A Repeat Dose Study With GSK1018921 to Assess Safety, Tolerability, Pharmacokinetics, Pharmacodynamics in Healthy Volunteers and Patients With Schizophrenia and to Evaluate Its Effect on PK of Midazolam. (GT1110791)

A 4-Part Parallel Group, Randomized, Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of Repeat Doses of GSK1018921 in Healthy Volunteers and Stable Patients With Schizophrenia and to Evaluate Its Effects on Pharmacokinetics of Midazolam.

The purpose of this study is to understand safety and tolerability of the drug GSK1018921 after 14 days of dosing in healthy volunteers and then in patient volunteers.

Study Overview

• Status: Terminated
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Glycine Transporter-1 inhibitor

Detailed Description

This is a four part, parallel group, randomised, study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of repeat doses of GSK1018921 in healthy volunteers and stable patients with schizophrenia and to evaluate its effect on pharmacokinetics of midazolam. Part A will evaluate 14 days repeat BID dosing in at least three cohorts of healthy volunteers, to assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK1018921. Part B will study the potential drug interaction of GSK1018921 (Maximum Tolerated Dose from Part A) with midazolam with 14 days repeat BID dosing in healthy volunteers and therefore will assess the PK, safety and tolerability. Part C will be a single dose study in healthy volunteers and will include CSF sampling to assess the concentration of GSK1018921 and glycine in CSF with two doses (80 and 200 mg). Part D will study stable patients with schizophrenia, to assess safety, tolerability, PK and PD following 28 days of repeat BID dosing.

Safety assessments will include physical examination, 12-lead ECGs, holter monitoring, vital signs, orthostatic vital signs, visual assessments, and clinical lab test. Tolerability will be assessed by collecting Adverse Events.

PD assessments will include glycine in red blood cells, plasma and CSF, as well as CogState Battery test, Visual Assessment Scale, Positive And Negative Symptom Scores (PANSS) and Clinical Global Impression scales of change.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • GSK Investigational Site
  • Texas
    • Bellaire, Texas, United States, 77401
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

All subjects (Healthy and Patients)

Exclusion Criteria:

• History of drug or alcohol abuse.
• Consumption of drug, food or drink affecting the CYP450 metabolism pathway.
• Has received investigational drug within 30 days to 5 half lives or twice the duration of the biological effect of any drug (which ever is the longer).
• Donation of blood in excess of 500mL within a 56 day period.

Patients eligibility

- Stable patients with schizophrenia.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GSK1018921; Glycine Transporter-1 inhibitor to modulate the NMDA receptor.	Drug: Glycine Transporter-1 inhibitor; GSK1018921 is a potent and selective inhibitor of the glycine transporter-1 (GlyT-1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Safety and tolerability endpoints consisting of: adverse events; 12-lead ECG; vital signs, clinical laboratory evaluations and PK parameters.	14 days twice daily dosing.
Part B: Midazolam PK following single and repeat doses of GSK1018921.	14 days twice daily dosing.
Part C: Plasma & CSF glycine concentrations following single doses og GSK1018921.	After single dosing.
Part D: Safety and tolerability endpoints consisting of: adverse events; 12-lead ECG; vital signs, clinical laboratory evaluations and movement scales Simpson Angus Scale, AIMS and Barnes akathisia Scale.	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Part A: Effects of GSK1018921 on VAS	14 days.
Part B: None
Part C: GSK1018921 plasma exposure-CSF glycine relationship	After single dosing.
Part D: Effects of GSK1018921 on VAS, PANSS and CGI	28 days.

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: June 25, 2009
• First Submitted That Met QC Criteria: June 25, 2009
• First Posted (Estimate): June 29, 2009

Study Record Updates

• Last Update Posted (Estimate): June 29, 2009
• Last Update Submitted That Met QC Criteria: June 25, 2009
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: Schizophrenia; Patient; Healthy Volunteers; Midazolam; CSF; GSK1018921; GlyT-1 inhibitor
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Glycine Agents; Glycine
• Other Study ID Numbers: 110791