Treatment Study for Cognitive Deficits in Schizophrenia

NCT00505076 | Completed Phase 2 Results DMC

• 2 other identifiers: TURNS02HHSN278200441003C
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 8

Brief Summary

Patients with schizophrenia are characterized by a broad range of neurocognitive abnormalities. These include impairments in attention, including abnormalities in sensory gating; executive function; visual and verbal learning and memory; working memory; processing speed; and social cognition (Nuechterlein et al, 2004). These impairments are major determinants of poor functional outcome in patients with schizophrenia (Green, 1996; Green et al, 2004). Conventional antipsychotics have limited effects on these impairments. Second generation antipsychotics may have modest benefits for cognitive function, but whether this represents a direct cognitive enhancing effect has not been established. Regardless, patients continue to exhibit pronounced cognitive impairments despite adequate second generation antipsychotic treatment. Adjunctive pharmacotherapy may offer a viable approach for the treatment of cognitive impairments. Adjunctive agents can be used to modulate specific neurotransmitter systems that are hypothesized to be involved in the pharmacology of cognitive functions. The standard of care for schizophrenia is antipsychotic medications to treat psychotic symptoms. However, cognitive impairments remain and these impairments have been found to be significantly associated with the poor psychosocial function observed in patients with schizophrenia. There is a considerable preclinical rationale for the use of drugs that act at the Gamma-amino-buyric acid (GABA) α2 subunit as adjunctive treatments to target cognitive impairments. MK-0777 GEM (Merck-0777 Gel Extrusion Module) formulation provides an opportunity to directly test this mechanism. The purpose of the proposed study is to examine the efficacy and safety of two doses of MK (Merck) -0777 GEM, 3 mg BID (twice daily) and 8 mg BID (twice daily), in the treatment of cognitive impairments in patients with schizophrenia. Secondary goals are to determine whether MK-0777 has beneficial effects on measures of functional capacity and patient self-report of cognitive function.

Conditions

Schizophrenia

Keywords

Cognition; Schizophrenia

Outcome Measures

Primary Outcomes (1)

• Composite MATRICS Consensus Cognitive Battery Score

  The primary outcome measure is the composite score on the Matrics Consensus Cognitive Battery (MCCB). The MCCB composite score is a standardized mean of the seven domain scores. T-scores are standardized to normative data, and have an estimated mean of 50 and SD of 10 in the general healthy population. Data reduction for analysis of neurocognitive testing used the following steps: i) individual neurocognitive test scores at baseline and follow-up were converted to t-scores; ii) t-scores within the pre-specified cognitive domains measured by more than one test were averaged to obtain a domain-specific t-score; and iii) domain-specific t-scores were averaged to create the MCCB composite score.

  4 weeks

Secondary Outcomes (2)

• UPSA(UCSD Performance-Based Skills Assessment) Summary Score

  Baseline and end of treatment, a total of four weeks.

• Schizophrenia Cognition Rating Scale (SCoRS) Score

  4 Weeks (Baseline to End of Treatment)

Study Arms (3)

MK-0777 8 mg

EXPERIMENTAL

MK-0777 8 mg tablet by mouth twice daily for 4 weeks

Drug: MK-0777

MK-0777 3 mg

EXPERIMENTAL

MK-0777 3 mg tablet by mouth twice daily for 4 weeks

Drug: MK-0777

Placebo

PLACEBO COMPARATOR

Placebo tablet by mouth twice daily for 4 weeks

Drug: placebo

Interventions

MK-0777 DRUG

MK-0777 GEM, 8 mg BID

MK-0777 8 mg

placebo DRUG

2 tablets placebo BID

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Diagnosis: DSM IV/DSM IV TR schizophrenia (including disorganized, paranoid, undifferentiated, and catatonic subtypes)
• Capable of providing informed consent
• Duration of illness equal to or greater than one year
• Treated with one or two of the following second generation antipsychotics: risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole for the previous two months, with no change in dose in the last month.
• Meet the following symptom criteria:
• Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior, Unusual Thought Content or Conceptual Disorganization item score ≤ 4
• All Scale for the Assessment of Negative Symptoms global items ≤ 3
• Simpson-Angus Scale total score ≤ 6
• Calgary Depression Scale total score ≤ 10
• Meet the following cognitive performance criteria:
• Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests: i.) Letter-number span (20); ii.) HVLT total (31); and iii.) CPT d-prime (3.47)
• Able to complete the baseline MCCB validly
• Raw score ≥6 on the WTAR

You may not qualify if:

• Current treatment (within 4 weeks) with conventional antipsychotics (e.g. fluphenazine, haloperidol) or clozapine
• Current treatment with psychotropic agents known to act at the GABAA receptor, including benzodiazepines; sedative-hypnotics other than trazadone and chloral hydrate; carbamazepine, gabapentin, lamotrigine, and valproic acid
• Current treatment with a drug that inhibits CYP3A4, including: cimetidine; cyclosporine; erythromycin or erythromycin-like drugs (e.g., azithromycin, clarithromycin); diltiazem; fluoxetine, fluovoxamine; itraconazole, ketoconazole or other systemic antifungal agents in the azole class; nefazodone; or induce CYP3A4, including: carbamazepine, modafinil; phenobarbital; phenytoin; rifampin; St. Johns wort; and troglitazone.
• Current treatment with psychotropic agents known to effect cognition: amphetamine; barbiturates; lithium; MAOIs; methylphenidate
• Current treatment with herbal preparations with possible psychotropic effects (e.g., St. Johns wort, kava-kava, Valerian, S-Adenosyl Methionine \[SAMe\])
• Current treatment with systemic steroids
• DSM-IV diagnosis of alcohol or substance abuse (other than nicotine) within the last month or a DSM-IV diagnosis of alcohol or substance dependence within the last 6 months
• Presence of PI or greater posterior subcapsular cataracts
• Uveitis with 1+ or greater flare or cells
• Nuclear or cortical cataracts
• History of significant head injury/trauma, as defined by one or more of the following: loss of consciousness (LOC) for more than 1 hour, seizures from the head injury, clear cognitive sequellae of the injury, or cognitive rehabilitation following the injury
• History of clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorders.
• Clinically significant abnormalities in physical examination, ECG, or laboratory assessments
• 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.
• Pregnant women or women of child-bearing potential, either not surgically-sterile or using appropriate methods of birth control

Sponsors & Collaborators

• University of California, Los Angeles: lead
• University of Maryland: collaborator
• Washington University School of Medicine: collaborator
• Massachusetts General Hospital: collaborator
• Nathan Kline Institute for Psychiatric Research: collaborator
• Columbia University: collaborator
• Duke University: collaborator
• Beth Israel Deaconess Medical Center: collaborator

Study Sites (8)

UCLA

Los Angeles, California, 90073, United States

Location

Maryland Psychiatric Research Center

Catonsville, Maryland, 21228, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Harvard Medical School

Boston, Massachusetts, 02115, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Nathan Kline Institute

Orangeburg, New York, 10962, United States

Location

Duke University Medical Center

Durham, North Carolina, 27509, United States

Location

Related Publications (20)

• Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995 Apr;52(4):258-66. doi: 10.1001/archpsyc.1995.03950160008002.

  PMID: 7702443 BACKGROUND

• Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, Goldberg TE, Weinberger DR. Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex. 1999 Jan-Feb;9(1):20-6. doi: 10.1093/cercor/9.1.20.

  PMID: 10022492 BACKGROUND

• Callicott JH, Ramsey NF, Tallent K, Bertolino A, Knable MB, Coppola R, Goldberg T, van Gelderen P, Mattay VS, Frank JA, Moonen CT, Weinberger DR. Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology. 1998 Mar;18(3):186-96. doi: 10.1016/S0893-133X(97)00096-1.

  PMID: 9471116 BACKGROUND

• Carpenter WT Jr, Buchanan RW, Kirkpatrick B, Breier AF. Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry. 1999 Feb;156(2):299-303. doi: 10.1176/ajp.156.2.299.

  PMID: 9989567 BACKGROUND

• Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M, Cohen JD. Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry. 1998 Sep;155(9):1285-7. doi: 10.1176/ajp.155.9.1285.

  PMID: 9734557 BACKGROUND

• Gold JM, Carpenter C, Randolph C, Goldberg TE, Weinberger DR. Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry. 1997 Feb;54(2):159-65. doi: 10.1001/archpsyc.1997.01830140071013.

  PMID: 9040284 BACKGROUND

• Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996 Mar;153(3):321-30. doi: 10.1176/ajp.153.3.321.

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• Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004 Dec 15;72(1):41-51. doi: 10.1016/j.schres.2004.09.009.

  PMID: 15531406 BACKGROUND

• Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000 Nov;57(11):1061-9. doi: 10.1001/archpsyc.57.11.1061.

  PMID: 11074872 BACKGROUND

• Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003 Jul 16;23(15):6315-26. doi: 10.1523/JNEUROSCI.23-15-06315.2003.

  PMID: 12867516 BACKGROUND

• Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005 Apr;6(4):312-24. doi: 10.1038/nrn1648.

  PMID: 15803162 BACKGROUND

• McMahon RP, Arndt S, Conley RR. More powerful two-sample tests for differences in repeated measures of adverse effects in psychiatric trials when only some patients may be at risk. Stat Med. 2005 Jan 15;24(1):11-21. doi: 10.1002/sim.1837.

  PMID: 15515151 BACKGROUND

• Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 2000 Oct;28(1):53-67. doi: 10.1016/s0896-6273(00)00085-4.

  PMID: 11086983 BACKGROUND

• Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004 Dec 15;72(1):29-39. doi: 10.1016/j.schres.2004.09.007.

  PMID: 15531405 BACKGROUND

• Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992 Dec;49(12):975-82. doi: 10.1001/archpsyc.1992.01820120063009.

  PMID: 1449384 BACKGROUND

• Pierri JN, Chaudry AS, Woo TU, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry. 1999 Nov;156(11):1709-19. doi: 10.1176/ajp.156.11.1709.

  PMID: 10553733 BACKGROUND

• Rao SG, Williams GV, Goldman-Rakic PS. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol. 1999 Apr;81(4):1903-16. doi: 10.1152/jn.1999.81.4.1903.

  PMID: 10200225 BACKGROUND

• Rao SG, Williams GV, Goldman-Rakic PS. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J Neurosci. 2000 Jan 1;20(1):485-94. doi: 10.1523/JNEUROSCI.20-01-00485.2000.

  PMID: 10627624 BACKGROUND

• Georgiades A, Davis VG, Atkins AS, Khan A, Walker TW, Loebel A, Haig G, Hilt DC, Dunayevich E, Umbricht D, Sand M, Keefe RSE. Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients. Schizophr Res. 2017 Dec;190:172-179. doi: 10.1016/j.schres.2017.03.040. Epub 2017 Apr 20.

  PMID: 28433500 DERIVED

• Buchanan RW, Keefe RS, Lieberman JA, Barch DM, Csernansky JG, Goff DC, Gold JM, Green MF, Jarskog LF, Javitt DC, Kimhy D, Kraus MS, McEvoy JP, Mesholam-Gately RI, Seidman LJ, Ball MP, McMahon RP, Kern RS, Robinson J, Marder SR. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry. 2011 Mar 1;69(5):442-9. doi: 10.1016/j.biopsych.2010.09.052. Epub 2010 Dec 8.

  PMID: 21145041 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Results Point of Contact

• Title: Stephen R. Marder
• Organization: Semel Institute at UCLA

marder@ucla.edu

310-268-3647

Study Officials

• Robert W Buchanan, M.D.

  Maryland Psychiatric Research Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 19, 2007
• First Posted: July 20, 2007
• Study Start: July 1, 2007
• Primary Completion: September 1, 2009
• Study Completion: September 1, 2009
• Last Updated: October 31, 2014
• Results First Posted: October 31, 2014

Record last verified: 2014-10

Locations

US (8)