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

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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia or Schizoaffective Disorder
• Intervention / Treatment: Drug: Placebo; Drug: AMG 581; Drug: Midazolam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Research Site
    • Glendale, California, United States
      • Parexel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AMG 581 - Dose 1	Drug: AMG 581; Active drug
Active Comparator: AMG 581 - Dose 2	Drug: AMG 581; Active drug
Active Comparator: AMG 581 - Dose 3	Drug: AMG 581; Active drug
Active Comparator: AMG 581 - Dose 4	Drug: AMG 581; Active drug
Placebo Comparator: Placebo - Dose 1	Drug: Placebo; Placebo; Drug: AMG 581; Active drug
Placebo Comparator: Placebo - Dose 2	Drug: Placebo; Placebo
Placebo Comparator: Placebo - Dose 3	Drug: Placebo; Placebo
Placebo Comparator: Placebo - Dose 4	Drug: Placebo; Placebo
Other: AMG 581/Midazolam - Drug Interaction	Drug: AMG 581; Active drug; Drug: Midazolam; Interaction

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AMG 581 metabolites in plasma	Metabolites of AMG 581 in plasma	39 days
Cmax and AUC of AMG 581 prior to versus following midazolam administration	Cmax and AUC prior to versus following AMG 581 administration	36 days
Subjective experience following administration of AMG 581	Subjective experience of study subjects following administration of AMG 581 as measured by the Bond and Lader visual analogue scales (VAS)	39 days
Changes in psychotic symptoms following administration of AMG 581	Subjective experience of study subjects following administration of AMG 581 as measured by the Positive and Negative Syndrome Scale (PANSS) (subjects with schizophrenia or schizoaffective disorder receiving antipsychotic treatment only)	39 days
Relationship between QTc and temperature	To explore the relationship between changes in QTc and changes in body temperature	39 days

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: July 8, 2015
• First Submitted That Met QC Criteria: July 20, 2015
• First Posted (Estimate): July 22, 2015

Study Record Updates

• Last Update Posted (Estimate): March 7, 2016
• Last Update Submitted That Met QC Criteria: March 4, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Schizophrenia or Schizoaffective Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 20130259