Clinical trial NCT01173874: Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone
Official title: Clinical and Biomarker Assessment of Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Keywords: Cognition
Function
Attention
Vigilance
Verbal Memory
Visual Memory
Processing Speed
Problem Solving
Social Cognition
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
First posted: 2010-08-02
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The investigators hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score and Cognitive Assessment Interview).

Detailed description: OVERVIEW \& SPECIFIC AIMS Marked cognitive impairment underlies much of the social \& occupational dysfunction associated with schizophrenia. Currently available antipsychotic medications are primarily effective in treating psychotic symptoms \& have demonstrated only limited potential in ameliorating cognitive deficits in schizophrenia patients.

Lurasidone is a novel compound synthesized by SEPRACOR, Inc.for the treatment of patients with schizophrenia \& bipolar disorder. It possesses high affinity for dopamine D2, serotonin 5-HT2A, 5-HT7, 5-HT1A \& noradrenaline α2C receptors. Compared with other atypical antipsychotics, lurasidone demonstrates similar binding affinities for the D2 \& 5-HT2A receptors, but greater affinity for serotonin 5-HT1A receptors. Lurasidone displays no affinity for histamine H1 or acetylcholine M1 receptors. In animal studies, lurasidone significantly reversed memory impairment induced by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, in a rat step-through type passive avoidance task. The maximum inhibitory effects of lurasidone were greater than those observed with risperidone, quetiapine, \& olanzapine, while aripiprazole was not effective in reversing the impairment induced by MK-801. Additionally, lurasidone significantly reversed memory impairment induced by the anticholinergic drug scopolamine in the passive avoidance task. The reversal of pharmacologically induced cognitive deficits in rats by lurasidone is promising \& warrants specific investigation in subjects with schizophrenia, given the prominence of cognitive deficits in this disorder.

From a different therapeutic perspective, the utility of cognitive remediation in ameliorating cognitive deficits \& improving functional outcomes in schizophrenia has recently been evaluated in several studies. A meta-analysis of these trials found effect sizes for improvement in cognitive \& psychosocial functioning in the low to moderate range (McGurck 2007). The best outcomes in psychosocial functioning were evident when cognitive remediation was combined with teaching of psychosocial skills.

Given the recalcitrant nature of cognitive deficits in schizophrenia \& their impact on functional capacity we felt that in designing a study to test the effectiveness of cognitive remediation we should maximize the likelihood of therapeutic benefit by administering cognitive remediation in the context of pharmacotherapy that may have potential for precognitive effects. By so doing we could possibly boost the effect sizes seen with cognitive remediation alone. In this study we will transition patients with schizophrenia (in whom a change in antipsychotic therapy is clinically warranted) from their current antipsychotic to lurasidone - clinicians will have eight weeks to complete the switch. Subjects who are successfully switched to lurasidone will then be randomized to receive either cognitive remediation or a non-specific mental activity control condition two times/week for a total of 30 sessions over a 4-6 month period. Our goal is to have 140 patients complete the cognitive remediation phase.

A subset of the sample will participate in 2 biomarker studies. Event related potentials \& fMRI will be done in these subjects at baseline \& study completion.

This study will be done as an Investigator initiated trial (J. Lieberman, M.D. - PI) under a separate IND.

Primary Aim: We hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score \& Cognitive Assessment Interview).

Additional aims

1. To compare cognitive remediation to active control on functional outcome as assessed by the change in UCSD Performance-Based Skills Assessment (UPSA-Brief) from baseline to end point of cognitive remediation phase.
2. To compare cognitive remediation to active control on changes from lurasidone stabilized baseline to end point in indices of functional brain activation (ERP \& fMRI) during cognitive activation tasks.
3. Evaluate the effect of 8 weeks of lurasidone treatment on cognitive \& functional outcomes as assessed by changes from baseline in the MATRICS composite score, CAI, \& UPSA-Brief.
4. Evaluate the effect of cognitive remediation compared to nonspecific mental activity on cognitive \& functional outcomes as assessed by changes from lurasidone stabilized baseline to end of cognitive remediation phase in the MATRICS composite score, CAI, \& UPSA-Brief.
5. Evaluate the efficacy, safety, \& tolerability of lurasidone in patients with schizophrenia as assessed by the change from baseline to week 8 \& to end of cognitive remediation phase in the PANSS total score, Side Effect Checklist, AIMS, SAS, BAS, \& frequency of abnormal laboratory values.

Eligibility criteria: Inclusion Criteria:

* Male or female between 18-55 years of age who meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder confirmed by the Structured Clinical Interview for DSM-IV Clinical trial version (SCID-CT version). Duration of illness \> 1 year. Outpatient status.
* Change in antipsychotic medication is clinically warranted as evidenced by

  * persistent psychosis despite adequate dose and duration of antipsychotic, or \* inability to achieve therapeutic dose because of dose-limiting side effects,
  * persistent side effects that either cause significant subjective distress or significantly increase medical risks, such as substantial weight gain or metabolic disturbances, or
  * patient preference to switch and treating psychiatrist is in agreement.
* No behaviors suggesting potential danger to self or others over the 6 months prior to participation.
* For the last 2 weeks of lurasidone stabilization phase, a score of 4 or less on PANSS items of conceptual disorganization, hallucinations, suspiciousness and unusual thought content items.
* At end of lurasidone stabilization phase, Simpson-Angus Scale total score \<
* At end of lurasidone stabilization phase, Calgary Depression Scale total score \<10.
* No acute medical problems; any chronic medical condition (e.g. hypertension) consistently treated and stable during the 1 month prior to participation.
* Able to provide signed informed consent and to cooperate with all study procedures.
* Able to attend twice weekly sessions (each lasting approximately 75 minutes) for cognitive remediation or active control sessions for the \~6 month duration of the cognitive remediation phase of the study.
* Must meet the following cognitive performance criteria:

  * Able to complete the baseline MATRICS validly at baseline as assessed by NP tester.
  * Raw score of 12 or greater on the WTAR (Wechsler Test of Adult Reading) at screening.
* Women who can become pregnant must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. Acceptable methods include oral, injectable or implanted contraceptives, intrauterine devices or barrier methods such as condoms, diaphragm and spermicides. Women who can become pregnant must have a negative urine pregnancy test at the Screening Visit. Women who can become pregnant include anyone who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy), or is not postmenopausal (defined as amenorrhea 12 consecutive months).

Exclusion Criteria:

* Documented history of learning disability.
* Hearing or visual impairment; not fluent in English.
* Current treatment with clozapine or history of treatment resistance as evidenced by failure to improve (in the judgment of the investigator) with 2 or more adequate dose antipsychotic trials of at least 6 weeks duration in preceding 1 year.
* Concomitant or anticipated treatment with potent CYP 3A4 inhibitor such a cimetidine, cyclosporine, erythromycin or erythromycin-like drugs (e.g., azithromycin, clarithromycin except short term acute treatment for 1 week or less), diltiazem, itraconazole, ketoconazole or other systemic antifungal agents in the azole class, nefazodone; or potent CYP3A4 inducer including: carbamazepine, modafinil, Phenobarbital, phenytoin, rifampin, St. Johns Wort, and troglitazone.
* Current treatment with psychotropic agents known to affect cognition such as amphetamines, topiramate.
* History of treatment with electroconvulsive therapy within the 6 months prior to participation or expectation that patient may require ECT during the study.
* History of neurological or neuropsychiatric conditions (e.g. stroke, traumatic brain injury, epilepsy, etc).
* Subjects with a history of clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorders (e.g. unstable angina, decompensate congestive heart failure, CNS infection or history of HIV seropositivity), which would pose a risk to the patient if they were to participate in the study or that might confound the results of the study. Active medical conditions that are minor or well controlled are not exclusionary if they do not affect risk to the patient of the study results. For example, the following are not exclusionary: a) stable and well-controlled hypertension; b) asthma (no serious attacks in the past year); c) hypothyroidism (TSH within normal limits).
* A positive test for Hepatitis C antibody with concurrent evidence of impaired hepatic function (increased AST or ALT greater than 2 times the upper limit of normal) or positive tests for Hepatitis A antibody IgM fraction or Hepatitis B surface antigen, irrespective of the AST or ALT values.
* History of alcohol or substance abuse or dependence during the 6 months prior to participation.
* Participation in a clinical trial involving an investigational medication within 3 months prior to participation or 2 or more investigational drug trials in the preceding 12 months.
* Pregnant women or women of child-bearing potential who are not using adequate birth control.
* Woman who are breast feeding.
* Individuals who: a) received any cognitive remediation in the 6 months prior to study entry or b)received more than 6 hours of cognitive remediation in the 12 months prior to study entry or c) received more than 15 hours in the 24 months prior to study entry. Cognitive remediation is defined as any behavioral intervention consisting of training activities that aim to target impairments in cognitive domains of sensory processing, attention, memory, processing speed, working memory, and executive functioning.

Primary outcomes:
measure: Cognitive Function Measured by MCCB Composite Score
timeFrame: 4-6 month period
measure: Cognitive Function as Measured by the University of California, San Diego, Performance-Based Skills Assessment-Brief (UPSA-B) Scale
timeFrame: 4-6 month period
Secondary outcomes:
measure: Cognition as Measured by Cognitive Assessment Interview (CAI)
timeFrame: 4-6 month period
measure: Efficacy as Measured by Positive and Negative Syndrome Scale (PANSS)
timeFrame: 4-6 month period
Other outcomes:
Locations:
city: Granada Hills
country: United States
facility: San Fernando Mental Health Center
state: California
city: Orange
country: United States
facility: University of California - Irvine
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Miami
country: United States
facility: University of Miami Department of Psychiatry
state: Florida
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Psychiatric Clinical Research Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Psychopharmacology Research Unit- Nathan KIine Institute for Psychiatric Research
state: New York
city: Butner
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center, San Antonio
state: Texas
Study officials:
affiliation: Columbia University
name: Jeffrey Lieberman, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Zafar Sharif, M.D.
role: PRINCIPAL_INVESTIGATOR
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