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A Single Site, Randomized, Double-blind, Placebo Controlled Trial of NIC5-15 in Subjects With Alzheimer's Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by James J. Peters Veterans Affairs Medical Center
Sponsor:
Collaborators:
Humanetics Corporation
Information provided by (Responsible Party):
Hillel Grossman, MD, James J. Peters Veterans Affairs Medical Center
ClinicalTrials.gov Identifier:
NCT01928420
First received: August 17, 2012
Last updated: August 20, 2013
Last verified: August 2013
  Purpose

The purpose of this study is to evaluate the safety and efficacy of NIC5-15 in the treatment of Alzheimer's Disease.


Condition Intervention Phase
Alzheimer's Disease
Dementia
Drug: Drug: NIC5-15
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Single Site, Randomized, Double-blind, Placebo Controlled Trial of NIC5-15 in Subjects With Alzheimer's Disease

Resource links provided by NLM:


Further study details as provided by James J. Peters Veterans Affairs Medical Center:

Primary Outcome Measures:
  • Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)Score [ Time Frame: Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis.


Secondary Outcome Measures:
  • Change in Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change (ADCS-CCGIC) Score [ Time Frame: Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    A systematic method for assessing clinically significant change in a clinical trial as viewed by an independent skilled and experienced clinician . The ADCS-CGIC focuses on clinician's observations of change in the subject's cognitive, functional, and behavioral performance since the beginning of a trial. It relies on both direct examination of the subject and an interview of an informant. Unlike a targeted symptom scale, it takes into account a subject's overall function in the cognitive, behavioral, and functional activity domains.

  • Change in Mini-Mental State Examination (MMSE) Score [ Time Frame: Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    A frequently used screening instrument for Alzheimer's disease drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons

  • Change in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) Score [ Time Frame: Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    ADCS-ADL assesses functional performance in subjects with Alzheimer's disease. In a structured interview format, informants are queried as to whether subjects attempted each item in the inventory during the prior 4 weeks and their level of performance. The ADCS-ADL scale discriminates well between normal controls and mild AD patients. It has good test-retest reliability. The ADCS-ADL includes some items from traditional basic ADL scales (e.g., grooming, dressing, walking, bathing, feeding, toileting) as well as items from instrumental activities of daily living scales (e.g., shopping, preparing meals, using household appliances, keeping appointments, reading).

  • Change in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology and behavior in AD based on interview with the informant.

  • Changes in AD Biomarkers [ Time Frame: Blood collected at visits 2 (week 2), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: No ]
    Plasma beta-amyloid proteins will be collected from blood samples obtained at visit 2 (week 2), visit 6 (week 12), and visit 8 (week 24).

  • APO-E genotyping [ Time Frame: Collected at visit 2 (week 2) ] [ Designated as safety issue: No ]
    APOe e4 is an important genetic risk factor for AD. In this trial, as in many studies of AD and memory and cognition in aging, the APOe e4 allele will be analyzed as a predictor of clinical change over time.


Other Outcome Measures:
  • Symptoms Checklist and Adverse Event Assessment [ Time Frame: 6 Months, conducted at visits 3 (week 2), 4 (week 4), 5 (week 8), 6 (week 12), 7 (week 18), 8 (week 24) ] [ Designated as safety issue: Yes ]
    Adverse events and symptoms checklist are used to monitor signs or symptoms that may or may not be related to study medication, abnormalities detected during physical examination, or clinical significant laboratory abnormalities.

  • Safety Laboratory Assessments [ Time Frame: 6 Months, conducted at visits 1 (week 1), 3 (week 2), 4 (week 4), 5 (week 8), 6 (week 12), 7 (week 18), 8 (week 24) ] [ Designated as safety issue: Yes ]
    Blood tests: hematology, serum chemistries, folate, B12, RPR, thyroid function (TSH or free thyroxine index), Urinalysis, Metabolic panel: HgbA1c, triglyceride profile serum albumin

  • Neurological examination [ Time Frame: 6 Months, conducted at visits 1 (week 1), 6 (week 12), 8 (week 24) ] [ Designated as safety issue: Yes ]
    Neurological examination measuring any possible sensory impairments and/or neurological abnormalities to determine if findings are consistent with eligibility for safety. This must be signed by a clinician.

  • Physical examination [ Time Frame: 6 Months, conducted at visits 1 (week 1), 3 (week 2), 5 (week 8), 6 (week 12), 7 (week 18), 8 (week 24) ] [ Designated as safety issue: Yes ]
    Standard physical examination of vital signs, weight and height (to calculate BMI), seated blood pressure, EKG, seated pulse rate, respiration rate, and temperature, to determine if findings are consistent with eligibility for safety, which must be signed by a clinician.

  • Pharmacokinetic analysis [ Time Frame: 6 Months, conducted at visits 2 (week 2), 8 (week 24) ] [ Designated as safety issue: No ]
    A single assay of NIC5-15 concentration in blood samples obtained at visit 2 (week 2) and visit 8 (week 24).


Estimated Enrollment: 40
Study Start Date: August 2010
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NIC5-15
Subjects with Alzheimer's Disease Intervention: Drug: NIC5-15
Drug: Drug: NIC5-15
A natural product, found in many foods and plants with mild insulin sensitizing effects
Other Name: Pinitol
Placebo Comparator: Placebo
Subjects with Alzheimer's Disease Intervention: Drug: Placebo
Drug: Placebo
Subjects with Alzheimer's Disease placebo comparator

Detailed Description:

Recent epidemiologic evidence, has suggested that diabetes mellitus significantly increases risk for the development of Alzheimer's disease, independent of vascular risk factors. Moreover, even patients who are simply insulin resistant, without frank diabetes, have been shown to share this elevated risk for the development of AD. As insulin's role as a neuromodulator in the brain has been revealed, several potential mechanisms for the interaction of diabetes or insulin resistance with AD have been suggested such as decreased cortical glucose utilization particularly in the hippocampus and entorhinal cortex; increased oxidative stress through the formation of advanced glycation end products; increased Tau phosphorylation and neurofibrillary tangle formation; and increased beta-amyloid aggregation through inhibition of insulin-degrading enzyme. The future treatment of AD might involve pharmacologic and dietary manipulations of insulin and glucose regulation

NIC5-15 is a single, small, naturally occurring molecule. Animal studies and some human trials have shown NIC5-15 to be safe and a potent insulin sensitizer at doses equivalent to 800-2000mg per day. In preclinical studies at doses higher than those previously studied in clinical trials, we found that NIC5-15 interferes with the accumulation of beta amyloid, an important step in the development of Alzheimer's pathology. These data suggest that NIC5-15 may be a reasonable therapeutic agent for the treatment of Alzheimer Disease for two reasons:

It is a -secretase inhibitor that is Notch-sparing. It is potentially an insulin-sensitizer.

However critical safety and human efficacy studies must be conducted. This application proposes to conduct these early critical human studies. The goal of the studies contained in this proposal is to establish safety and efficacy of NIC5-15 for the treatment of AD. The specific objectives of this study are to:

Specific Objective #1) Conduct a multiple dose safety study of NIC5-15 to establish safety in the doses that appear to block amyloid accumulation. These studies will characterize the safety profile, pharmacokinetics, and tolerability

This objective was met with completion of the initial study ID#NCT00470418.

The current study continues investigations of NIC5-15 in Alzheimer's disease with the following objective:

Specific Objective #2) Conduct a double blind placebo controlled pilot efficacy study of NIC5-15 in patients with AD. The goals of this study are to:

A) Demonstrate feasibility for a multi-site trial that will be used to guide the design of a future larger effort. Demonstration of feasibility will include examination of accrual rate, overall recruitment, adherence to protocol, compliance with medication and willingness to complete a randomized trial, and lack of short term toxicity.

B) Collect preliminary evidence of efficacy in terms of cognitive and global measures as well as secondary efficacy outcomes of activities of daily living, behavioral disturbances and AD biomarkers.

  Eligibility

Ages Eligible for Study:   40 Years to 95 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • NINCDS/ADRDA criteria for probable AD
  • MMSE between 12-27
  • Treatment with a cholinesterase inhibitor or an NMDA (N-methyl-D-asparate) antagonist with stable dose for at least 12 weeks
  • Home monitoring available for supervision of medications
  • Caregiver available to accompany patient to all visits and willing to participate in study as informant
  • Fluent in English or Spanish
  • Medical stability for this study as confirmed by review of records, internist's physical exam, neurological exam, and laboratory tests
  • Stable doses of non-excluded medication
  • No evidence of hepatic insufficiency
  • Able to swallow oral medications
  • Ability to participate in the informed consent process

Exclusion Criteria:

  • History of Diabetes Mellitus (OGTT criteria) requiring treatment with an excluded antidiabetic medication (see below) or history of hypoglycemia
  • Active hepatic or renal disease
  • Cardiac disease including history of congestive heart failure or current treatment for CHF; history of recent myocardial infarction
  • Use of another investigational drug within the past two months
  • History of clinically significant stroke
  • History of seizure or head trauma with disturbance of consciousness within the past two years
  • Major mental illness including psychotic disorders, bipolar disorder, or major depressive episode within the past two years Medication Exclusion
  • Current use of oral hypoglycemic agents including sulfonylureas and meglintinides
  • Current or past treatment with insulin for longer than two weeks
  • Current use of drugs with significant anticholinergic or antihistaminic properties
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01928420

Contacts
Contact: Hillel Grossman, MD 718-584-9000 ext 5752 hillel.grossman2@va.gov

Locations
United States, New York
James J Peters Veterans Affairs Medical Center Recruiting
Bronx, New York, United States, 10468
Contact: Emily Exter, BA    718-584-9000 ext 5179    emily.exter@mssm.edu   
Contact: Amanda Burden, BA    718-584-9000 ext 5199    amanda.burden@mssm.edu   
Principal Investigator: Hillel Grossman, MD         
Sponsors and Collaborators
James J. Peters Veterans Affairs Medical Center
Humanetics Corporation
Investigators
Principal Investigator: Hillel Grossman, MD James J. Peters Veterans Affairs Medical Center
  More Information

Additional Information:
No publications provided

Responsible Party: Hillel Grossman, MD, Attending Physician, James J. Peters Veterans Affairs Medical Center
ClinicalTrials.gov Identifier: NCT01928420     History of Changes
Other Study ID Numbers: NCT00470419, R21 AT003302-01A1, MHBB-009-06S
Study First Received: August 17, 2012
Last Updated: August 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by James J. Peters Veterans Affairs Medical Center:
Alzheimer Disease
Alzheimer Type Senile Dementia
Alzheimer's Disease
Senile Dementia, Alzheimer
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Disorders
Mental Disorders
clinical trial
dementia
diabetes
dietary supplements
Therapeutics
Delirium, Dementia, Amnestic, Cognitive

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies

ClinicalTrials.gov processed this record on November 24, 2014