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Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02503501
Recruitment Status : Terminated (Study will not have power to show a difference between groups.)
First Posted : July 21, 2015
Results First Posted : April 9, 2020
Last Update Posted : April 9, 2020
Sponsor:
Information provided by (Responsible Party):
HealthPartners Institute

Tracking Information
First Submitted Date  ICMJE July 14, 2015
First Posted Date  ICMJE July 21, 2015
Results First Submitted Date  ICMJE March 6, 2020
Results First Posted Date  ICMJE April 9, 2020
Last Update Posted Date April 9, 2020
Actual Study Start Date  ICMJE September 28, 2015
Actual Primary Completion Date February 11, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2020)
  • Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13) [ Time Frame: Baseline and 6 months ]
    The ADAS-Cog was developed as an outcome measure for global cognition in clinical trials for Alzheimer's disease. The ADAS-Cog assesses multiple cognitive domains including memory, language, praxis, and orientation. The modified ADAS-Cog 13-item scale includes all original ADAS-Cog items with the addition of a number cancellation task and a delayed free recall task, for a total of 85 points (0: no cognitive impairment; 85: severe impairment).
  • Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale [ Time Frame: Baseline and 6 months ]
    The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. Possible scores on the CDR are 0 (no impairment), 0.5 (very mild), 1 (mild), 2 (moderate), and 3 (severe). The total CDR ratings for each of the six cognitive/functional domains can be added to create a CDR sum of boxes (SOB). The overall SOB score ranges from 0 to 18; with 18 indicating severe impairment and 0 indicating no impairment.
  • Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ) [ Time Frame: Baseline and 6 months ]
    The FAQ measures instrumental activities of daily living (IADLs), such as preparing balanced meals and managing personal finances. The FAQ is a sum of scores ranging from 0 (normal) to 30 (complete dependence on others).
Original Primary Outcome Measures  ICMJE
 (submitted: July 17, 2015)
  • Change in Cognition as Measured by the Alzheimer's Disease Assessment Scale - Cognitive 13 (ADAS-Cog 13) [ Time Frame: Baseline, 3 months, 6 months ]
    The ADAS-Cog was developed as an outcome measure for global cognition in clinical trials for Alzheimer's disease. The ADAS-Cog assesses multiple cognitive domains including memory, language, praxis, and orientation. The modified ADAS-Cog 13-item scale includes all original ADAS-Cog items with the addition of a number cancellation task and a delayed free recall task, for a total of 85 points (0: no cognitive impairment; 85: severe impairment).
  • Change in Functional Performance as Measured by the Clinical Dementia Rating (CDR) Scale [ Time Frame: Baseline, 3 months, 6 months ]
    The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. Scores on the CDR range from 0 (no impairment) to 3 (severe impairment). The total CDR ratings for each of the six cognitive/functional domains can be added to create a CDR sum of boxes (SOB).
  • Change in Functional Performance as Measured by the Functional Activities Questionnaire (FAQ) [ Time Frame: Baseline, 3 months, 6 months ]
    The FAQ measures instrumental activities of daily living (IADLs), such as preparing balanced meals and managing personal finances. The FAQ is a sum of scores ranging from 0 (normal) to 30 (complete dependence on others).
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: July 17, 2015)
  • Change in auditory working memory as measured by the Digit Span subtest from the Wechsler Adult Intelligence Scale - 4th Edition (WAIS-IV) [ Time Frame: Baseline, 3 months, 6 months ]
    Subjects are read a random list of numbers at a rate of one per second and immediately asked to repeat them in a forward sequence or a backward sequence. Digit strings gradually expand and become lengthier until the subject makes consistent errors, at which point the test is discontinued.
  • Change in mental flexibility as measured by the Trail Making Test, Parts A and B [ Time Frame: Baseline, 3 months, 6 months ]
    Part A requires subjects to connect a series of numbered dots in order as quickly as possible. Part B requires subjects to connect numbered and lettered dots as quickly as possible by alternating back and forth between the two without making mistakes. Scores include both time to completion and various error types.
  • Change in executive functioning as measured by the Controlled Oral Word Association Test (COWAT) [ Time Frame: Baseline, 3 months, 6 months ]
    Subjects are asked to name words beginning with a specific letter for one minute. This is repeated three times. More correct words named indicates higher fluency and executive functioning.
  • Change in executive functioning as measured by the Animal Naming test [ Time Frame: Baseline, 3 months, 6 months ]
    Subjects are asked to name all of the animals he/she can think of in 60 seconds. Scores are the number of animals named. A score below 14 can be an indication of impaired executive function and/or language abilities.
  • Change in memory functions as measured by the Weschler Memory Scale Logical Memory (WMS-LM) [ Time Frame: Baseline, 3 months, 6 months ]
    Logical memory represents one of 7 memory subtests that are included within the WMS-IV. Subjects are read two thematically independent stories and later asked to recall each story immediately and later, thirty minutes after the reading. Patients struggling with recall of story contents are provided cues to assist with recognition.
  • Change in feelings of depression as measured by the Geriatric Depression Scale-15 (GDS) [ Time Frame: Baseline, 3 months, 6 months ]
    The GDS-15 is a 15 yes or no, item depression screening tool used to. Scores range from 0 (normal, no depression) to 15 (severely depressed)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: July 17, 2015)
  • Change in Cerebrospinal fluid (CSF) AD related biomarkers [ Time Frame: Baseline, 6 months ]
    Specific biomarker measured is A beta 42.
  • Change in Cerebrospinal fluid (CSF) AD related biomarkers [ Time Frame: Baseline, 6 months ]
    Specific biomarker measured is tau.
  • Change in Cerebrospinal fluid (CSF) AD related biomarkers [ Time Frame: Baseline, 6 months ]
    Specific biomarker measured is phosphotau.
  • Changes in Fludeoxyglucose Positron Emission Tomography (FDG PET) metabolism [ Time Frame: Baseline, 6 months ]
    Specific region measured by FDG-PET is posterior parietotemporal cortex.
  • Changes in Fludeoxyglucose Positron Emission Tomography (FDG PET) metabolism [ Time Frame: Baseline, 6 months ]
    Specific region measured by FDG-PET is cingulate cortex/precuneus.
 
Descriptive Information
Brief Title  ICMJE Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease
Official Title  ICMJE A Phase II, Single Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and the Therapeutic Effectiveness of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease
Brief Summary This study evaluates the safety and effectiveness of intranasal (IN) glulisine in patients with amnestic mild cognitive impairment (aMCI) and probable Alzheimer's disease. Half of participants will receive IN glulisine, while the other half will receive IN placebo.
Detailed Description

Disruption of central nervous system (CNS) insulin signaling has been increasingly associated with Alzheimer's Disease pathogenesis, and consequently this disease has been referred to as a type III diabetes of the brain. Clinical trials of intranasal insulin in AD have demonstrated therapeutic effects of intranasal (IN) insulin in memory-impaired adults in terms of memory recall without significantly altering serum insulin or glucose levels. In this study, the investigators are investigating the chronic effects of the rapid acting insulin, glulisine, administered intranasally (IN) 20 IU two times daily in adults with amnestic-mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD). The investigation will enroll n=90 subjects and follow them over a 6 month period.

This study has the following objectives:

  1. Primary:

    a. To measure the chronic effects of IN insulin glulisine on cognition and function in subjects with aMCI and probable mild AD over a 6 month period.

  2. Secondary:

    1. To measure the effect of IN insulin glulisine on mood in subjects with aMCI and mild AD over a 6 month period.
    2. To measure the safety and efficacy of IN glulisine in aMCI and mild AD subjects with non-insulin dependent diabetes over a 6 month period.
  3. Exploratory:

    1. To measure the effect of IN delivery of insulin glulisine on parieto-temporal and posterior cingulate/precuneus glucose metabolism in subjects with aMCI and mild AD over a 6 month period.
    2. To measure the chronic effect of IN delivery of insulin glulisine on AD-specific cerebrospinal (CSF) biomarkers (Abeta42, tau, and phospho-tau) in subjects with aMCI and mild AD over a 6 month period.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Mild Cognitive Impairment
  • Alzheimer's Disease (AD)
Intervention  ICMJE
  • Drug: Insulin glulisine
    Other Name: Apidra
  • Drug: Placebo
    Bacteriostatic 0.9% Sodium Chloride
    Other Name: Saline
Study Arms  ICMJE
  • Experimental: Insulin Glulisine
    Insulin Glulisine 20 IU (0.1ml/10 units in each nostril) per intranasal dose, 2 times per day for 6 months
    Intervention: Drug: Insulin glulisine
  • Placebo Comparator: Placebo
    Saline 20 IU (0.1 ml in each nostril) per intranasal dose, 2 times per day for 6 months
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: August 7, 2019)
49
Original Estimated Enrollment  ICMJE
 (submitted: July 17, 2015)
90
Actual Study Completion Date  ICMJE February 15, 2019
Actual Primary Completion Date February 11, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Subject is/has

  • clinical and research diagnosis of amnestic-MCI OR probable mild AD in accordance with National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria
  • Montreal Cognitive Assessment (MoCA) score 18-27
  • Hachinski Ischemia Score <4
  • 50-90 years of age
  • Females at least 2 years post-menopausal or surgically sterile
  • Proficiency in speaking, reading and understanding English
  • Dedicated family member /caregiver, who will be able to attend all visits and report on subject's status
  • (and family member/caregiver) provided fully informed written consent prior to participation. In the event that subject is legally unable to provide informed written consent due to deterioration in cognitive abilities, fully informed written consent must be provided by a legally authorized representative
  • If AD, a brain computed tomography (CT) or magnetic resonance imaging (MRI) in the initial diagnostic workup or subsequent care that is compatible with the diagnosis of probable AD

Exclusion Criteria:

Subject has/have/is

  • medical history and/or clinically determined evidence of other central nervous system (CNS) disorders including, but not limited to brain tumor, active subdural hematoma, seizure disorder, multiple sclerosis, dementia with Lewy bodies, vascular dementia, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease, multiple system atrophy, frontotemporal dementia, normal pressure hydrocephalus, Huntington's disease, or Jakob-Creutzfeldt disease presenting as dementia
  • medical history and/or clinically determined disorders: current B12 deficiency, chronic sinusitis, any untreated thyroid disease, significant head trauma and history of difficulty with smell and/or taste prior to AD diagnosis
  • history of any of the following: moderate to severe pulmonary disease, poorly controlled congestive heart failure, significant cardiovascular and/or cerebrovascular events within previous 6 months, condition known to affect absorption, distribution, metabolism, or excretion of drugs such as any hepatic, renal or gastrointestinal disease or any other clinically relevant abnormality that inclusion would pose a safety risk to the subject as determined by investigator
  • previous nasal and/or oto-pharyngeal surgery and severe deviated septum and/or other anomalies
  • history of any psychiatric illness, with the exception of major depressive and anxiety disorder (according to Diagnostic and Statistical Manual of Mental Disorders, version 5, Text Revision (DSM-IV TR)) currently in remission or stable with treatment for > 2 yrs, or any other psychiatric condition that inclusion would pose a safety risk to the subject as determined by investigator
  • currently taking any medications, herbals and food supplements that are medically/clinically contraindicated as determined by investigator in order to comply with procedural testing of cognitive function as well as ensure study safety. See list of prohibited medications and compounds
  • undergone a recent change (<1mo) in their prescribed acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine) or memantine.
  • undergone a recent change (<1mo) in their selective serotonin re-uptake inhibitor (SSRI) or anti-depressant medication
  • current or recent drug or alcohol abuse or dependence as defined by DSM-IV TR
  • laboratory results that are medically relevant, in which inclusion would pose a safety risk to the subject as determined by investigator
  • participated in any other research study at least 3 mos prior to this study
  • an insulin allergy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02503501
Other Study ID Numbers  ICMJE IN-INSUL-MCI-AD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party HealthPartners Institute
Study Sponsor  ICMJE HealthPartners Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michael H Rosenbloom, MD HealthPartners Institute
PRS Account HealthPartners Institute
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP