A Multicenter Study of NAP (AL-108) in Schizophrenia - Full Text View

Sponsors and Collaborators:	University of California, Los Angeles University of Maryland Washington University School of Medicine Massachusetts General Hospital Nathan Kline Institute for Psychiatric Research Columbia University Duke University Beth Israel Deaconess Medical Center
Information provided by:	University of California, Los Angeles
ClinicalTrials.gov Identifier:	NCT00505765

Purpose

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.). Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications for the treatment of schizophrenia, many patients continue to be plagued by impairments in social and work functioning. Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention, memory, and executive functioning (the ability and organize one's behavior). Importantly, a large body of literature now shows a link between cognition and community functioning in schizophrenia. It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning.

One approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness. A promising agent is called AL-108. This drug is administered as a nasal spray. Studies in animals suggest that this drug may protect neurons and may improve cognition in schizophrenia. The current study is a twelve-week multicenter, double-blind, randomized clinical trial of two doses of AL-108 (5 and 30 mg/day intranasally) versus placebo in the treatment of persistent cognitive dysfunction in schizophrenia. The study medication will be added to patients' current atypical antipsychotic medication or to their current injectable first-generation antipsychotic medication. The primary outcome measure will consist of the composite score of the MATRICS neuropsychological battery. Secondary outcome measures will include scores on symptoms, functional outcome, and safety measures. Sixty clinically stable patients with schizophrenia, drawn from eight sites, will participate in the study. Twenty-five patients will be enrolled at UCLA.

Condition	Intervention	Phase
Schizophrenia	Drug: AL-108 Drug: placebo	Phase II

MedlinePlus related topics: Schizophrenia

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Multicenter Ascending Dose, Double Blind, Placebo-Controlled Study of NAP (AL-108) in Chronic Schizophrenia

Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:

Primary: MCCB: MATRICS Consensus Cognitive Battery [ Time Frame: Baseline, week 6, study end ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Secondary: UPSA: UCSD Performance-Based Skills Assessment; SCoRS: Schizophrenia Cognition Rating Scale [ Time Frame: Baseline, week 6, study end ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	July 2007
Estimated Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental AL-108, 30 mg/day- 3 sprays in each nostril, twice per day	Drug: AL-108 AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
2: Experimental AL-108, 5 mg/day- one spray in each nostril once per day	Drug: AL-108 AL-108, 5 mg/day- one spray in each nostril once per day
3: Placebo Comparator Placebo- 3 sprays in each nostril, twice per day	Drug: placebo Placebo- 3 sprays in each nostril, twice per day
4: Placebo Comparator Placebo- one spray in each nostril, once per day	Drug: placebo Placebo- one spray in each nostril, once per day

Detailed Description:

Background

AL-108 is an intranasal drug product containing NAP, an 8 amino-acid peptide (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln; NAPVSIPQ, MW=824.9) fragment of the much larger (approx. 124KD) Activity-Dependent Neuroprotective Protein (ADNP), which participates in neurodevelopment and neuroprotection. In mice, ADNP knockouts are lethal exhibiting CNS dysgenesis. ADNP mediates its effects in part through interaction with microtubules. Because of its large size, ADNP is assumed to not penetrate the BBB and thus cannot be used pharmacologically. NAP was chosen because it represents the epitope most associated with microtubule interaction and neuroprotection. NAP is absorbed following IV or intranasal administration, and has been shown to cross the BBB.

Rationale for NAP treatment: tubulin function in brain function

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. The cytoskeleton is made up of microfilaments, intermediate filaments and microtubules. Microfilaments (4-9 nm diameter) are made up of actin monomers and they function mainly to provide mechanical support and locomotion to the cell. Intermediate filaments are cytoplasmic fibers of ~10nm diameter. They provide supporting framework within the cell. Microtubules (~24nm diameter) consist of tubulin and microtubule associate proteins. They function to transport nutrients and chemical messengers along the cell. Neurofibrillary tangles are twisted bundles of neurofibrils formed when the microtubule-associated protein, tau, dissociates from microtubules and clusters to form an insoluble mass. Under normal conditions tau binds to microtubules, stabilizing neuronal structure and integrity.

Hyperphosphorylation of tau is assumed to be the cause for the formation of neurofibrillary tangles. Although neurofibrillary tangles are most associated with cognitive dysfunction in Alzheimers disease, some increase in neurofibrillary pathology has also been reported in schizophrenia, potentially as consequence of antipsychotic medication (1). Thus, mechanisms underlying microtubular function may be relevant to schizophrenia as well. In association with tubulin polymerization into microtubules, NAP influences tau dynamics by increasing the ratio of non-phosphorylated tau to phosphorylated tau, implying a dynamic process of cellular maintenance of the microtubular network, which is essential for the survival of the cell.

In brain, tubulin frameworks are stabilized by recently described STOP proteins (2) (aka MAP6). Linkages to allelic variation in STOP genes has been reported in schizophrenia, along with altered STOP protein expression in some brain regions (3). STOP knockdown mice show disturbances in dopaminergic neurotransmission (4) along with deficits in PPI and hypermotility that were partially reversed with clozapine (5). Thus, neuropathological features of schizophrenia may be due, in part, to abnormal STOP-related stabilization of microtubular structure, and NAP may stabilize STOP-related abnormal neurophysiological processes in schizophrenia.

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

DSM IV/DSM IV TR diagnosis of schizophrenia
Capable of providing informed consent
Males and Females
Age: 18 and 55
Caucasian or Non Caucasian
Subjects will be treated with one of the following second generation antipsychotics: risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole for the previous two months, with no change in dose in the last month, and/or with injectable depot antipsychotics (fluphenazine or haloperidol decanoate) with no change in last 3 months.
Subjects will meet the following symptom criteria:
- Average Brief Psychiatric Rating Scale (BPRS) item score >3 (mild)
- Simpson-Angus Scale total score less than or equal to 6
- Calgary Depression Scale total score less than or equal to 10
Subjects will meet the following cognitive performance criteria:
- Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests:
  - Letter-number span (20);
  - HVLT total (31); and
  - CPT d-prime (3.47)
- Able to complete the baseline MCCB validly as assessed by Chief Neuropsychologist or NP tester
- Raw score of 6 or greater on the WTAR

Exclusion Criteria:

Current treatment with oral conventional antipsychotics (e.g. fluphenazine, haloperidol) or clozapine.
Subjects with a 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 (other than nicotine) within the last 6 months
Subjects with a history of significant head injury/trauma, as defined by one or more of the following:
- Loss of consciousness (LOC) for more than 1 hour
- Recurring seizures resulting from the head injury
- Clear cognitive sequellae of the injury
- Cognitive rehabilitation following the injury
Subjects with a clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder (e.g. unstable angina, decompensated 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.
Clinically significant abnormalities in physical examination, ECG, or laboratory assessments.
Clinically significant renal disease.
Women who are pregnant or of child-bearing potential, either not surgically-sterile nor using appropriate methods of birth control
Women who are breast-feeding
Prior participation in a clinical trial of investigational medication within 60 days.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00505765

Locations

United States, California
UCLA	Recruiting
Los Angeles, California, United States, 90073
Contact: Stephen R Marder, MD 310-268-3647 marder@ucla.edu
Contact: Robert S Kern, PhD 3104783711 ext 49229 rkern@ucla.edu
Principal Investigator: Stephen R Marder, MD
United States, Maryland
Maryland Psychiatric Research Center	Recruiting
Catonsville, Maryland, United States, 21228
Contact: Robert W Buchanan, MD 410-402-7876 rwbuchanan@mprc.umaryland.edu
Principal Investigator: Robert W Buchanan, MD
United States, Massachusetts
Harvard Medical School	Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Larry J Seidman, PhD
Principal Investigator: Larry J Seidman, MD
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Donald C Goff, MD 617-912-7899 goff@psych.mgh.harvard.edu
Principal Investigator: Donald C Goff, MD
United States, Missouri
Washington University School of Medicine	Recruiting
St. Louis, Missouri, United States, 63110
Contact: John G Csernansky, MD 314-747-2160 jgc@conte.wustl.edu
Principal Investigator: John G Csernansky, MD
United States, New York
Columbia University Medical Center	Recruiting
New York, New York, United States, 10032
Contact: Jeffrey A Lieberman, MD 212-543-5300 jlieberman@pi.cpmc.columbia.edu
Principal Investigator: Jeffrey A Lieberman, MD
Nathan Kline Institute	Recruiting
Orangeburg, New York, United States, 10962
Contact: Daniel Javitt, MD, PhD 845-398-6534 javitt@nki.rfmh.org
Principal Investigator: Daniel Javitt, MD, PhD
United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: Joseph P McEvoy, MD 919-575-7213 joseph.mcevoy@duke.edu
Principal Investigator: Joseph P McEvoy, MD

Sponsors and Collaborators

University of California, Los Angeles

University of Maryland

Washington University School of Medicine

Massachusetts General Hospital

Nathan Kline Institute for Psychiatric Research

Columbia University

Duke University

Beth Israel Deaconess Medical Center

Investigators

Principal Investigator:

Daniel C Javitt, MD, PhD

Nathan Kline Institute

More Information

Publications:

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Jackman AH, Doty RL. Utility of a three-item smell identification test in detecting olfactory dysfunction. Laryngoscope. 2005 Dec;115(12):2209-12.

Gozes I, Divinski I. The femtomolar-acting NAP interacts with microtubules: Novel aspects of astrocyte protection. J Alzheimers Dis. 2004 Dec;6(6 Suppl):S37-41.

Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun. 2001 Dec;15(4):319-39. Review.

Rapaport MH, Delrahim KK. An abbreviated review of immune abnormalities in schizophrenia. CNS Spectr. 2001 May;6(5):392-7.

Kelly DL, Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology. 2006 Apr;31(3):340-6. Epub 2005 Sep 28.

Gozes I, Meltzer E, Rubinrout S, Brenneman DE, Fridkin M. Vasoactive intestinal peptide potentiates sexual behavior: inhibition by novel antagonist. Endocrinology. 1989 Dec;125(6):2945-9.

Rotstein M, Bassan H, Kariv N, Speiser Z, Harel S, Gozes I. NAP enhances neurodevelopment of newborn apolipoprotein E-deficient mice subjected to hypoxia. J Pharmacol Exp Ther. 2006 Oct;319(1):332-9. Epub 2006 Jul 5. Erratum in: J Pharmacol Exp Ther. 2007 Jan;320(1):498.

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21.

Braga RJ, Mendlowicz MV, Marrocos RP, Figueira IL. Anxiety disorders in outpatients with schizophrenia: prevalence and impact on the subjective quality of life. J Psychiatr Res. 2005 Jul;39(4):409-14. Epub 2004 Nov 13.

Alcalay RN, Giladi E, Pick CG, Gozes I. Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze. Neurosci Lett. 2004 May 6;361(1-3):128-31.

Gozes I, Alcalay R, Giladi E, Pinhasov A, Furman S, Brenneman DE. NAP accelerates the performance of normal rats in the water maze. J Mol Neurosci. 2002 Aug-Oct;19(1-2):167-70.

Gozes I, Giladi E, Pinhasov A, Bardea A, Brenneman DE. Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a water maze. J Pharmacol Exp Ther. 2000 Jun;293(3):1091-8.

Ito M, Depaz I, Wilce P, Suzuki T, Niwa S, Matsumoto I. Expression of human neuronal protein 22, a novel cytoskeleton-associated protein, was decreased in the anterior cingulate cortex of schizophrenia. Neurosci Lett. 2005 Apr 22;378(3):125-30.

Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord. 2004 Dec;3(6):515-33. Review.

Kolluri N, Sun Z, Sampson AR, Lewis DA. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry. 2005 Jun;162(6):1200-2.

Hill JJ, Hashimoto T, Lewis DA. Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2006 Jun;11(6):557-66.

Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999 Apr;122 ( Pt 4):593-624. Review.

Smith-Swintosky VL, Gozes I, Brenneman DE, D'Andrea MR, Plata-Salaman CR. Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth in rat hippocampal and cortical cultures. J Mol Neurosci. 2005;25(3):225-38.

Fradley RL, O'Meara GF, Newman RJ, Andrieux A, Job D, Reynolds DS. STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. Behav Brain Res. 2005 Sep 8;163(2):257-64.

Brun P, Begou M, Andrieux A, Mouly-Badina L, Clerget M, Schweitzer A, Scarna H, Renaud B, Job D, Suaud-Chagny MF. Dopaminergic transmission in STOP null mice. J Neurochem. 2005 Jul;94(1):63-73.

Shimizu H, Iwayama Y, Yamada K, Toyota T, Minabe Y, Nakamura K, Nakajima M, Hattori E, Mori N, Osumi N, Yoshikawa T. Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. Schizophr Res. 2006 Jun;84(2-3):244-52. Epub 2006 Apr 19.

Bosc C, Andrieux A, Job D. STOP proteins. Biochemistry. 2003 Oct 28;42(42):12125-32.

Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res. 1999 Nov 30;40(2):87-99. Review.

Responsible Party:	University of California, Los Angeles ( Stephen R. Marder, M.D. )
Study ID Numbers:	TURNS03, HHSN 278200441003C
Study First Received:	July 20, 2007
Last Updated:	June 3, 2008
ClinicalTrials.gov Identifier:	NCT00505765
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of California, Los Angeles:

Cognition
Schizophrenia

Study placed in the following topic categories:

Schizophrenia
Mental Disorders
Psychotic Disorders
Schizophrenia and Disorders with Psychotic Features

ClinicalTrials.gov processed this record on January 16, 2009