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

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

Study Overview

• Status: Completed
• Conditions: Dementia; Alzheimer's Disease
• Intervention / Treatment: Drug: Drug: NIC5-15; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10468
      • James J Peters Veterans Affairs Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Pinitol
Placebo Comparator: Placebo; Subjects with Alzheimer's Disease Intervention: Drug: Placebo	Drug: Placebo; Subjects with Alzheimer's Disease placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)Score	A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis.	Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change (ADCS-CCGIC) Score	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.	Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24)
Change in Mini-Mental State Examination (MMSE) Score	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	Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24)
Change in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) Score	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).	Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24)
Change in Neuropsychiatric Inventory (NPI) Score	The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology and behavior in AD based on interview with the informant.	Over 6 months, measured at visits 2 (week 2), 6 (week 12), 8 (week 24)
Changes in AD Biomarkers	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).	Blood collected at visits 2 (week 2), 6 (week 12), 8 (week 24)
APO-E genotyping	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.	Collected at visit 2 (week 2)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptoms Checklist and Adverse Event Assessment	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.	6 Months, conducted at visits 3 (week 2), 4 (week 4), 5 (week 8), 6 (week 12), 7 (week 18), 8 (week 24)
Safety Laboratory Assessments	Blood tests: hematology, serum chemistries, folate, B12, RPR, thyroid function (TSH or free thyroxine index), Urinalysis, Metabolic panel: HgbA1c, triglyceride profile serum albumin	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)
Neurological examination	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.	6 Months, conducted at visits 1 (week 1), 6 (week 12), 8 (week 24)
Physical examination	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.	6 Months, conducted at visits 1 (week 1), 3 (week 2), 5 (week 8), 6 (week 12), 7 (week 18), 8 (week 24)
Pharmacokinetic analysis	A single assay of NIC5-15 concentration in blood samples obtained at visit 2 (week 2) and visit 8 (week 24).	6 Months, conducted at visits 2 (week 2), 8 (week 24)

Collaborators and Investigators

• Sponsor: Humanetics Corporation
• Collaborators: National Center for Complementary and Integrative Health (NCCIH); James J. Peters Veterans Affairs Medical Center
• Investigators: Principal Investigator: Hillel Grossman, MD, James J. Peters Veterans Affairs Medical Center

Publications and helpful links

Helpful Links

• Mount Sinai School of Medicine Alzheimer's Disease Research Center

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: August 17, 2012
• First Submitted That Met QC Criteria: August 20, 2013
• First Posted (Estimate): August 26, 2013

Study Record Updates

• Last Update Posted (Estimate): October 17, 2016
• Last Update Submitted That Met QC Criteria: October 14, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: diabetes; dementia; Alzheimer's Disease; Nervous System Diseases; clinical trial; Therapeutics; Alzheimer Disease; Central Nervous System Diseases; Neurodegenerative Diseases; dietary supplements; Mental Disorders; Brain Diseases; Alzheimer Type Senile Dementia; Senile Dementia, Alzheimer; Delirium, Dementia, Amnestic, Cognitive; Disorders
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Dementia; Alzheimer Disease
• Other Study ID Numbers: NCT01928420; R21AT003302-01A1 (NIH); MHBB-009-06S (Department of Veterans Affairs)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided