Clinical trial NCT00825539: Pharmacodynamic/Pharmacokinetic Study of AQW051 in Schizophrenia
Official title: A Single-dose, Placebo-controlled, Stratified, Randomized, Double-blind, Crossover to Study Pharmacodynamic Effects of AQW051 Followed by a 4-week Multiple-dose Safety and Tolerability in People With Chronic Stable Schizophrenia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Schizophrenia
Keywords: Schizophrenia
Manic depression
anxiety
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-01-21
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Part 1 of the study will assess the enhancement of task-related brain activation (BOLD response) in key brain areas in schizophrenia during the performance of working memory, episodic memory and visual activation tasks as measured by functional magnetic resonance imaging (fMRI) in people with schizophrenia. Part 2 of the study will assess the safety and tolerability of multiple doses of AQW051 in people with schizophrenia.


Eligibility criteria: Inclusion Criteria:

1. Diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV/DSM IV TR)
2. Subjects will be currently treated with the stable regimen of one or more of the following second generation antipsychotics: olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole.
3. Subjects will meet the following symptom criteria:

   * Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior or Unusual Thought Content item scores less than or equal to 5
   * BPRS Conceptual Disorganization item score less than or equal to 4
   * Simpson-Angus Scale (SAS) total score less than or equal to 6
   * Calgary Depression Scale (CDS) total score less than or equal to 10
4. Subjects will meet the following cognitive performance criteria:

   * Maximum performance level: Performance below 1.0 SD from perfect performance on the Hopkins Verbal Learning Test (HVLT) total (31 or less),
   * Minimum performance level: subject must be able to validly complete the fMRI cognitive paradigms
   * WTAR: 5th grade reading level assessment
5. Subjects must be symptomatically stable and not suffer from an acute exacerbation of their psychosis
6. Female subjects of childbearing potential must be using two acceptable methods of contraception, (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening and for the duration of the study, through study completion. Pregnancy tests are required of all female subjects regardless of reported sterilization.

   When performed at screening and practice visit, the result of this test must be received before the subject may be dosed.
7. Male subjects must be using two acceptable methods of contraception, (e.g., spermicidal gel plus condom) for the entire duration of the studyuntil the Study Completion visit.
8. Subject must have sufficiently stable overall health, as determined by the Investigator. The regular intake of concomitant drugs will be allowed, if the patient is on stable treatment for at least 3 months prior to study enrollment and the concomitant drug does not belong to the list of medication that are not allowed according to Appendix 3. If the patient takes more than one concomitant medication, it is at the Investigator's discretion to decide about the patient's eligibility, depending on the nature of the concomitant medications and the patient's overall health.

Exclusion criteria:

1. Current treatment with conventional antipsychotics (e.g. fluphenazine, haloperidol) or clozapine
2. Current treatment with an anticholinergic or other agent known to adversely interfere with the cholinergic system
3. Subjects with a DSM-IV diagnosis of substance abuse (other than nicotine) within the last month.
4. Subjects with a history of significant head injury/trauma, as defined by:

   * Loss of consciousness (LOC) for more than 1 hour
   * Recurring seizures resulting from the head injury
   * Clear cognitive sequelae of the injury
   * Cognitive rehabilitation following the injury
5. Subjects with a medical or neurological disorder or treatment for such disorder that could interfere with the study medication of the assessment of the subject
6. Use of certain concomitant medication

No grapefruit or grapefruit juice is to be consumed for 14 days prior to dosing until 7 days following the last dose.

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Part 1: Assess BOLD response in key brain areas in schizophrenia patients during the performance of tasks as measured by (fMRI) in people with schizophrenia.
timeFrame: 2 years (Part 1: 1 year)
measure: Part 2: Assess safety and tolerability of multiple doses of AQW051 schizophrenia patients.
timeFrame: Part 2: 8 months
Secondary outcomes:
measure: Measure: To assess the effects of a single dose of AQW051 on performance of working and episodic memory tasks in people with schizophrenia. (Part 1)
timeFrame: Time Frame: 2 years (Part 1: 1 year; Part 2: 8 months)
measure: Measure: To determine the relationship of exposure to brain activation after a single dose of AQW051 in people with schizophrenia. (Part 1)
timeFrame: 2 years (Part 1: 1 year; Part 2: 8 months)
measure: Measure: To determine the dose-exposure response relationship of multiple doses of AQW051 in people with schizophrenia. (Part 2)
timeFrame: 2 years (Part 1: 1 year; Part 2: 8 months)
measure: Measure: To explore effects of multiple doses of AQW051 on measures of cognition in people with schizophrenia. (Part 2)
timeFrame: 2 years (Part 1: 1 year; Part 2: 8 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: West LA VA Healthcare Center (UCLA)
state: California
city: Chicago
country: United States
facility: Department of Psychiatry & Behavioural Sciences, Feinberg School of Medicine (Northwestern University)
state: Illinois
city: Baltimore
country: United States
facility: Maryland Psychiatric Research Centre, Spring Grove Hospital Grounds
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital (Freedom Trail Clinic)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Butner
country: United States
facility: JUH Clinical Research (Duke University),
state: North Carolina
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Barch DM, Marder SR, Harms MP, Jarskog LF, Buchanan RW, Cronenwett W, Chen LS, Weiss M, Maguire RP, Pezous N, Feuerbach D, Lopez-Lopez C, Johns DR, Behrje RB, Gomez-Mancilla B. Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Nov 3;71:66-75. doi: 10.1016/j.pnpbp.2016.06.013. Epub 2016 Jun 28.