blind Placebo Multiple Dose

PLACEBO COMPARATOR

Matching placebo capsules will be administered orally as a single daily dose on days 1 through 14 with water. On days 1, 7, and 14, matching placebo capsules will be administered with food. On days 2-6 and 8-13, matching placebo will be administered under fed conditions.

Drug: Matching Placebo

Open-Label ASP4345

EXPERIMENTAL

ASP4345 will be administered orally as a single daily dose on days 1 through 14 with water. On days 1, 7, and 14, ASP4345 will be administered with food. On days 2-6 and 8-13, ASP4345 will be administered under fed conditions. This is an optional cohort where subjects will be enrolled to further characterize pharmacodynamics in the event a higher sample size is necessary to determine changes in electrophysiological biomarkers.

Drug: ASP4345

Interventions

ASP4345 DRUG

Oral

Double-Blind ASP4345 Multiple Dose Levels; Open-Label ASP4345

Matching Placebo DRUG

Oral

Double-Blind Placebo Multiple Dose

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patient has a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria.
• A patient is considered operationally stable if the patient has a low to moderate positive symptoms score and moderate negative symptom score on the Positive and Negative Syndrome Scale (PANSS): No more than moderate rating on more than 2 PANSS items P1, P2, P3, P5, P6 (positive symptom section); No more than moderate severity rating for the negative items, N1, N2, N3, N4, N5, N6, N7 (negative symptom section); total PANSS score no more than 80.
• Patient must be in ongoing maintenance antipsychotic therapy other than clozapine (oral or depot), on a stable (≤ 25% change in dose) medication treatment regimen (approved oral or depot formulations of risperidone, quetiapine, olanzapine, ziprasidone, brexpiprazole, aripiprazole, paliperidone or lurasidone) for ≥ 2 months for oral formulations or ≥ 3 months for depot formulations prior to screening, including concomitant psychotropic medications, such as, trazodone and zolpidem for sleep.
• Patient has a body mass index (BMI) range of 18.5 to 40.0 kg/m2, inclusive, and weighs at least 50 kg at screening.
• Female patient must be of nonchildbearing potential:
• Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
• Documented surgically sterile (at least 1 month prior to screening defined as hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy)
• Female patient must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration.
• Male patient and their female spouse/partners who are of childbearing potential must be using 2 forms of highly effective birth control† (1 of which must be a barrier method‡) starting at screening and continue throughout the study period and for 90 days after the final study drug administration.
• †Highly effective forms of birth control include:
• Consistent and correct usage of established oral contraception
• Injected or implanted hormonal methods of contraception
• Established intrauterine device or intrauterine system
• Bilateral tubal ligation
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments and complies with the preferred and usual lifestyle of the patient.

You may not qualify if:

• Female patient who has been pregnant within 6 months prior to screening assessment or breastfeeding within 3 months prior to screening.
• Patient has a known or suspected hypersensitivity to ASP4345 or any components of the formulation used.
• Patient has had previous exposure with ASP4345.
• Patient has a history of suicide attempt or suicidal behavior within 2 years prior to screening. Any suicidal ideation that meets criteria at a level of 4 or 5 by using C-SSRS within the last 3 months or who is at significant risk to commit suicide at screening or at admission to the clinical unit (day 2) will be excluded.
• Patient has any clinically significant liver chemistry test result aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase, total bilirubin (TBL) or a result \> than 1.5 times above the ULN at screening or at admission to the clinical unit (day 2). In such a case, the assessment may be repeated once.
• Patient has any history of allergic conditions deemed clinically significant.
• Patient has any history or evidence of any clinically significant cardiovascular, gastrointestinal endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric (other than schizophrenia or schizoaffective disorder), renal and/or other major disease or malignancy. Patient has any condition, which, makes the patient unsuitable for clinical study participation.
• Patient has been diagnosed with moderate or severe tardive dyskinesia, bipolar disorder, major depressive disorder, personality disorders, neuroleptic malignancy syndrome or anxiety disorder.
• Patient has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 1 week prior to admission to the clinical unit (day 2).
• Patient has any clinically significant abnormality at screening or at admission to the clinical unit (day 2).
• Patient has a mean pulse \< 40 or \> 100 bpm; mean systolic blood pressure (SBP) \> 160 mmHg; mean diastolic blood pressure (DBP) \> 90 mmHg (vital signs measurements taken in triplicate after patient has been resting in supine position for 5 minutes; pulse will be measured automatically) at screening or at admission to the clinical unit (day 2). If the mean blood pressure exceeds the limits above, 1 additional triplicate can be taken on day 2.
• Patient has a mean QTcF \> 440 msec (for male patients) and \> 460 msec (for female patients) at screening or at admission to the clinical unit (day 2). If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken on day 2.
• Patient uses any prescribed or nonprescribed drugs (including vitamins, natural and herbal remedies, e.g., Valerian) in the 2 weeks prior to study drug administration, except for:
• Approved antipsychotics (risperidone, quetiapine, olanzapine, ziprasidone, brexpiprazole, aripiprazole, paliperidone or lurasidone), or
• Approved intermittent use of trazodone or zolpidem (no less than 12 hours prior to dosing), or

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (1)

Site US10001

Glendale, California, 91206, United States

Location

Related Publications (1)

• Desai A, Benner L, Wu R, Gertsik L, Maruff P, Light GA, Uz T, Marek GJ, Zhu T. Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia. Neuropsychopharmacology. 2021 May;46(6):1145-1151. doi: 10.1038/s41386-020-00908-0. Epub 2020 Nov 17.

  PMID: 33203954 DERIVED

Related Links

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

MeSH Terms

Conditions

Schizophrenia

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Senior Medical Director

  Clinical Pharmacology and Exploratory Development

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2016
• First Posted: March 25, 2016
• Study Start: March 28, 2016
• Primary Completion: June 8, 2017
• Study Completion: June 8, 2017
• Last Updated: October 31, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)