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

This study has been completed.
Sponsor:
Collaborators:
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 (Responsible Party):
Stephen R. Marder, University of California, Los Angeles
ClinicalTrials.gov Identifier:
NCT00505765
First received: July 20, 2007
Last updated: April 25, 2012
Last verified: April 2012
History of Changes
  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 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter Ascending Dose, Double Blind, Placebo-controlled Study of NAP (AL-108) in Chronic Schizophrenia

Resource links provided by NLM:

MedlinePlus related topics: Schizophrenia
U.S. FDA Resources

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 ]

Enrollment: 63
Study Start Date: July 2007
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
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
Experimental: 2
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
Placebo Comparator: 3
Placebo- 3 sprays in each nostril, twice per day
 Drug: placebo
Placebo- 3 sprays in each nostril, twice per day
Placebo Comparator: 4
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 60 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 60
  • 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
Los Angeles, California, United States, 90073
United States, Maryland
Maryland Psychiatric Research Center
Catonsville, Maryland, United States, 21228
United States, Massachusetts
Harvard Medical School
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Nathan Kline Institute
Orangeburg, New York, United States, 10962
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
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:

Responsible Party: Stephen R. Marder, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT00505765     History of Changes
Other Study ID Numbers: TURNS03, HHSN 278200441003C
Study First Received: July 20, 2007
Last Updated: April 25, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, Los Angeles:
Cognition
Schizophrenia

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Mental Disorders

ClinicalTrials.gov processed this record on October 17, 2012