Org 24448 (Ampakine) for Cognitive Deficits in Schizophrenia

This study is an eight-week, randomized, placebo-controlled, parallel group, fixed dose
trial comparing two doses of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA) receptor positive modulator, Org 24448, added to a stable dose of atypical
antipsychotic medication in 135 patients with schizophrenia studied at seven sites. The
primary endpoint for this trial is a composite score derived from the MATRICS cognitive
battery. Measures of psychiatric symptoms and functioning are secondary endpoints. Because
previous trials in animals and humans with this and other AMPA modulators detected
persistence of cognitive benefits, this trial will also repeat clinical assessments at
follow-up, four weeks after completion of the study medication.

Primary Objective:

1. Compare the effects of an eight-week trial of Org 24448 250 mg BID, 500 mg BID and
placebo upon cognitive function as assessed by the MATRICS cognitive battery.

Secondary Objectives:

2. Compare the effects of an eight-week trial of Org 24448 250 mg BID, 500 mg BID and
placebo upon level of functioning as measured by the SCoRS and UPSA.

3. Compare effects of Org 24448 250 mg BID, 500 mg BID and placebo on overall symptoms
measured by the BPRS total, psychotic symptoms measured by the BPRS positive symptom
items, and negative symptoms measured by the SANS total.

4. Evaluate tolerability of Org 24448 250 mg BID and 500 mg BID compared to placebo
measured by the Side Effect Checklist, AIMS, SAS, study completion rates, and frequency
of abnormal laboratory values.

Tertiary Objective:

5. Evaluate persistence of effects on clinical ratings 4 weeks after completion of the
8-week trial.

Methods:

Study Locations: This study will be coordinated by the study PI, Dr. Goff, and the TURNS
Treatment Management Unit under the direction of Dr. Buchanan. Patients will be recruited
from the Massachusetts General Hospital and Massachusetts Mental Health Center in Boston
(Dr. Goff), the Lemuel Shattuck Hospital and Beth Israel Deaconess Medical Center (Dr.
Seidman), the Nathan Kline Institute (Drs. Javitt and Nolan), Washington University Medical
Center (Drs. Csernansky and Barch), the Maryland Psychiatric Research Center (Drs. Buchanan
and Gold), Duke School of Medicine (Drs. McEvoy and Keefe), the University of California at
Los Angeles (Drs. Marder and Green) and Columbia University (Drs. Lieberman and Kimhy). The
TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of
cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.). Data
management will be performed by the Clinical Trials Data Management Unit of the Nathan Kline
Institute under the direction of Jim Robinson, M.S., and statistical analysis will be
performed by Dr. Robert McMahon of the Maryland Psychiatric Research Center. Org 24448 and
matching placebo capsules will be provided by Organon Pharmaceuticals. Laboratory assays
will be performed by Quest Diagnostics.

Subjects: Subjects will include 135 inpatients or outpatients with schizophrenia treated for
at least 8 weeks with a stable dose of an atypical antipsychotic other than clozapine. Prior
to enrollment, it will be determined that the clinician has optimized the dose of the
antipsychotic and maintained the medication at a constant dose for at least 4 weeks.
Diagnoses will be confirmed using the SCID. Patients will be excluded for significant
medical illness, seizure disorder, substance abuse, or inability to provide informed
consent. Because our primary hypothesis is that Org 24448 will improve measures of attention
and memory, patients must be capable of completing the neuropsychological battery, but no
minimum threshold of cognitive impairment is required for inclusion.

Screening: The diagnosis of schizophrenia will be confirmed by a research psychiatrist using
a modified version of the Structured Clinical Interview for DSM IV (SCID). The BPRS, SANS,
CDRS and SAS will be administered to verify that inclusionary criteria are met. A physical
examination, including neurological exam, will be performed and medical history, vital signs
(weight, heart rate, oral temperature, sitting and standing blood pressure), and demographic
information will be obtained. Laboratory assessments will include standard screening blood
tests: electrolytes, creatinine, blood urea nitrogen (BUN), fasting glucose, liver enzymes,
T4, calcium, phosphate, magnesium, albumin and complete blood count (CBC) with differential
and platelet count. A pregnancy test will be done in all premenopausal women. A routine
urinalysis, drug screen, EKG and EEG with hyperventilation and photic stimulation will also
be performed. The screening visits will collect all data required to complete inclusionary
and exclusionary criteria except for performance on the MATRICS battery and WTAR, which will
be administered as a baseline measurement at week 1 of the stabilization phase to minimize
practice effects. In addition, subjects must continue to meet inclusionary and exclusionary
criteria on baseline symptom ratings which will be performed at the completion of the
stabilization phase (stabilization week 2).

Stabilization Phase: After informed consent is obtained and screening completed, subjects
will enter a two-week, single-blind placebo lead-in stabilization phase. Placebo will be
administered as two capsules twice daily dispensed in blister packs identical to those that
will be used during the randomized, double-blind treatment phase. Baseline assessments will
be completed during the stabilization phase and compliance with study medication will be
assessed. Plasma will be obtained for assay of antipsychotic concentrations at week 2 of the
stabilization phase. The plasma sample will be drawn as a trough level. This phase is
intended to reduce placebo-response during the double-blind treatment phase, allow
completion of baseline assessments, and provide an opportunity for investigators to identify
and resolve potential problems with compliance.

The MATRICS Consensus Cognitive Battery (MCCB), the Wechsler Test of Adult Reading (WTAR),
the Schizophrenia Cognitive Rating Scale (SCoRS), and the University of California San Diego
(UCSD) Performance-Based Skills Assessment (UPSA) will be completed at stabilization week 1;
the clinical scales (described under "Assessments") will be completed at stabilization week
2.

Double-Blind Phase: Patients will be randomized in a 1:1:1 ratio to placebo, Org 24448 250
mg BID or Org 24448 500 mg BID administered in identical-appearing capsules for eight weeks.
Study drug will be dispensed weekly in blister packs containing placebo or Org 24448 250 mg
capsules after completing the stabilization phase (stabilization week 2 and baseline
assessments). Subjects will be given three extra days of medication in case of a missed
appointment. All subjects will take two capsules twice daily. The antipsychotic dose will be
unchanged during the trial. Patients will be asked to bring their previous blister pack to
each visit; a count of remaining capsules will be performed and recorded. Patients will
return for follow-up at week 12, four weeks after completing the double-blind trial.
Investigators may reduce the morning (AM) dose of study drug by one capsule (250 mg) if
necessary due to poor tolerance. Subjects may continue at the reduced dose or, after one
week, the investigator may attempt to resume the full dose (two capsules BID). If the
reduced dose (three capsules daily) is not tolerated, subjects will be discontinued from the
study. Patients who miss 7 consecutive days of study drug or who are found to have taken 75%
or fewer study doses at two or more pill counts will be dropped from study.

Assessments: The following scales will be completed at stabilization week 2 (baseline) and
at weeks 2, 4, 6, 8 & 12 and will comprise the clinical assessment battery: Brief
Psychiatric Rating Scale (BPRS), Scale for Assessment of Negative Symptoms (SANS), Calgary
Depression Rating Scale (CDRS) and Clinical Global Impression (CGI). In addition, the
Abnormal Involuntary Movement Scale (AIMS) and the Simpson Angus Scale for Extrapyramidal
Symptoms (SAS) will be performed at baseline and weeks 4, 8 & 12. Assessment of functioning
will be performed at baseline, weeks 4 & 8 (or end of study) using the Schizophrenia
Cognitive Rating Scale (SCoRS) and UCSD Performance-based Skills Assessment (UPSA). The
SCoRS will be repeated at week 12. Cognitive functioning will be assessed at baseline, week
4 and week 8 (or end of study) using the MATRICS battery plus the NAB Daily Living Memory
and a Delayed Recall Trial of the Hopkins Verbal Learning Test. A one-week window (up to 3
days before or 4 days after the scheduled visit) will be allowed for the completion of
assessments to accommodate unusual or unavoidable circumstances only. All sites will be
certified in the administration of the MATRICS, SCoRS and UPSA assessments prior to
initiation of study. Inter-rater reliability will be established for the BPRS and SANS
before the start of the study and will be reassessed every three months by the circulation
of videotaped interviews.

Safety Assessments: Vital signs and the Side Effects Checklist will be performed and adverse
events recorded weekly during the two-week stabilization phase and the 8 week trial and
weekly for 4 weeks following completion of the trial . Laboratory assessments, including
urinalysis, will be repeated at weeks 4, 6 and 8 (or end of study). An EKG will be repeated
at weeks 2, 4 and 8. A white blood count (WBC) and absolute neutrophil count (ANC) will be
repeated weekly during the 8 week trial and weekly for 4 weeks following completion of the
trial. A physical examination, including neurological examination, will be repeated at week
8 (or end of study).Drug Plasma Concentrations: Plasma will be obtained at baseline and
weeks 4 and 8 for assay of antipsychotic concentrations. Plasma samples will be drawn as
trough levels.

Inclusion Criteria:

1. Diagnosis: schizophrenia, any subtype (DSM-IV/DSM-IV-TR)

2. Age: 18-55 years

3. Gender: male or female

4. Capable of providing informed consent

5. Antipsychotic: aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone.

6. Subjects must have been maintained on current psychotropic medications for 8 weeks
and on current doses for 4 weeks.

7. Subjects must be clinically stable and in the residual (non-acute) phase of their
illness for at least 12 weeks.

8. Symptom Ratings:

- No more than a "moderate" severity rating on hallucinations and delusions (i.e.,
Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior or Unusual Thought
Content item score 4)

- No more than a "moderate" severity rating on positive formal thought disorder
(i.e., BPRS Conceptual Disorganization item score 4)

- No more than "moderate" severity rating on negative symptoms (i.e., all Scale
for the Assessment of Negative Symptoms global items 3)

- A minimal level of extrapyramidal symptoms (i.e., Simpson-Angus Scale total
score 6)

- A minimal level of depressive symptoms (i.e., Calgary Depression Scale total
score 10).

9. Cognitive Status:

- Performance less than the maximum cutoff (in parentheses) for ONE of the
following MCCB tests:

- Letter-number span (.20)

- Hopkins Verbal Learning Test (HVLT) total (.31) and

- Continuous Performance Test- Identical Pairs (CPT) d-prime (.3.47)

- Able to complete the baseline MCCB validly as assessed by Chief
Neuropsychologist or neuropsychology tester

- Raw score of 6 or greater on the WTAR

Exclusion Criteria:

1. Concomitant medications are allowed except for:

- Conventional antipsychotics and clozapine

- Antipsychotic polypharmacy

- Anticholinergic agents (including anticholinergic antidepressants)

- Carbamazepine, phenytoin and lamotrigine

2. DSM-IV/DSM-IV-TR diagnosis of alcohol or substance abuse (other than nicotine) within
the last 3 months or a DSM-IV/DSM-IV-TR diagnosis of alcohol or substance dependence
(other than nicotine) within the last 6 months

3. 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

4. History of seizures or abnormal EEG

5. Epileptogenic abnormalities on screening EEG

6. A baseline white blood count (WBC) less than 3500/mm3 or absolute neutrophil count
(ANC) less than 2000/mm3

7. Serious medical or neurological illness (unstable cardiac disease, AIDS, malignancy,
liver or renal impairment) or treatment for a medical disorder that could interfere
with study participation.

8. History of transient ischemic attack (TIA) or cerebral vascular accident (CVA)

9. History of neutropenia or medication-induced blood dyscrasia

10. Clinically-significant abnormalities on screening laboratory or EKG.

11. Untreated hyper- or hypothyroidism

12. Pregnancy, nursing, or if female and fertile, unwilling to use appropriate birth
control measures during study participation

13. Unable to complete neuropsychological tests

14. Serious suicidal or homicidal risk within the past six months

15. Participation in a trial of another investigational agent within 2 months

16. Treatment with Electroconvulsive therapy (ECT) within 2 months