Safety and Effectiveness Study of Intranasal Insulin Glulisine on Cognitive and Memory in Mild-Mod AD Patients.

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of the rapidly acting intranasal insulin derivative (glulisine) on memory and cognition in 12 patients suffering from mild-moderate Alzheimer's Disease (AD) using a double-blind placebo-controlled single dose study. This study will further assess safety of insulin glulisine as well as the effects of this drug on olfaction.

Detailed Description
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A single center, phase II randomized, double-blind, placebo-controlled, cross-over study designed to assess the efficacy and safety of intranasally (IN) delivered insulin glulisine versus placebo in patients aged 65-85 with mild-moderate Alzheimer's Disease (AD). Twelve AD subjects (six female and six male) will be randomized to receive a single dose of either 20 IU/IN insulin glulisine or placebo using the MAD 300 device.

Official Title
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A Double-Blind, Placebo-Controlled Single Dose Study of the Safety and Efficacy of Glulisine on Cognitive Function and Memory in Individuals Diagnosed With Probable Mild to Moderate Alzheimer's Disease/Intranasal Insulin Study.

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Insulin glulisine
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject with a clinical diagnosis of probable 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 and Dementia Rating Scale (McKhann 1984). Mini-Mental State Examination (MMSE) score of 18-26. Hachinski Ischemia Score < 4. Age is > 65 and <85 years Females must be > 2 years post-menopausal or surgically sterile. Must be able to speak, read and understand English in order to comply with testing of cognitive function, memory and physiology. Must have a dedicated family member /caregiver, able to attend all visits and report on subject's status. Subject and family member/caregiver have both 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. On a stable dose (≥ 1 months) of a prescribed acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine) and/or memantine. A brain CT or MRI in the last 2 years compatible with the diagnosis of probable Alzheimer's Disease. A Clinical Dementia Rating (CDR) ranging from 1 to 2. Exclusion Criteria: Medical history and/or clinically determined evidence of other central nervous system (CNS) disorders including 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. Personal medical history and/or clinically determined disorders: current B12 deficiency, positive syphilis serology, chronic sinusitis or any untreated thyroid disease, significant head trauma, or history of difficulty with smell and/or taste prior to AD diagnosis. Diagnosis with any form of diabetes mellitus, actively takes insulin, or has HbA1c > 6.1 % at screening. Personal history of any of the following: moderate to severe pulmonary disease, congestive heart failure, significant cardiovascular and/or cerebrovascular events in 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. Heavy smoker (defined as smoking half a pack or more per day in the last 10 years prior to entry in the study). Personal history of any psychiatric illness, except major depressive disorder (according to Diagnostic and Statistical Manual (DSM)-IV TR) currently in remission or stable with treatment for > 2 years, or any other psychiatric condition that inclusion would pose a safety risk to the subject as determined by Investigator. Patients with active depression (Geriatric Depression Score>9) are excluded from the study. Currently taking any medications, herbals and food supplements that are determined by Investigator to interfere with procedural testing of cognitive function as well as ensure study safety. Recent change (< 1 months) in prescribed acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine) or memantine. Current or recent drug or alcohol abuse or dependence defined by DSM-IV TR. Systolic blood pressure > 160 or < 90 mmHg or diastolic blood pressure > 100 or < 60 mmHg at Screening. Screening laboratory results that are medically relevant and which would pose a safety risk to the subject as determined by Investigator. Participation in any other research study at least 3 months prior to this study. Insulin allergy. History of significant traumatic brain injury History of acute and chronic rhinitis and/or sinusitis. Legally unable to provide informed written consent due to deterioration in cognitive abilities.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin glulisine<br>A randomized, double-blind, placebo-controlled, cross-over designed - all subject will receive intervention (insulin glulisine) and placebo (saline) during separate visits. | Drug: Insulin glulisine<br>* Single treatment, 20 IU/Intranasal (.1ml/10 units Intranasally in each nostril)<br>* Other names: Apidra;|
| Placebo Comparator: Saline<br>A randomized, double-blind, placebo-controlled, cross-over designed - all subject will receive intervention (insulin glulisine) and placebo (saline) during separate visits. | Drug: Saline<br>* Single treatment,(saline) 20 IU/Intranasal (.1ml/10units intranasally in each nostril)<br>* Other names: salt water;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Performance | The results are presented as a mean number of correct responses for each cognitive assessment. For each of these, a lower number correct is indicative of a higher cognitive deficit. Ranges are as follows: RBANS List Learning (0-40), RBANS Story Memory (0-24), RBANS Figure Copy (0-20), RBANSLine Orientation (0-20), RBANS Semantic Fluency (0-unlimited), RBANS List Recall (0-10), RBANS List Recognition (0-20), RBANS Story Recall (0-12), RBANS Figure Recall (0-20), Digit Span Forward (0-16), Digit Span Backward (0-16), Boston Naming (0-15). | 20 minutes post-intranasal administration | 
| Trails B - Seconds | The results are presented as the number of seconds to complete Trails B. For each of these, a higher number of seconds is indicative of a higher cognitive deficit. | 20 minutes post-intranasal administration | 
| Trails B - Errors | The results are presented as the mean sum of the errors during the Trails B assessment For each of these, a higher number of errors is indicative of a higher cognitive deficit. | 20 minutes post-intranasal administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Olfactory Function | The Sniff Magnitude Test (SMT) measures olfactory function not influenced by cognitive problems (minimal dependence on language, cognitive ability, memory, and odor naming ability). Sniff magnitude ratios are calculated as a ratio of sniff magnitudes (area under the sniff curve). Lower sniff magnitude ratios indicate more impairment. [average sniff magnitude of malodor/average sniff magnitude to a null odor] | 60 minute post intranasal administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Memory, Insulin glulisine, Alzheimer's Disease