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

January 30, 2017 updated by: University of California, Los Angeles

A Multicenter Ascending Dose, Double Blind, Placebo-controlled Study of NAP (AL-108) in Chronic Schizophrenia

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

63

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90073
        • UCLA
    • Maryland
      • Catonsville, Maryland, United States, 21228
        • Maryland Psychiatric Research Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02215
        • Harvard Medical School
    • Missouri
      • St. Louis, Missouri, United States, 63110
        • Washington University School of Medicine
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • Orangeburg, New York, United States, 10962
        • Nathan Kline Institute
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: AL-108, 30 mg/day
AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
Drug: AL-108
AL-108, 5 mg/day- one spray in each nostril once per day
Drug: AL-108
AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
Experimental: AL-108, 5 mg/day
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
Drug: AL-108
AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
Placebo Comparator: Placebo, 3 sprays BID
Placebo- 3 sprays in each nostril, twice per day
Drug: Placebo
Placebo- 3 sprays in each nostril, twice per day
Drug: Placebo
Placebo- one spray in each nostril, once per day
Placebo Comparator: Placebo, 1 Spray Daily
Placebo- one spray in each nostril, once per day
Drug: Placebo
Placebo- 3 sprays in each nostril, twice per day
Drug: Placebo
Placebo- one spray in each nostril, once per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in MATRICS Consensus Cognitive Battery Composite Score Change
Time Frame: Baseline, week 6
The MATRICS Consensus Cognitive Battery (MCCB) measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and < 40 (below normal range).
Baseline, week 6
Change in MATRICS Consensus Cognitive Battery (MCCB)
Time Frame: Baseline, 12 weeks
The MATRICS Consensus Cognitive Battery (MCCB) measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and < 40 (below normal range).
Baseline, 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in UCSD Performance-Based Skills Assessment (UPSA) Summary Scores
Time Frame: Baseline, week 6
UPSA includes 5 skill areas (subscales) with scores that each range from 0-20. The UPSA yields an overall total score which is the sum of the five subscales and ranges from 0-100. Higher scores are associated with more independent living.
Baseline, week 6
Change in UCSD Performance-Based Skills Assessment (UPSA) Summary Scores
Time Frame: Baseline, 12 weeks
UPSA includes 5 skill areas (subscales) with scores that each range from 0-20. The UPSA yields an overall total score which is the sum of the five subscales and ranges from 0-100. Higher scores are associated with more independent living.
Baseline, 12 weeks
Change in SCoRS Interviewer Global Rating
Time Frame: Baseline, 6 weeks
Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity by completing a 20-question rating scale via interviews with the subject and an informant, focusing on cognitive impairment and its impact on daily functioning. After the interview, the interviewer rated subject's overall difficulty on a Global Scale of 1-10. Higher scores indicate greater cognitive impairment.
Baseline, 6 weeks
Change in SCoRS Interviewer Global Rating
Time Frame: Baseline, 12 weeks
Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity by completing a 20-question rating scale via interviews with the subject and an informant, focusing on cognitive impairment and its impact on daily functioning. After the interview, the interviewer rated subject's overall difficulty on a Global Scale of 1-10. Higher scores indicate greater cognitive impairment.
Baseline, 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Los Angeles

Collaborators

Massachusetts General Hospital
Washington University School of Medicine
University of Maryland
Beth Israel Deaconess Medical Center
Columbia University
Duke University
Nathan Kline Institute for Psychiatric Research

Investigators

  • Principal Investigator: Daniel C Javitt, MD, PhD, Nathan Kline Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (Actual)

April 1, 2009

Study Completion (Actual)

April 1, 2009

Study Registration Dates

First Submitted

July 20, 2007

First Submitted That Met QC Criteria

July 20, 2007

First Posted (Estimate)

July 23, 2007

Study Record Updates

Last Update Posted (Actual)

March 10, 2017

Last Update Submitted That Met QC Criteria

January 30, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TURNS03
  • HHSN 278200441003C (Other Grant/Funding Number: NIMH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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