Multiple Ascending Dose Study on Safety, Tolerability, and Pharmacokinetics of AMG 581 in Healthy Subjects or Subjects With Schizophrenia or Schizoaffective

Study Overview
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Brief Summary
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The purpose of this study is to find out the time it takes to absorb, distribute, breakdown and remove the drug from the body in healthy participants and subjects with schizophrenia and whether it causes any side effects.

Detailed Description
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The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetic profile of ascending multiple oral doses of AMG 581 in healthy subjects or subjects with schizophrenia or schizoaffective disorder on antipsychotic medication. The study will also assess the effects of AMG 581 on midazolam PK in healthy subjects or subjects with schizophrenia or schizoaffective disorder on antipsychotic medication.

Official Title
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A Phase I, Randomized, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 581 in Healthy Subjects or Subjects With Schizophrenia or Schizoaffective Disorder on Antipsychotic Medication

Conditions
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Schizophrenia or Schizoaffective Disorder

Intervention / Treatment
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* Drug: AMG 581
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Provided informed consent prior to initiation of any study-specific activities/procedures; -male or female subjects should be between the ages of 18 and 45 years (18-55 years for subjects with schizophrenia);-non-nicotine or non-tobacco (healthy subjects only); - no history of relevant medical disorders; - BMI ≥ 18.0; - females of non-reproductive potential; - males practicing effective birth control; - avoid tanning/direct sunlight; - schizophrenia or schizoaffective disorder; PANSS score ≤ 4 points on following items (i.e. conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, depression, anxiety, disorientation, uncooperativeness, disturbance of volition, and poor impulse control) / total score ≤ 80 points Exclusion Criteria: females lactating/breastfeeding; pregnant partners of male subjects; essential tremor or gait disturbance; - history of hereditary shorten QT syndrome; - malignancy or tumor (other than skin cancers); - history of GI disease that could interfere with absorption; - QTc ≥ 450 msec or ≤ 380 msec; - HbA1c ≥ 7%;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AMG 581 - Dose 1<br> | Drug: AMG 581<br>* Active drug<br>|
| Active Comparator: AMG 581 - Dose 2<br> | Drug: AMG 581<br>* Active drug<br>|
| Active Comparator: AMG 581 - Dose 3<br> | Drug: AMG 581<br>* Active drug<br>|
| Active Comparator: AMG 581 - Dose 4<br> | Drug: AMG 581<br>* Active drug<br>|
| Placebo Comparator: Placebo - Dose 1<br> | Drug: AMG 581<br>* Active drug<br>Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo - Dose 2<br> | Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo - Dose 3<br> | Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo - Dose 4<br> | Drug: Placebo<br>* Placebo<br>|
| Other: AMG 581/Midazolam - Drug Interaction<br> | Drug: AMG 581<br>* Active drug<br>Drug: Midazolam<br>* Interaction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reported treatment-emergent adverse events | Number and percent of subjects experiencing adverse events | 39 days | 
| Changes in systolic/diastolic blood pressure | Summaries over time and/or changes from baseline over time in systolic and/or diastolic blood pressure | 39 days | 
| Changes in heart rate | Summaries over time and/or changes from baseline over time in heart rate | 39 days | 
| Changes in respiratory rate | Summaries over time and/or changes from baseline over time in respiratory rate | 39 days | 
| Changes in temperature | Summaries over time and/or changes from baseline over time in temperature | 39 days | 
| Changes in ECGs | Summaries over time and/or changes from baseline over time in ECGs | 39 days | 
| Maximum change from baseline in QTc in ECGs and number and percentage of subjects with maximum changes exceeding prespecified limits in each group | Subjects' maximum change from baseline in QTc and the number and percentage of subjects in each group | 39 days | 
| Maximum post-baseline QTc values and number and percentage of subjects with maximum post-baseline QTc values exceeding prespecified limits in each group | Subjects' maximum post-baseline values and the number and percentage of subjects in each group | 39 days | 
| Scores at each study visit for Simpson Angus Scale (SAS) | Summaries over time and/or changes from baseline over time in changes in Simpson Angus Scale (SAS) score | 39 days | 
| Scores at each study visit for Barnes Akathisia Rating Scale (BARS) | Summaries over time and/or changes from baseline over time in in Barnes Akathisia Rating Scale (BARS) score | 39 days | 
| Subject incidence of treatment-emergent suicidal ideation and behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | Subject incidence of treatment-emergent suicidal ideation and behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) summarized by cohort | 39 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare PK parameter (Cmax) between Day 1 and Day 18 | Compare PK parameter (Cmax) between Day 1 and Day 18 | 18 days | 
| Compare PK parameter (AUC) between Day 1 and Day 18 | Compare PK parameter (AUC) between Day 1 and Day 18 | 18 days | 
| Compare PK parameter (tmax) Compare PK parameter (tmax) between Day 1 and Day 18 | Compare PK parameter (tmax) Compare PK parameter (tmax) between Day 1 and Day 18 | 18 days | 
| Plasma PK parameters of midazolam and 1-OH midazolam | Cmax and AUC prior to versus following AMG 581 administration | 36 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia or Schizoaffective Disorder