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

• ClinicalTrials.gov Identifier: NCT01928420
• Recruitment Status: Completed
• First Posted: August 26, 2013
• Last Update Posted: October 17, 2016
• Sponsor: Humanetics Corporation
• Collaborators: National Center for Complementary and Integrative Health (NCCIH); James J. Peters Veterans Affairs Medical Center
• Information provided by (Responsible Party): Humanetics Corporation

Tracking Information

• First Submitted Date: August 17, 2012
• First Posted Date: August 26, 2013
• Last Update Posted Date: October 17, 2016
• Study Start Date: April 2007
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 20, 2013)

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) ]

A psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT01928420 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: August 20, 2013)

• 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) ]
  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) ]
  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) ]
  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) ]
  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) ]
  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) ]
  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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 20, 2013)

• 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) ]
  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) ]
  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) ]
  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) ]
  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) ]
  A single assay of NIC5-15 concentration in blood samples obtained at visit 2 (week 2) and visit 8 (week 24).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: A Single Site, Randomized, Double-blind, Placebo Controlled Trial of NIC5-15 in Subjects With Alzheimer's Disease
• Official Title: A Single Site, Randomized, Double-blind, Placebo Controlled Trial of NIC5-15 in Subjects With Alzheimer's Disease
• Brief Summary: The purpose of this study is to evaluate the safety and efficacy of NIC5-15 in the treatment of Alzheimer's Disease.

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Alzheimer's Disease
• Dementia

Intervention

• Drug: Drug: NIC5-15
  A natural product, found in many foods and plants with mild insulin sensitizing effects
  Other Name: Pinitol
• Drug: Placebo
  Subjects with Alzheimer's Disease placebo comparator

Study Arms

• Experimental: NIC5-15
  Subjects with Alzheimer's Disease Intervention: Drug: NIC5-15
  Intervention: Drug: Drug: NIC5-15
• Placebo Comparator: Placebo
  Subjects with Alzheimer's Disease Intervention: Drug: Placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 14, 2016): 30
• Original Estimated Enrollment (submitted: August 20, 2013): 40
• Actual Study Completion Date: June 2014
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 95 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01928420
• Other Study ID Numbers: R21AT003302-01A1 ( U.S. NIH Grant/Contract ); MHBB-009-06S ( Other Grant/Funding Number: Department of Veterans Affairs )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Humanetics Corporation
• Study 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

• PRS Account: Humanetics Corporation
• Verification Date: October 2016